PATENT ABSTRACT
The present invention relates generally to azatriocyclic containing pharmaceutical agents, and in particular, to azatricyclic metalloprotease inhibiting compounds. More particularly, the present invention provides a new class of azatricyclic MMP-3, MMP-8 and/or MMP-13 inhibiting compounds, that exhibit an increased potency and selectivity in relation to currently known MMP-13, MMP-8 and MMP-3 inhibitors.

PATENT DESCRIPTION
[0001]    This application claims the benefit of U.S. Provisional Application No. 60/860,195, filed Nov. 20, 2006, which is hereby incorporated by reference. 
     
    
     FIELD OF THE INVENTION 
       [0002]    The present invention relates generally to amide containing azatricyclic metalloprotease inhibiting compounds, and more particularly to azatricyclic amide MMP-13, MMP-8, MMP-3 and MMP-2 inhibiting compounds. 
       BACKGROUND OF THE INVENTION 
       [0003]    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 in inflammatory, malignant and degenerative disease processes. MMPs and aggrecanases are, therefore, targets for therapeutic inhibitors in several inflammatory, malignant and degenerative diseases such as rheumatoid arthritis, osteoarthritis, osteoporosis, periodontitis, multiple sclerosis, gingivitis, corneal epidermal and gastric ulceration, atherosclerosis, neointimal proliferation (which leads to restenosis and ischemic heart failure) and tumor metastasis. 
         [0004]    The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain enzymes 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). 
         [0005]    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). 
         [0006]    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-1 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. 
         [0007]    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). 
         [0008]    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). 
         [0009]    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). 
         [0010]    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, 3, 107-13 ; Clin. Orthop. Relat. Res.  2004, 427, S118-22). MMP-3 can activate other MMP family members such as MMP-1, MMP-7, MMP-8, MMP-9 and MMP-13 ( Ann. Rheum. Dis.  2001, 60 Suppl 3:iii62-7). 
         [0011]    MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGFβ 1  from the ECM, activating TNFα, inactivating IL-1β 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). 
         [0012]    MMP-8 (collagenase-2; neutrophil collagenase; EC 3.4.24.34) is another member of the MMP family ( Biochemistry  1990, 29, 10628-34). Human MMP-8 was initially located in human neutrophils ( Biochemistry  1990, 29, 10620-7). It is also expressed by macrophages, human mucosal keratinocytes, bronchial epithelial cells, ginigival fibroblasts, resident synovial and articular chondrodrocytes mainly in the course of inflammatory conditions ( Cytokine  &amp;  Growth Factor Rev.  2006, 17, 217-23). 
         [0013]    The activity of MMP-8 is tightly regulated and mostly limited to the sites of inflammation. MMP-8 is expressed and stored as an inactive pro-enzyme in the granules of the neutrophils. Only after the activation of the neutrophils by proinflammatory mediators, MMP-8 is released and activated to exert its function. 
         [0014]    MMP-8 plays a key role in the migration of immune cells to the sites of inflammation. MMP-8 degrades components of the extracellular matrix (ECM) such as collagen type I, II, III, VII, X, cartilage aggrecan, laminin-5, nidogen, fibronectin, proteoglycans and tenascin, thereby facilitating the cells migration through the ECM barrier. MMP-8 also influences the biological activity of its substrates. Through proteolytic processing of the chemokines IL-8, GCP-2, ENA-78, MMP-8 increases the chemokines ability to activate the infiltrating immune cells. While MMP-8 inactivates the serine protease inhibitor alpha-1 antitrypsin through its cleavage ( Eur. J. Biochem.  2003, 270, 3739-49 ; PloS One  2007, 3, 1-10 ; Cytokine  &amp;  Growth Factor Rev.  2006, 17, 217-23). 
         [0015]    MMP-8 has been implicated in the pathogenesis of several chronic inflammatory diseases characterized by the excessive influx and activation of neutrophils, including cystic fibrosis ( Am. J. Resprir. Critic. Care Med  1994, 150, 818-22), rheumatoid arthritis ( Clin. Chim. Acta  1996, 129-43), chronic periodontal disease ( Annals Med.  2006, 38, 306-321) and chronic wounds ( J. Surg. Res.  1999, 81, 189-195). 
         [0016]    In osteoarthritis patients, MMP-8 protein expression is significantly elevated in inflamed human articular cartilage in the knee and ankle joints ( Lab Invest.  1996, 74, 232-40 ; J. Biol. Chem.  1996, 271, 11023-6). 
         [0017]    The levels of activated MMP-8 in BALF is an indicator of the disease severity and correlates with the airway obstruction in patients with asthma, COPD, pulmonary emphysema and bronchiectasis ( Lab Invest.  2002, 82, 1535-45 ; Am. J. Respir. Crit. Care Med  1999, 159, 1985-91 ; Respir. Med.  2005, 99, 703-10 ; J. Pathol.  2001, 194, 232-38). 
       SUMMARY OF THE INVENTION 
       [0018]    The present invention relates to a new class of azatricyclic amide containing pharmaceutical agents which inhibits metalloproteases. In particular, the present invention provides a new class of metalloprotease inhibiting compounds that exhibit potent MMP-13 inhibiting activity and/or activity towards MMP-8, MMP-3 and MMP-2. 
         [0019]    The present invention provides several new classes of amide containing azatricyclic metalloprotease compounds, which are represented by the following general formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein all variables in the preceding Formula (I) are as defined hereinbelow. 
         [0020]    The azatricyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of metalloprotease mediated diseases, such as rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, multiple sclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson&#39;s disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, chronic wound healing, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn&#39;s disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayed type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi&#39;s sarcoma associated virus, liver fibrosis, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, chronic periodontitis, periodontitis, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze. 
         [0021]    In particular, the azatricyclic metalloprotease inhibiting compounds of the present invention may be used in the treatment of MMP-13, MMP-8, MMP-3 and MMP-2 mediated osteoarthritis and may be used for other MMP-13, MMP-8, MMP-3 and MMP-2 mediated symptoms, inflammatory, malignant and degenerative diseases characterized by excessive extracellular matrix degradation and/or remodelling, such as cancer, and chronic inflammatory diseases such as arthritis, rheumatoid arthritis, osteoarthritis, atherosclerosis, abdominal aortic aneurysm, inflammation, multiple sclerosis, and chronic obstructive pulmonary disease, and pain, such as inflammatory pain, bone pain and joint pain. 
         [0022]    The present invention also provides azatricyclic metalloprotease inhibiting compounds that are useful as active ingredients in pharmaceutical compositions for treatment or prevention of metalloprotease—especially MMP-13, MMP-8, MMP-3 and MMP-2—mediated diseases. The present invention also contemplates use of such compounds in pharmaceutical compositions for oral or parenteral administration, comprising one or more of the azatricyclic metalloprotease inhibiting compounds disclosed herein. 
         [0023]    The present invention further provides methods of inhibiting metalloproteases, by administering formulations, including, but not limited to, oral, rectal, topical, intravenous, parenteral (including, but not limited to, intramuscular, intravenous), ocular (ophthalmic), transdermal, inhalative (including, but not limited to, pulmonary, aerosol inhalation), nasal, sublingual, subcutaneous or intraarticular formulations, comprising the azatricyclic metalloprotease inhibiting compounds by standard methods known in medical practice, for the treatment of diseases or symptoms arising from or associated with metalloprotease, especially MMP-13, MMP-8, MMP-3 and MMP-2, including prophylactic and therapeutic treatment. 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 are conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy. 
         [0024]    The azatricyclic metalloprotease inhibiting compounds of the present invention may be used in combination with a disease modifying antirheumatic drug, a nonsteroidal anti-inflammatory drug, a COX-2 selective inhibitor, a COX-1 inhibitor, an immunosuppressive, a steroid, a biological response modifier or other anti-inflammatory agents or therapeutics useful for the treatment of chemokines mediated diseases. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0025]    One aspect of the invention relates to a compound of Formula (I): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein 
         [0026]    R 1  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, 
         [0027]    wherein R 1  is optionally substituted one or more times, or 
         [0028]    wherein R 1  is optionally substituted by one R 16  group and optionally substituted by one or more R 9  groups; 
         [0029]    R 2  is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R 1  and R 2  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 NR 50  and which is optionally substituted one or more times; 
         [0030]    R 4  in each occurrence is independently selected from R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF 3 , (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) n R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) n —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) n —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 10 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R″, (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 10 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, 
         [0031]    wherein each R 4  group is optionally substituted one or more times, or 
         [0032]    wherein each R 4  group is optionally substituted by one or more R 14  groups, or 
         [0033]    wherein optionally two R 4  groups, when taken together with the nitrogen or carbon to which they are attached complete a 3- to 8-membered saturated ring or multicyclic ring or unsaturated ring containing carbon atoms and optionally containing one or more heteroatom independently selected from O, S(O) x , N, or NR 50  and which is optionally substituted one or more times, or 
         [0034]    optionally two R 4  groups together at one saturated carbon atom form ═O, ═S,═NR 10  or ═NOR 10 ; 
         [0035]    R 5  is independently selected from hydrogen, alkyl, C(O)NR 10 R 11 , aryl, arylalkyl, SO 2 NR 10 R 11  and C(O)OR 10  wherein alkyl, aryl and arylalkyl are optionally substituted one or more times; 
         [0036]    R 8  is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R 10  and NR 10 R 11  wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted one or more times; 
         [0037]    R 9  in each occurrence is independently selected from R 10 , hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF 2 , CF 3 , OR 10 , SR 10 , COOR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 1 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) n R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR OR 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 11 SO 2 R 11 , C(O)NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, C(O)NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 11 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 11 —(C 0 -C 6 )-alkyl-heteroaryl, S(O) 2 NR 10 -alkyl, S(O) 2 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 —(C 0 -C 6 )-alkyl-heteroaryl, (C 0 -C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O)—(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O)—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 11 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 11 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, 
         [0038]    wherein each R 9  group is optionally substituted, or 
         [0039]    wherein each R 9  group is optionally substituted by one or more R 14  groups; 
         [0040]    R 10  and R 11  in each occurrence are independently selected from hydrogen, alkyl, 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 R 10  and R 11  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 NR 50  and which is optionally substituted one or more times; 
         [0041]    R 14  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. 
         [0042]    R 16  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): 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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; 
         [0043]    R 17  is selected from R 1 , R 4  and R 21 ; 
         [0044]    R 21  is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and 
         [0045]    wherein R 21  is optionally substituted one or more times, or 
         [0046]    wherein R 21  is optionally substituted by one or more R 9  groups; 
         [0047]    R 30  is selected from alkyl and (C 0 -C 6 )-alkyl-aryl, wherein alkyl and aryl are optionally substituted; 
         [0048]    R 50  in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R 80 , C(O)NR 80 R 81 , SO 2 R 80  and SO 2 NR 80 R 81 , wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times; 
         [0049]    R 80  and R 81  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 R 80  and R 81  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; 
         [0050]    E is selected from a bond, CR 10 R 11 , O, NR 5 , S, S═O, S(═O) 2 , C(═O), N(R 10 )(C═O), (C═O)N(R 10 ), N(R 10 )S(═O) 2 , S(═O) 2 N(R 10 ), C═N—OR 11 , —C(R 10 R 11 )C(R 10 R 11 )—, —CH 2 —W 1 — and 
         [0000]    
       
                 
         
             
             
         
       
     
         [0051]    L a  is independently selected from CR 9  and N; 
         [0052]    L b  is independently selected from C and N with the proviso, that both L b  are not N, and that the bond between L b  and L b  is optionally a double bond only if both L b  are C; 
         [0053]    L c  is selected from a single bond or an acyclic, straight or branched, saturated or unsaturated hydrocarbon chain having 1 to 10 carbon atoms, optionally containing 1 to 3 groups independently selected from —S—, —O—, NR 0 —, —NR 10 CO—, —CONR 10 —, —S(O) n —, —SO 2 NR 10 —, —NR 10 SO 2 —, NR 10 SO 2 NR 10 —, —NR 10 CONR 10 —, —OC(O)NR 10 —, —NR 10 C(O)O—, which replace a corresponding number of non-adjacent carbon atoms, and wherein the hydrocarbon chain is optionally substituted one or more times; 
         [0054]    Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected from aryl and heteroaryl, 
         [0055]    wherein Q is optionally substituted one or more times, or 
         [0056]    wherein Q is optionally substituted one or more times with R 4 , or 
         [0057]    wherein Q is fused via two of its adjacent atoms, which are selected from N and C with a further cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which is optionally independently substituted one or more times; 
         [0058]    U is selected from C(R 5 R 10 ), NR 5 , O, S, S═O and S(═O) 2 ; 
         [0059]    W 1  is selected from O, NR 5 , S, S═O, S(═O) 2 , N(R 10 )(C═O), N(R 10 )S(═O) 2 ; and S(═O) 2 N(R 10 ); 
         [0060]    X is selected from a bond and (CR 10 R 11 ) w E(CR 10 R 11 ) w ; 
         [0061]    X 1  is independently selected from O, S, NR 10 , N—CN, NCOR 10 , N—NO 2 , or N—SO 2 R 10 ; 
         [0062]    g and h are independently selected from 0-2; 
         [0063]    w is selected from 0-4; 
         [0064]    x is selected from 0 to 2; 
         [0065]    y is selected from 1 and 2; 
         [0066]    the dotted line optionally represents a double bond; and 
         [0067]    N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof. 
         [0068]    In one embodiment, in conjunction with any above or below embodiments, Q is phenyl or thiophene that is fused via two of its adjacent atoms with a further cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl and heteroaryl system, which is optionally independently substituted one or more times. 
         [0069]    In another embodiment, in conjunction with any above or below embodiments, L a  is N. 
         [0070]    In another embodiment, in conjunction with any above or below embodiments, L a  is N; and L b  is C. 
         [0071]    In another embodiment, in conjunction with any above or below embodiments, the compound has the structure: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl. 
         [0072]    In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused cycloalkyl. 
         [0073]    In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heterocycloalkyl. 
         [0074]    In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heterobicycloalkyl. 
         [0075]    In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl. 
         [0076]    In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused phenyl. 
         [0077]    In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heteroaryl. 
         [0078]    In another embodiment, in conjunction with any above or below embodiments, the compound is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0079]    In another embodiment, in conjunction with any above or below embodiments, R 8  is H. 
         [0080]    In another embodiment, in conjunction with any above or below embodiments, R 17  is selected from 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein: 
         [0081]    R 6  is selected from R 9 , cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OR 10 , CH(CH 3 )CO 2 H, (C 0 -C 6 )-alkyl-COR 10 , (C 0 -C 6 )-alkyl-OR 10 , (C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y OR 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 )-alkyl-S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-alkyl-S(O) x R 10 , (C 0 -C 6 )-alkyl-OC(O)R 10 , (C 0 -C 6 )-alkyl-OC(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═NR 10 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═NR 11 )NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—CN)NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(═N—NO 2 )NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)OR 10 , (C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 SO 2 R 11 , C(O)NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, C(O)NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 NR 10 —(C 0 -C 6 )-alkyl-heteroaryl, S(O) 2 NR 10 -alkyl, S(O) 2 —(C 0 -C 6 )-alkyl-aryl, S(O) 2 —(C 0 -C 6 )-alkyl-heteroaryl, (CO—C 6 )-alkyl-C(O)—NR 11 —CN, O—(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , S(O) x —(C 0 -C 6 )-alkyl-C(O)OR 10 , S(O) n —(C 0 -C 6 )-alkyl-C(O)NR 10 R 11 , (C 0 -C 6 )-alkyl-C(O)NR 10 —(C 0 -C 6 )-alkyl-NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —C(O)R 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)OR 10 , (C 0 -C 6 )-alkyl-NR 10 —C(O)—NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y NR 10 R 11 , (C 0 -C 6 )-alkyl-NR 10 —S(O) y R 11 , O—(C 0 -C 6 )-alkyl-aryl and O—(C 0 -C 6 )-alkyl-heteroaryl, wherein each R 6  group is optionally substituted by one or more R 14  groups; 
         [0082]    R 9  is independently selected from hydrogen, alkyl, halo, CHF 2 , CF 3 , OR 10 , NR 10 R 11 , NO 2 , and CN, wherein alkyl is optionally substituted one or more times; 
         [0083]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0084]    wherein: 
         [0085]    R 18  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times; 
         [0086]    R 25  is selected from hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times; 
         [0087]    B 1  is selected from NR 10 , O and S; 
         [0088]    D 2 , G 2 , L 2 , M 2  and T 2  are independently selected from CR 18  and N; and 
         [0089]    Z is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl and heteroaryl, wherein cycloalkyl, heterocycloalkyl, aryl and heteroaryl are optionally substituted one or more times. 
         [0090]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0091]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0092]    wherein: 
         [0093]    R 12  and R 13  are independently selected from hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R 32  and 
         [0094]    R 13  together form ═O, ═S,═NR 10  or ═NOR 10 ; 
         [0095]    R 18  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 10 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times; 
         [0096]    R 19  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R 19  groups together at one carbon atom form ═O, ═S,═NR 10  or ═NOR 10 ; 
         [0097]    R 25  is selected from hydrogen, alkyl, cycloalkyl, C(O)NR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times; 
         [0098]    J and K are independently selected from CR 10 R 18 , NR 10 , O and S(O) x ; 
         [0099]    A 1  is selected from NR 10 , O and S(O) x ; and 
         [0100]    D 2 , G 2 , J 2 , L 2 , M 2  and T 2  are independently selected from CR 18  and N. 
         [0101]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0102]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0103]    wherein: 
         [0104]    R 18  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times; 
         [0105]    R 19  is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR 10 R 11 , CO 2 R 10 , OR 10 , OCF 3 , OCHF 2 , NR 10 CONR 10 R 11 , NR 10 COR 11 , NR 10 SO 2 R 10 , NR 10 SO 2 NR 10 R 11 , SO 2 NR 10 R 11  and NR 10 R 11 , wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R 19  groups together at one carbon atom form ═O, ═S,═NR 10  or ═NOR 11 ; 
         [0106]    R 25  is selected from hydrogen, alkyl, cycloalkyl, CONR 10 R 11  and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times; 
         [0107]    L 2 , M 2 , and T 2  are independently selected from CR 18  and N; 
         [0108]    D 3 , G 3 , L 3 , M 3 , and T 3  are independently selected from N, CR 18 , (i) and (ii) 
         [0000]    
       
                 
         
             
             
         
       
     
         [0109]    with the proviso that one of L 3 , M 3 , T 3 , D 3 , and G 3  is (i) or (ii); 
         [0110]    B 1  is selected from the group consisting of NR 10 , O and S(O) x ; and 
         [0111]    Q 2  is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R 19 . 
         [0112]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0113]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
     
         [0114]    In another embodiment, in conjunction with any above or below embodiments, R 1  is selected from: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0115]    In another embodiment, in conjunction with any above or below embodiments, the compounds have the structure: 
         [0000]    
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
                 
         
             
             
         
       
       
         
           
             N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof. 
           
         
       
     
         [0117]    Another aspect of the invention relates to a pharmaceutical composition comprising an effective amount of the compound according to any of the above or below embodiments. 
         [0118]    Another aspect of the invention relates to a method of treating a metalloprotease mediated disease, comprising administering to a subject in need of such treatment an effective amount of a compound according to any of the above or below embodiments. 
         [0119]    In another embodiment, in conjunction with any above or below embodiments, the disease is selected from rheumatoid arthritis, osteoarthritis, inflammation, atherosclerosis and multiple sclerosis. 
         [0120]    Another aspect of the invention relates to a pharmaceutical composition comprising: 
         [0000]    A) an effective amount of a compound according to any of the above or below embodiments;
 
B) a pharmaceutically acceptable carrier; and
 
C) a drug, agent or therapeutic selected from: (a) a disease modifying antirheumatic drug; (b) a nonsteroidal anti-inflammatory drug; (c) a COX-2 selective inhibitor; (d) a COX-1 inhibitor; (e) an immunosuppressive; (f) a steroid; (g) a biological response modifier; and (h) a small molecule inhibitor of pro-inflammatory cytokine production.
 
         [0121]    Another aspect of the invention relates to a method of inhibiting a metalloprotease enzyme, comprising administering a compound according to any of the above or below embodiments. 
         [0122]    In another embodiment, in conjunction with any above or below embodiments, the metalloproteinase is selected from MMP-2, MMP-3, MMP-8, and MMP-13. 
         [0123]    In another embodiment, in conjunction with any above or below embodiments, the disease is selected from the group consisting of: rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, cancer (e.g. but not limited to melanoma, gastric carcinoma or non-small cell lung carcinoma), inflammation, atherosclerosis, chronic obstructive pulmonary disease, ocular diseases (e.g. but not limited to ocular inflammation, retinopathy of prematurity, macular degeneration with the wet type preferred and corneal neovascularization), neurologic diseases, psychiatric diseases, thrombosis, bacterial infection, Parkinson&#39;s disease, fatigue, tremor, diabetic retinopathy, vascular diseases of the retina, aging, dementia, cardiomyopathy, renal tubular impairment, diabetes, psychosis, dyskinesia, pigmentary abnormalities, deafness, inflammatory and fibrotic syndromes, intestinal bowel syndrome, allergies, Alzheimers disease, arterial plaque formation, oncology, periodontal, viral infection, stroke, atherosclerosis, cardiovascular disease, reperfusion injury, trauma, chemical exposure or oxidative damage to tissues, wound healing, hemorroid, skin beautifying, pain, inflammatory pain, bone pain and joint pain, acne, acute alcoholic hepatitis, acute inflammation, acute pancreatitis, acute respiratory distress syndrome, adult respiratory disease, airflow obstruction, airway hyperresponsiveness, alcoholic liver disease, allograft rejections, angiogenesis, angiogenic ocular disease, arthritis, asthma, atopic dermatitis, bronchiectasis, bronchiolitis, bronchiolitis obliterans, burn therapy, cardiac and renal reperfusion injury, celiac disease, cerebral and cardiac ischemia, CNS tumors, CNS vasculitis, colds, contusions, cor pulmonae, cough, Crohn&#39;s disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayed type hypersensitivity reaction, duodenal ulcers, dyspnea, early transplantation rejection, emphysema, encephalitis, endotoxic shock, esophagitis, gastric ulcers, gingivitis, glomerulonephritis, glossitis, gout, graft vs. host reaction, gram negative sepsis, granulocytic ehrlichiosis, hepatitis viruses, herpes, herpes viruses, HIV, hypercapnea, hyperinflation, hyperoxia-induced inflammation, hypoxia, hypersensitivity, hypoxemia, inflammatory bowel disease, interstitial pneumonitis, ischemia reperfusion injury, kaposi&#39;s sarcoma associated virus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, chronic periodontitis, periodontitis, peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD), pre-term labor, polymyositis, post surgical trauma, pruritis, psoriasis, psoriatic arthritis, pulmatory fibrosis, pulmatory hypertension, renal reperfusion injury, respiratory viruses, restinosis, right ventricular hypertrophy, sarcoidosis, septic shock, small airway disease, sprains, strains, subarachnoid hemorrhage, surgical lung volume reduction, thrombosis, toxic shock syndrome, transplant reperfusion injury, traumatic brain injury, ulcerative colitis, vasculitis, ventilation-perfusion mismatching, and wheeze. 
         [0124]    Another aspect of the invention relates to the use of a compound according to any of the above or below embodiments for the manufacture of a medicament for treating an metalloprotease mediated disease. 
         [0125]    In another embodiment, in conjunction with any of the above or below embodiments, the metalloprotease mediated disease is selected from the group consisting of MMP-2, MMP-3, MMP-8 and MMP-13 mediated diseases. 
         [0126]    The specification and claims contain listing of species using the language “selected from . . . and . . .” and “is . . . or . . . ” (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise stated it is meant to include the group as a whole, or any single members thereof, or any subgroups thereof. The use of this language is merely for shorthand purposes and is not meant in any way to limit the removal of individual elements or subgroups as needed. 
         [0127]    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 (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10  or R 11  are as defined below, except that at least one of R 10  or R 11  is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH). 
         [0128]    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 (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10  or R 11  are as defined below, except that at least one of R 10  or R 11  is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH). 
         [0129]    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. 
         [0130]    The term “alkoxy” denotes an alkyl group as described above bonded through an oxygen linkage (—O—). 
         [0131]    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 (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10  or R 11  are as defined below, except that at least one of R 10  or R 11  is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH). 
         [0132]    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 (NH 2 —CO—), substituted carbamoyl ((R 10 )(R 11 )N—CO— wherein R 10  or R 11  are as defined below, except that at least one of R 10  or R 11  is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (—SH). 
         [0133]    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. 
         [0134]    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. 
         [0135]    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. 
         [0136]    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. 
         [0137]    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. 
         [0138]    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. 
         [0139]    Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-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-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isatinoyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, morpholinyl, 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-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. 
         [0140]    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 1-aza-bicyclo[2.2.2]octane. 
         [0141]    “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 &amp; Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960), 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. 
         [0142]    “Heterocyclyl,” or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or multicyclic 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. 
         [0143]    “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 &amp; Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). 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. 
         [0144]    “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 &amp; Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960). 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[1,2-a]pyridine, imidazo[2,1-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-1,2,4-diazolyl, thiomorpholino, thiophenyl, thiopyranyl, triazolyl and triazolonyl. 
         [0145]    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[1,4]dioxine, 4H-benzo[1,4]oxazin-3-one, 3H-Benzooxazol-2-one and 3,4-dihydro-2H-benzo[f] [1,4]oxazepin-5-one. 
         [0146]    The term “amino” denotes the radical —NH 2  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. 
         [0147]    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. 
         [0148]    The term “arylalkyl” denotes an aryl group as described above bonded through an alkyl, as defined above. 
         [0149]    The term “heteroarylalkyl” denotes a heteroaryl group as described above bonded through an alkyl, as defined above. 
         [0150]    The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above. 
         [0151]    The terms “halogen”, “halo”, or “hal”, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine. 
         [0152]    The term “haloalkyl” denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group. 
         [0153]    The term “aminoalkyl” denotes an amino group as defined above bonded through an alkyl, as defined above. 
         [0154]    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. 
         [0155]    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, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene. 
         [0156]    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, choline, lysine, arginine or N-methyl-glucamine salts, and the like. 
         [0157]    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. 
         [0158]    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&#39;s Pharmaceutical Sciences,  18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference. 
         [0159]    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. 
         [0160]    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, 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&#39;s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference. 
         [0161]    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. 
         [0162]    Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example celluloses, lactose, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with non-aqueous or oil medium, such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil. 
         [0163]    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. 
         [0164]    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 n-propyl p-hydroxy-benzoate; one or more coloring agents; one or more flavoring agents; and one or more sweetening agents such as sucrose or saccharin. 
         [0165]    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. 
         [0166]    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. 
         [0167]    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 −10-80° C., desirably about 0° C. 
         [0168]    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. 
         [0169]    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. 
         [0170]    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) and (II). 
         [0171]    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 33:2725 (1977); 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 &amp; 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. 
         [0172]    “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&#39;s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced. 
         [0173]    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: 
         [0174]    C 1 -C 4  alkyl; 
         [0175]    C 2 -C 4  alkenyl; 
         [0176]    C 2 -C 4  alkynyl; 
         [0177]    CF 3 ; 
         [0178]    halo; 
         [0179]    OH; 
         [0180]    O—(C 1 -C 4  alkyl); 
         [0181]    OCH 2 F; 
         [0182]    OCHF 2 ; 
         [0183]    OCF 3 ; 
         [0184]    ONO 2 ; 
         [0185]    OC(O)—(C 1 -C 4  alkyl); 
         [0186]    OC(O)—(C 1 -C 4  alkyl); 
         [0187]    OC(O)NH—(C 1 -C 4  alkyl); 
         [0188]    OC(O)N(C 1 -C 4  alkyl) 2 ; 
         [0189]    OC(S)NH—(C 1 -C 4  alkyl); 
         [0190]    OC(S)N(C 1 -C 4  alkyl) 2 ; 
         [0191]    SH; 
         [0192]    S—(C 1 -C 4  alkyl); 
         [0193]    S(O)—(C 1 -C 4  alkyl); 
         [0194]    S(O) 2 —(C 1 -C 4  alkyl); 
         [0195]    SC(O)—(C 1 -C 4  alkyl); 
         [0196]    SC(O)O—(C 1 -C 4  alkyl); 
         [0197]    NH 2 ; 
         [0198]    N(H)—(C 1 -C 4  alkyl); 
         [0199]    N(C 1 -C 4  alkyl) 2 ; 
         [0200]    N(H)C(O)—(C 1 -C 4  alkyl); 
         [0201]    N(CH 3 )C(O)—(C 1 -C 4  alkyl); 
         [0202]    N(H)C(O)—CF 3 ; 
         [0203]    N(CH 3 )C(O)—CF 3 ; 
         [0204]    N(H)C(S)—(C 1 -C 4  alkyl); 
         [0205]    N(CH 3 )C(S)—(C 1 -C 4  alkyl); 
         [0206]    N(H)S(O) 2 —(C 1 -C 4  alkyl); 
         [0207]    N(H)C(O)NH 2 ; 
         [0208]    N(H)C(O)NH—(C 1 -C 4  alkyl); 
         [0209]    N(CH 3 )C(O)NH—(C 1 -C 4  alkyl); 
         [0210]    N(H)C(O)N(C 1 -C 4  alkyl) 2 ; 
         [0211]    N(CH 3 )C(O)N(C 1 -C 4  alkyl) 2 ; 
         [0212]    N(H)S(O) 2 NH 2 ); 
         [0213]    N(H)S(O) 2 NH—(C 1 -C 4  alkyl); 
         [0214]    N(CH 3 )S(O) 2 NH—(C 1 -C 4  alkyl); 
         [0215]    N(H)S(O) 2 N(C 1 -C 4  alkyl) 2 ; 
         [0216]    N(CH 3 )S(O) 2 N(C 1 -C 4  alkyl) 2 ; 
         [0217]    N(H)C(O)O—(C 1 -C 4  alkyl); 
         [0218]    N(CH 3 )C(O)O—(C 1 -C 4  alkyl); 
         [0219]    N(H)S(O) 2 O—(C 1 -C 4  alkyl); 
         [0220]    N(CH 3 )S(O) 2 O—(C 1 -C 4  alkyl); 
         [0221]    N(CH 3 )C(S)NH—(C 1 -C 4  alkyl); 
         [0222]    N(CH 3 )C(S)N(C 1 -C 4  alkyl) 2 ; 
         [0223]    N(CH 3 )C(S)O—(C 1 -C 4  alkyl); 
         [0224]    N(H)C(S)NH 2 ; 
         [0225]    NO 2 ; 
         [0226]    CO 2 H; 
         [0227]    CO 2 —(C 1 -C 4  alkyl); 
         [0228]    C(O)N(H)OH; 
         [0229]    C(O)N(CH 3 )OH: 
         [0230]    C(O)N(CH 3 )OH; 
         [0231]    C(O)N(CH 3 )O—(C 1 -C 4  alkyl); 
         [0232]    C(O)N(H)—(C 1 -C 4  alkyl); 
         [0233]    C(O)N(C 1 -C 4  alkyl) 2 ; 
         [0234]    C(S)N(H)—(C 1 -C 4  alkyl); 
         [0235]    C(S)N(C 1 -C 4  alkyl) 2 ; 
         [0236]    C(NH)N(H)—(C 1 -C 4  alkyl); 
         [0237]    C(NH)N(C 1 -C 4  alkyl) 2 ; 
         [0238]    C(NCH 3 )N(H)—(C 1 -C 4  alkyl); 
         [0239]    C(NCH 3 )N(C 1 -C 4  alkyl) 2 ; 
         [0240]    C(O)—(C 1 -C 4  alkyl); 
         [0241]    C(NH)—(C 1 -C 4  alkyl); 
         [0242]    C(NCH 3 )—(C 1 -C 4  alkyl); 
         [0243]    C(NOH)—(C 1 -C 4  alkyl); 
         [0244]    C(NOCH 3 )—(C 1 -C 4  alkyl); 
         [0245]    CN; 
         [0246]    CHO; 
         [0247]    CH 2 OH; 
         [0248]    CH 2 O—(C 1 -C 4  alkyl); 
         [0249]    CH 2 NH 2 ; 
         [0250]    CH 2 N(H)—(C 1 -C 4  alkyl); 
         [0251]    CH 2 N(C 1 -C 4  alkyl) 2 ; 
         [0252]    aryl; 
         [0253]    heteroaryl; 
         [0254]    cycloalkyl; and 
         [0255]    heterocyclyl. 
         [0256]    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 X  were defined as being: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    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: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0257]    These configurations are illustrative and are not meant to limit the scope of the invention in any way. 
       Biological Activity 
       [0258]    The inhibiting activity towards different metalloproteases of the heterocyclic metalloprotease inhibiting compounds of the present invention may be measured using any suitable assay known in the art. A standard in vitro assay for measuring the metalloprotease inhibiting activity is described in Examples 1700 to 1706. The heterocyclic metalloprotease inhibiting compounds show activity towards MMP-2, MMP-3, MMP-8, MMP-12, MMP-13, ADAMTS-4 and/or ADAMTS-5. 
         [0259]    The heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-13 inhibition activity (IC 50  MMP-13) ranging from below 0.2 nM to about 20 μM, and typically, from about 0.2 nM to about 1 μM. Heterocyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging from about 0.2 nM to about 20 nM. Table 1 lists typical examples of heterocyclic metalloprotease inhibiting compounds of the invention that have an MMP-13 activity lower than 100 nM (Group A) and from 100 nM to 20 μM (Group B). 
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 1 
               
             
             
               
                   
               
               
                 Summary of MMP-13 Activity for Compounds 
               
             
          
           
               
                 Group 
                 Ex. # 
               
               
                   
               
               
                 A 
                 1, 2/25, 2/29, 2/33, 2/52, 2/67, 2/89, 2/90, 2/94, 2/95, 2/103, 
               
               
                   
                 2/104, 2/107, 2/108, 2/113, 2/114, 2/117, 2/118, 2/119, 2/120, 
               
               
                   
                 2/121, 2/122, 2/125, 2/126, 2/129, 2/131, 2/132, 2/145, 2/152, 
               
               
                   
                 2/153, 2/166, 2/167, 2/169, 2/170, 2/171, 2/173, 2/174, 2/175, 
               
               
                   
                 2/176, 2/188, 2/208, 2/209, 2/210, 2/211, 2/219, 2/224, 2/231, 
               
               
                   
                 2/240, 2/245, 2/246, 2/251, 2/255, 2/267, 2/290, 2/309, 2/313, 
               
               
                   
                 2/316, 2/332, 2/354, 2/359, 2/367, 3/382, 2/413, 2/417, 2/526, 
               
               
                   
                 2/528, 3, 4/14, 4/15, 15, 15/2, 15/4, 15/5, 19, 22, 22/1, 22/2, 
               
               
                   
                 26, 28, 41, 42/2, 43 
               
               
                 B 
                 2/24, 2/34, 2/130, 2/143, 2/144, 2/146, 2/291, 2/292, 2/294, 
               
               
                   
                 2/302, 2/305, 2/307, 2/319, 2/323, 2/327, 2/328, 2/333, 2/344, 
               
               
                   
                 2/352, 2/355, 2/368, 2/383, 2/384, 2/428, 2/433, 2/530, 2/538, 
               
               
                   
                 39/7, 39/20 
               
               
                   
               
             
          
         
       
     
         [0260]    Some heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-8 inhibition activity (IC 50  MMP-8) ranging from below 5 nM to about 20 μM, and typically, from about 10 nM to about 2 μM. Heterocyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging below 100 nM. Table 2 lists typical examples of heterocyclic metalloprotease inhibiting compounds of the invention that have an MMP-8 activity lower than 250 nM (Group A) and from 250 nM to 20 μM (Group B). 
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 2 
               
             
             
               
                   
               
               
                 Summary of MMP-8 Activity for Compounds 
               
             
          
           
               
                 Group 
                 Ex. # 
               
               
                   
               
               
                 A 
                 1, 2/25, 2/33, 2/52, 2/94, 2/95, 2/103, 2/104, 2/107, 2/113, 
               
               
                   
                 2/114, 2/117, 2/118, 2/121, 2/122, 2/125, 2/126, 2/131, 2/132, 
               
               
                   
                 2/152, 2/153, 2/166, 2/167, 2/169, 2/170, 2/171, 2/174, 2/175, 
               
               
                   
                 2/176, 2/188, 2/209, 2/211, 2/218, 2/223, 2/224, 2/230, 2/240, 
               
               
                   
                 2/251, 2/255, 2/267, 2/269, 2/313, 2/413, 4/14, 4/15, 15, 15/2, 
               
               
                   
                 19, 22/1, 26, 42/2, 43/1 
               
               
                 B 
                 2/129, 2/130, 2/173, 2/290, 2/292, 2/316, 2/382, 2/383, 2/384, 
               
               
                   
                 2/387, 2/417, 2/428, 2/433, 2/528, 2/529, 2/538, 3, 15/3, 22, 
               
               
                   
                 22/2, 39/7, 39/20, 41, 42, 42/1 
               
               
                   
               
             
          
         
       
     
         [0261]    Some heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-3 inhibition activity (IC 50  MMP-3) ranging from below 10 nM to about 20 μM, and typically, from about 50 nM to about 2 nM. Heterocyclic metalloprotease inhibiting compounds of the invention desirably have an MMP inhibition activity ranging below 100 nM. Table 3 lists typical examples of heterocyclic metalloprotease inhibiting compounds of the invention that have an MMP-3 activity lower than 250 nM (Group A) and from 250 nM to 20 μM (Group B). 
         [0000]    
       
         
               
             
               
               
             
           
               
                 TABLE 3 
               
             
             
               
                   
               
               
                 Summary of MMP-3 Activity for Compounds 
               
             
          
           
               
                 Group 
                 Ex. # 
               
               
                   
               
               
                 A 
                 2/103, 2/104, 28, 42/2, 43 
               
               
                 B 
                 2/95, 2/107, 2/108, 2/132, 2/171, 2/188, 2/208, 2/209, 2/210, 
               
               
                   
                 2/211, 2/212, 2/231, 2/232, 2/236, 2/240, 2/245, 3, 4/15, 15, 
               
               
                   
                 15/2, 19, 22, 22/1, 22/2, 26, 39/7, 42/1 
               
               
                   
               
             
          
         
       
     
         [0262]    The synthesis of metalloprotease inhibiting compounds of the invention and their biological activity assay are described in the following examples which are not intended to be limiting in any way. 
       Schemes 
       [0263]    Provided below are schemes according to which compounds of the present invention may be prepared. 
         [0264]    In some embodiments the compounds of Formula (I) and (II) are synthesized by the general methods shown in Scheme 1 to Scheme 3. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    route A 
         [0265]    An carbonic acid and amino substituted compound (e.g. 4-amino-nicotinic acid) is condensed (e.g. EtOH/reflux) with chloro-oxo-acetic acid ethyl ester as previously described e.g. in WO2005/105760 in pyridine to give an oxazine ethyl ester (Scheme 1). This intermediate is then converted into the corresponding pyrimidine derivative using a suitable reagent (e.g. NH 4 OAc, HOAc, EtOH/80° C.). For example, when ring Q is a pyridine ring. the compound can be obtained according this route A. 
         [0000]    route B 
         [0266]    An ester and amino substituted compound (e.g. 2-amino-benzoic acid ethyl ester) is condensed (e.g. 4N HCl, dioxane/50° C.) with ethyl cyanoformate as previously described e.g. in WO2005/105760, to give a 1,3-pyrimidine-4-one ethyl ester (Scheme 1). 
         [0000]    route C 
         [0267]    An carboxamide and amino substituted compound (e.g. 2-amino-benzamide) is condensed with an suitable reagent (e.g oxalic acid diethyl ester or acetic acid anhydride as described in DD272079A1 or chloro-oxo-acetic acid ethyl ester as described in  J. Med. Chem.  1979, 22(5), 505-510) to give a 1,3-pyrimidine-4-one ethyl ester (Scheme 1). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0268]    Saponification (e.g. aqueous LiOH) of the 1,3-pyrimidine-4-one derivative of Scheme 1 above gives the corresponding bicyclic carboxylic acid (Scheme 2). Activated acid coupling (e.g. EDCI/HOAt) with R 1 R 2 NH (e.g. 6-aminomethyl-4H-benzo[1,4]oxazin-3-one) in a suitable solvent gives the desired amide. The saponification/coupling step can be combined by stirring the ester with the free amine at elevated temperature (e.g. 200° C., 15 min) under microwave irradiation. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0269]    A substituted ketone (e.g. tetrahydrothiophen-3-one) is condensed (e.g. toluene/reflux with Dean-Stark apparatus) with ethyl cyanoacetate, acetic acid and ammonium acetate to afford the desired ethyl ester-cyano substituted double bond. (Scheme 3). This intermediate is then converted into the corresponding thiophene derivative using suitable reagents (e.g. sulphur, Et 2 NH, EtOH/50° C.) as previously described e.g. in  J. prakt. Chem.  1973, 315, 39-43 or  Monatsh. Chem.  2001, 132, 279-293. 
         [0270]    The Knoevenage/cyclisation step can be combined by stirring the ketone with ethyl cyanoacetate, sulphur and a base (e.g. Et 3 N) in a suitable solvent (e.g EtOH/50° C.), following the Gewald type reaction as described e.g. in  J. prakt. Chem.  1973, 315, 39-43 or  Bioorg. Med. Chem.  2002, 10, 3113-3122. 
         [0271]    In compounds, where the one L b  in formula (I) is a nitrogen atom, the following procedure can be applied (Scheme 4). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0272]    For example, N-(pyrazol-3-yl)acetamide acetate can be cyclizised with carbonic acid diethyl ester to 2-methylpyrazolo[1,5a]-s-triazine-4-one ( J. Heterocycl. Chem.  1985, 22, 601-634) and further oxidized to the corresponding acid (e.g. by SeO 2  and then oxone). 
         [0273]    In ring Q of the product in Scheme 1 to Scheme 4, further functional group manipulation can be applied (e.g. J. March, Advanced Organic Chemistry, Wiley&amp;Sons), e.g. palladium catalyzed halogen-cyanide exchange or nucleophilic substitution. 
       EXAMPLES AND METHODS 
       [0274]    All reagents and solvents were obtained from commercial sources and used without further purification. Proton spectra ( 1 H-NMR) were recorded on a 400 MHz and a 250 MHz NMR spectrometer in deuterated solvents. Purification by column chromatography was performed using silica gel, grade 60, 0.06-0.2 mm (chromatography) or silica gel, grade 60, 0.04-0.063 mm (flash chromatography) and suitable organic solvents as indicated in specific examples. Preparative thin layer chromatography was carried out on silica gel plates with UV detection. 
         [0275]    Preparative Examples are directed to intermediate compounds useful in preparing the compounds of the present invention. 
       Preparative Example 4 
       [0276]    
       
                 
         
             
             
         
       
     
       Step A 
       [0277]    2-Amino-5,6-dihydro-4H-cyclopenta[b]thiophene-3-carboxylic acid methyl ester (1 g) was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL) and cyanoacetic acid ethyl ester (0.6 mL) was added. The mixture was stirred at 40° C. overnight, concentrated and purified by extraction with ethyl acetate from an aqueous solution to afford the title compound (1.3 g, 99%). [MH] + =265. 
       Preparative Examples 5/7 to 5/106 
       [0278]    Following similar procedures as described in the Preparative Examples 4 except using the amines indicated in Table 1.2 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE I.2 
               
               
                   
               
               
                 Ex. # 
                 amine 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 5/7  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  59%[MH] +  = 275 
               
               
                   
               
               
                 5/10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 294 
               
               
                   
               
               
                 5/35 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  74%[MH] +  = 306 
               
               
                   
               
               
                 5/36 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  36%[MH] +  = 322 
               
               
                   
               
               
                 5/41 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  88%[MH] +  = 329 
               
               
                   
               
               
                 5/43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  46%[MH] +  = 357 
               
               
                   
               
               
                 5/45 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  89%[MH] +  = 337 
               
               
                   
               
               
                 5/47 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 293 
               
               
                   
               
               
                 5/48 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  27%[MH] +  = 297 
               
               
                   
               
               
                 5/49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 283 
               
               
                   
               
               
                 5/51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  95%[MH] +  = 307 
               
               
                   
               
               
                 5/53 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 297 
               
               
                   
               
               
                 5/59 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  84%[MH] +  = 331 
               
               
                   
               
               
                 5/60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  96%[MH] +  = 355 
               
               
                   
               
               
                 5/63 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  7%[MH] +  = 281 
               
               
                   
               
               
                 5/64 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  28%[MH] +  = 394 
               
               
                   
               
               
                 5/69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 406 
               
               
                   
               
               
                 5/71 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  97%[MH] +  = 351 
               
               
                   
               
               
                 5/72 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  96%[MH] +  = 337 
               
               
                   
               
               
                 5/73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  35%[MH] +  = 295 
               
               
                   
               
               
                 5/74 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  30%(cryst from,CH 2 Cl 2 -cyclohexane)[MH] +  = 311 
               
               
                   
               
               
                 5/76 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  38%[MH] +  = 365 
               
               
                   
               
               
                 5/87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 351 
               
               
                   
               
               
                 5/88 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  69%[MH] +  = 351 
               
               
                   
               
               
                 5/89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 323 
               
               
                   
               
               
                 5/91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 351 
               
               
                   
               
               
                 5/95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  35%[MH] +  = 400 
               
               
                   
               
               
                  5/106 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = n.d. 
               
               
                   
               
             
          
         
       
     
       Preparative Example 9 
       [0279]    
       
                 
         
             
             
         
       
     
       Step A 
       [0280]    A solution of the commercially available 4-Isopropyl-phenylamine (1.35 g) and N-Bromosuccinimide (2.0 g) in benzene (20 mL) was stirred at room temperature. After 12 h, the precipitated solid was filtered off, and the filtrate was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford the title compound (1.8 g, 89%). [MH] + =214. 
       Step B 
       [0281]    A solution of the intermediate from Step A above (800 mg), xantphos (36 mg), Pd 2 (dba) 3  (20 mg), triethylamine (1.4 mL) in methanol (10 mL) was heated in autoclave under carbon monoxide at 50 psi at 100° C. for 6 h. The solution was concentrated and purified by chromatography (silica, hexane/EtOAc) to afford the title compound (360 mg, 49%). [MH] + =194. 
       Preparative Example 10/4 
       [0282]    Following similar procedures as described in the Preparative Example 9 except using the aniline derivative indicated in Table 1.4 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE I.4 
               
               
                   
               
               
                 Ex. # 
                 aniline 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 10/4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 10%[MH] +  = 259 
               
               
                   
               
             
          
         
       
     
       Preparative Example 11 
       [0283]    
       
                 
         
             
             
         
       
     
       Step A 
       [0284]    To a solution of the Preparative Example 4 above (503 mg) in THF (20 mL) was added 1M aqueous LiOH (5 mL). The resulting mixture was stirred at room temperature for 1 h, concentrated and neutralized with 1M aqueous HCl. The residue was filtered off and used without further purification (420 mg, 87%). [MH] + =237. 
       Preparative Examples 12/9-12/104 
       [0285]    Following a similar procedure as described in the Preparative Example 11 except using the ester indicated in Table 1.5 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE I.5 
               
               
                   
               
               
                 Ex. # 
                 ester 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 12/9  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 &gt;99%[MH] +  = 247 
               
               
                   
               
               
                 12/12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 266 
               
               
                   
               
               
                 12/13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  83%[MH] +  = 251 
               
               
                   
               
               
                 12/43 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 278 
               
               
                   
               
               
                 12/44 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  92%[MH] +  = 294 
               
               
                   
               
               
                 12/49 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  31%[MH] +  = 301 
               
               
                   
               
               
                 12/51 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  78%[MH] +  = 329 
               
               
                   
               
               
                 12/54 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  56%[MH] +  = 309 
               
               
                   
               
               
                 12/56 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  68%[MH] +  = 265 
               
               
                   
               
               
                 12/57 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 269 
               
               
                   
               
               
                 12/58 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  69%[MH] +  = 255 
               
               
                   
               
               
                 12/60 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  84%[MH] +  = 279 
               
               
                   
               
               
                 12/62 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  65%[MH] +  = 269 
               
               
                   
               
               
                 12/68 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  89%[MH] +  = 303 
               
               
                   
               
               
                 12/69 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 327 
               
               
                   
               
               
                 12/73 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 100%[MH] +  = 253 
               
               
                   
               
               
                 12/77 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  45%[MH] +  = 366 
               
               
                   
               
               
                 12/84 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 378 
               
               
                   
               
               
                 12/85 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  63%[MH] +  = 323 
               
               
                   
               
               
                 12/86 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  18%[MH] +  = 309 
               
               
                   
               
               
                 12/87 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  74%[MH] +  = 267 
               
               
                   
               
               
                 12/89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  93%[MH] +  = 283 
               
               
                   
               
               
                 12/91 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  63%[MH] +  = 337 
               
               
                   
               
               
                 12/92 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  91%[MH] +  = 323 
               
               
                   
               
               
                 12/93 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  70%[MH] +  = 323 
               
               
                   
               
               
                 12/94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  21%(2 steps)[MH] +  = 295 
               
               
                   
               
               
                 12/96 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  47%[MH] +  = 323 
               
               
                   
               
               
                 12/97 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  68%[MH] +  = 352 
               
               
                   
               
               
                  12/104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  92%[MH] +  = 372 
               
               
                   
               
             
          
         
       
     
       Preparative Example 13 
       [0286]    
       
                 
         
             
             
         
       
     
       Step A 
       [0287]    A degassed suspension of commercially available 6-Bromo-4H-benzo[1,4]oxazin-3-one (8.39 g), Zn(CN) 2  (3.46 g) and Pd(PPh 3 ) 4  (2.13 g) in DMF (70 mL) was stirred in a oil bath (80° C.) overnight. The mixture was cooled to room temperature and then poured into water (500 mL). The precipitate was collected by suction, air dried, washed with pentane, dissolved in CH 2 Cl 2 /MeOH (1:1), filtered through an silica pad and concentrated to yield a yellow solid (5.68 g, 89%). [MH] + =175. 
       Step B 
       [0288]    To an ice cooled solution of the title compound from Step A above (5.6 g), di-tert-butyl dicarbonate (14.06 g) and NiCl 2 .6H 2 O (1.53 g) in MeOH, NaBH 4  (8.51 g) was added in portions. The mixture was vigorously stirred for 1 h at 0° C. and 1 h at room temperature. After the addition of diethylenetriamine (3.5 mL) the mixture was concentrated, diluted with EtOAc, washed subsequently with 1N HCl, saturated aqueous NaHCO 3  and saturated aqueous NaCl, dried (MgSO 4 ), concentrated to afford the title compound as an off-white solid (7.91 g, 88%). [M+Na] + =397. 
       Step C 
       [0289]    The title compound from Step B above (7.91 g) was dissolved in a 4M solution of HCl in 1,4-dioxane (120 mL), stirred for 14 h, concentrated, suspended in Et 2 O, filtered and dried to afford the title compound as an off-white solid (5.81 g, 96%). [M-NH 3 Cl] + =162. 
       Preparative Example 14 
       [0290]    
       
                 
         
             
             
         
       
     
       Step A 
       [0291]    A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K 2 CO 3  (3.60 g) and benzylchloroformate (2.7 mL) in THF/H 2 O was stirred overnight and then concentrated. The residue was diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO 3  and brine, dried (MgSO 4 ) and concentrated. The residue was dissolved in MeOH (100 mL) and di-tert-butyl dicarbonate (7.60 g) and NiCl 2 .6H 2 O (400 mg) was added. The solution was cooled to 0° C. and NaBH 4  (2.60 g) was added in portions. The mixture was allowed to reach room temperature and then vigorously stirred overnight. After the addition of diethylenetriamine (2 mL) the mixture was concentrated, diluted with EtOAc, washed subsequently with 10% aqueous citric acid, saturated aqueous NaHCO 3  and saturated aqueous NaCl, dried (MgSO 4 ), concentrated and purified by chromatography (silica, CH 2 Cl 2 /MeOH) to afford the title compound as a colorless oil (1.81 g, 26%). [MH] + =397. 
       Preparative Example 15 
       [0292]    
       
                 
         
             
             
         
       
     
       Step A 
       [0293]    A mixture of the title compound from the Preparative Example 14 (1.81 g) and Pd/C (10 wt %, 200 mg) in EtOH (50 mL) was hydrogenated at atmospheric pressure overnight, filtered and concentrated to a volume of ˜20 mL. 3,4-Diethoxy-3-cyclobutene-1,2-dione (0.68 mL) and NEt 3  (0.5 mL) were added and the mixture was heated to reflux for 4 h. Concentration and purification by chromatography (silica, cyclohexane/EtOAc) afforded a slowly crystallizing colorless oil. This oil was dissolved in EtOH (20 mL) and a 28% solution of NH 3  in H 2 O (100 mL) was added. The mixture was stirred for 3 h, concentrated, slurried in H 2 O, filtered and dried under reduced pressure. The remaining residue was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL), stirred for 14 h, concentrated, suspended in Et 2 O, filtered and dried to afford the title compound as an off-white solid (1.08 g, 92%). [M-Cl] + =258. 
       Preparative Example 16 
       [0294]    
       
                 
         
             
             
         
       
     
       Step A 
       [0295]    Tetrahydrothiophen-3-one (1 g), ethyl cyanoacetate (1.44 g), acetic acid (70 μL) and ammonium acetate (30 mg) in toluene were heated to reflux in presence of a Dean-Stark overnight. After concentration of the mixture, a purification by chromatography (silica cyclohexane/EtOAc 9/1) afforded a yellow oil (1.04 g, 54%). [MH] + =198. 
       Preparative Examples 17/1 to 17/20 
       [0296]    Following similar procedures as described in the Preparative Examples 16 except using the ketones indicated in Table 1.6 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE I.6 
               
               
                   
               
               
                 Ex. # 
                 Ketone 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 17/1  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 27%[MH] +  = 212 
               
               
                   
               
               
                 17/2  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 309 
               
               
                   
               
               
                 17/5  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = n.d. 
               
               
                   
               
               
                 17/7  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 93%[MH] +  = 266 
               
               
                   
               
               
                 17/8  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 83%[MH] +  = 252 
               
               
                   
               
               
                 17/9  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 37%[MH] +  = 210 
               
               
                   
               
               
                 17/10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 226 
               
               
                   
               
               
                 17/12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 280 
               
               
                   
               
               
                 17/13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 40%[MH] +  = 266 
               
               
                   
               
               
                 17/14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 266 
               
               
                   
               
               
                 17/15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = 238 
               
               
                   
               
               
                 17/17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 41%[MH] +  = 266 
               
               
                   
               
               
                 17/20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 n.d.[MH] +  = n.d. 
               
               
                   
               
             
          
         
       
     
       Preparative Example 18 
       [0297]    
       
                 
         
             
             
         
       
     
       Step A 
       [0298]    A mixture of the title compound from the Preparative Example 16 (0.5 g) and sulfur (86 mg) in MeOH (5 mL) were heated at 50° C. Diethylamine (135 μL) was added slowly and the mixture was stirred at 50° C. for 2 h. After concentration of the mixture, a purification by chromatography (silica cyclohexane/EtOAc 9/1) afforded a orange solid (345 mg, 59%). [MH] + =230. 
       Preparative Examples 18/1 to 18/21 
       [0299]    Following similar procedures as described in the Preparative Examples 18 except using the adduct indicated in Table 1.7 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE I.7 
               
               
                   
               
               
                 Ex. # 
                 adduct 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 18/1  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 43%[MH] +  = 244 
               
               
                   
               
               
                 18/2  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 62%(2 steps)[MH] +  = 341 
               
               
                   
               
               
                 18/5  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 98%(2 steps)[MH] +  = 353 
               
               
                   
               
               
                 18/7  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 82%[MH] +  = 298 
               
               
                   
               
               
                 18/8  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 65%[MH] +  = 284 
               
               
                   
               
               
                 18/9  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 80%[MH] +  = 242 
               
               
                   
               
               
                 18/10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 92%(2 steps)[MH] +  = 258 
               
               
                   
               
               
                 18/12 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 47%(2 steps)[MH] +  = 312 
               
               
                   
               
               
                 18/13 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 79%[MH] +  = 298 
               
               
                   
               
               
                 18/14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 38%(2 steps)[MH] +  = 298 
               
               
                   
               
               
                 18/15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 62%(2 steps)[MH] +  = 270 
               
               
                   
               
               
                 18/17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 61%[MH] +  = 298 
               
               
                   
               
               
                 18/21 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 30%(2 steps).[MH] +  = 347 
               
               
                   
               
             
          
         
       
     
       Preparative Example 19 
       [0300]    
       
                 
         
             
             
         
       
     
       Step A 
       [0301]    Ethyl-2-amino-6-terbutoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-3-carboxylate (0.5 g) was dissolved in a 4M solution of HCl in 1,4-dioxane (20 mL) and nitriloacetic acid ethyl ester (0.25 mL) was added. The mixture was stirred at 50° C. for 3 h and concentrated. The decarboxylation of the ester was observed. This product was used in the following step without further purification. [MH] + =280. 
       Step B 
       [0302]    The title compound of Step A above was dissolved in DMF and triethylamine (0.32 mL) was added. Di-tert-butyl dicarbonate (0.5 g) was added and the mixture was stirred at room temperature for 1 h. The solvent was removed by evaporation. The residue was dissolved in dichloromethane and washed with water, dried and evaporated to give the title compound (580 mg) as a yellow solid. [MH] + =380. 
       Preparative Example 20 
       [0303]    
       
                 
         
             
             
         
       
     
       Step A 
       [0304]    Tetrahydro-2H-pyran-4-one (1 g) was placed in methanol in presence of barium oxide (0.1 g). Nitrosomethylurethane (1.3 g) was added slowly to the reaction mixture. During the addition, barium oxide (0.2 g) was added by small portion. The reaction was stirred 3 hours at room temperature and then filtrated. The methanol was evaporated, diethyl ether was then added to the residue, a precipitate was formed. The mixture was filtrated and diethyl ether evaporated to afford the title compound (790 mg, 70%) as a yellow oil. [MH] + =115. 
       Preparative Example 20/1 
       [0305]    Following similar procedures as described in the Preparative Examples 20, except using the educt indicated in Table I.13 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE I.13 
               
               
                   
               
               
                 Ex. # 
                 Educt 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 20/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 76%[MH] +  = 143 
               
               
                   
               
             
          
         
       
     
       Example 1 
       [0306]    
       
                 
         
             
             
         
       
     
       Step A 
       [0307]    To a solution of the title compound from Preparative Example 11 above (30 mg), EDCI (50 mg) and HOAt (22 mg) in DMF (10 mL) were added N-methylmorpholine (50 μL) and the title compound from the Preparative Example 13 (50 mg). The mixture was stirred overnight and then concentrated. The remaining residue was suspended in 10% aqueous citric acid and the residue was filtered to afford the title compound as an off white solid (38 mg, 74%). [MH] + =397. 
       Example 1a 
       [0308]    
       
                 
         
             
             
         
       
     
       Step A 
       [0309]    To a solution of the title compound from Preparative Example 12/16 above (9.5 mg), HATU (23.3 mg) and HOAt (8.2 mg) in DMA (200 μL) was added a 0.1 M solution of morpholine in DMA/pyridine(1:1, 440 μL). The resulting mixture was agitated (˜600 rpm) at room temperature for 4 h, concentrated and purified by HPLC(RP-C18, ACN/H 2 O) to afford the title compound. [MH] + =305. 
       Examples 2/24-2/547 
       [0310]    Following similar procedures as described in the Examples 1 (method A) or 1a (method B), except using the amines and acids indicated in Table 11.1 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
               
               
             
           
               
                 TABLE II.1 
               
               
                   
               
               
                   
                   
                   
                 method, 
               
               
                 Ex. # 
                 amine, acid 
                 product 
                 yield 
               
               
                   
               
             
             
               
                 2/24 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 95%[MH] +  = 407 
               
               
                   
               
               
                 2/25 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 26%[MH] +  = 407 
               
               
                   
               
               
                 2/29 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 12%[MH] +  = 426 
               
               
                   
               
               
                 2/30 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, n.d.[MH] +  = 426 
               
               
                   
               
               
                 2/33 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 29%[MH] +  = 411 
               
               
                   
               
               
                 2/34 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 77%[MH] +  = 411 
               
               
                   
               
               
                 2/52 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 85%[MH] +  = 476 
               
               
                   
               
               
                 2/67 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 76%[MH] +  = 486 
               
               
                   
               
               
                 2/89 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 27%[MH] +  = 438 
               
               
                   
               
               
                 2/90 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 63%[MH] +  = 517 
               
               
                   
               
               
                 2/94 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 83%[MH] +  = 454 
               
               
                   
               
               
                 2/95 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 70%[MH] +  = 533 
               
               
                   
               
               
                 2/103 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 81%[MH] +  = 461 
               
               
                   
               
               
                 2/104 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 64%[MH] +  = 540 
               
               
                   
               
               
                 2/107 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 85%[MH] +  = 489 
               
               
                   
               
               
                 2/108 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, quant.[MH] +  = 489 
               
               
                   
               
               
                 2/113 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 40%[MH] +  = 469 
               
               
                   
               
               
                 2/114 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 88%[MH] +  = 548 
               
               
                   
               
               
                 2/117 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 93%[MH] +  = 425 
               
               
                   
               
               
                 2/118 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 98%[MH] +  = 504 
               
               
                   
               
               
                 2/119 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 65%[MH] +  = 429 
               
               
                   
               
               
                 2/120 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 76%[MH] +  = 508 
               
               
                   
               
               
                 2/121 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 86%[MH] +  = 415 
               
               
                   
               
               
                 2/122 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 91%[MH] +  = 494 
               
               
                   
               
               
                 2/125 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 68%[MH] +  = 439 
               
               
                   
               
               
                 2/126 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 43%[MH] +  = 518 
               
               
                   
               
               
                 2/129 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 31%[MH] +  = 420 
               
               
                   
               
               
                 2/130 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 10%[MH] +  = 422 
               
               
                   
               
               
                 2/131 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 77%[MH] +  = 429 
               
               
                   
               
               
                 2/132 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 31%[MH] +  = 508 
               
               
                   
               
               
                 2/143 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 80%[MH] +  = 463 
               
               
                   
               
               
                 2/144 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 5%[MH] +  = 542 
               
               
                   
               
               
                 2/145 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 27%[MH] +  = 487 
               
               
                   
               
               
                 2/146 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 74%[MH] +  = 566 
               
               
                   
               
               
                 2/152 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 45%[MH] +  = 413 
               
               
                   
               
               
                 2/153 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 60%[MH] +  = 492 
               
               
                   
               
               
                 2/166 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 75%[MH] +  = 440 
               
               
                   
               
               
                 2/167 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 99%[MH] +  = 530 
               
               
                   
               
               
                 2/168 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 40%[MH] +  = 620 
               
               
                   
               
               
                 2/169 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 34%[MH] +  = 587 
               
               
                   
               
               
                 2/170 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 50%[MH] +  = 608 
               
               
                   
               
               
                 2/171 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 78%[MH] +  = 526 
               
               
                   
               
               
                 2/172 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 26%[MH] +  = 454 
               
               
                   
               
               
                 2/173 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 23%[MH] +  = 468 
               
               
                   
               
               
                 2/174 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 80%[MH] +  = 548 
               
               
                   
               
               
                 2/175 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 39%[MH] +  = 544 
               
               
                   
               
               
                 2/176 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 36%[MH] +  = 562 
               
               
                   
               
               
                 2/177 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 86%[MH] +  = 562 
               
               
                   
               
               
                 2/178 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 76%[MH] +  = 562 
               
               
                   
               
               
                 2/188 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, n.d.[MH] +  = 538 
               
               
                   
               
               
                 2/208 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 25%[MH] +  = 483 
               
               
                   
               
               
                 2/209 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 22%[MH] +  = 562 
               
               
                   
               
               
                 2/210 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 7%[MH] +  = 469 
               
               
                   
               
               
                 2/211 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 79%[MH] +  = 427 
               
               
                   
               
               
                 2/212 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 87%[MH] +  = 506 
               
               
                   
               
               
                 2/218 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 66%[MH] +  = 443 
               
               
                   
               
               
                 2/219 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 56%[MH] +  = 522 
               
               
                   
               
               
                 2/223 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 61%[MH] +  = 478 
               
               
                   
               
               
                 2/224 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 58%[MH] +  = 554 
               
               
                   
               
               
                 2/225 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 34%[MH] +  = 482 
               
               
                   
               
               
                 2/230 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 48%[MH] +  = 534 
               
               
                   
               
               
                 2/231 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 87%[MH] +  = 496 
               
               
                   
               
               
                 2/232 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 70%[MH] +  = 519 
               
               
                   
               
               
                 2/236 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 98%[MH] +  = 497 
               
               
                   
               
               
                 2/237 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 78%[MH] +  = 482 
               
               
                   
               
               
                 2/238 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 80%[MH] +  = 582 
               
               
                   
               
               
                 2/239 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 79%[MH] +  = 468 
               
               
                   
               
               
                 2/240 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 69%[MH] +  = 468 
               
               
                   
               
               
                 2/245 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 26%[MH] +  = 391 
               
               
                   
               
               
                 2/246 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 10%[MH] +  = 391 
               
               
                   
               
               
                 2/249 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 67%[MH] +  = 526 
               
               
                   
               
               
                 2/250 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 69%[MH] +  = 526 
               
               
                   
               
               
                 2/251 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 90%[MH] +  = 506 
               
               
                   
               
               
                 2/252 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 96%[MH] +  = 483 
               
               
                   
               
               
                 2/253 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 16%[MH] +  = 454 
               
               
                   
               
               
                 2/254 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 26%[MH] +  = 468 
               
               
                   
               
               
                 2/255 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 25%[MH] +  = 497 
               
               
                   
               
               
                 2/256 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 86%[MH] +  = 525 
               
               
                   
               
               
                 2/257 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 85%[MH] +  = 483 
               
               
                   
               
               
                 2/258 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 43%[MH] +  = 454 
               
               
                   
               
               
                 2/259 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 20%[MH] +  = 468 
               
               
                   
               
               
                 2/260 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 30%[MH] +  = 482 
               
               
                   
               
               
                 2/261 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 14%[MH] +  = 492 
               
               
                   
               
               
                 2/262 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 78%[MH] +  = 454 
               
               
                   
               
               
                 2/263 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 60%[MH] +  = 468 
               
               
                   
               
               
                 2/264 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 23%[MH] +  = 455 
               
               
                   
               
               
                 2/266 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 95%[MH] +  = 483 
               
               
                   
               
               
                 2/267 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 96%[MH] +  = 468 
               
               
                   
               
               
                 2/268 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 57%[MH] +  = 482 
               
               
                   
               
               
                 2/269 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 72%[MH] +  = 496 
               
               
                   
               
               
                 2/270 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 85%[MH] +  = 512 
               
               
                   
               
               
                 2/289 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 315 
               
               
                   
               
               
                 2/290 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 343 
               
               
                   
               
               
                 2/291 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 289 
               
               
                   
               
               
                 2/292 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 343 
               
               
                   
               
               
                 2/293 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 303 
               
               
                   
               
               
                 2/294 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 277 
               
               
                   
               
               
                 2/295 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 303 
               
               
                   
               
               
                 2/296 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 325 
               
               
                   
               
               
                 2/297 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 331 
               
               
                   
               
               
                 2/298 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 334 
               
               
                   
               
               
                 2/299 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 263 
               
               
                   
               
               
                 2/300 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 317 
               
               
                   
               
               
                 2/301 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =306 
               
               
                   
               
               
                 2/302 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 403 
               
               
                   
               
               
                 2/303 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 249 
               
               
                   
               
               
                 2/304 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 339 
               
               
                   
               
               
                 2/305 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 357 
               
               
                   
               
               
                 2/306 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =318 
               
               
                   
               
               
                 2/307 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 365 
               
               
                   
               
               
                 2/308 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 292 
               
               
                   
               
               
                 2/309 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =326 
               
               
                   
               
               
                 2/310 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 339 
               
               
                   
               
               
                 2/311 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 339 
               
               
                   
               
               
                 2/312 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 318 
               
               
                   
               
               
                 2/313 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 357 
               
               
                   
               
               
                 2/314 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 404 
               
               
                   
               
               
                 2/315 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 409 
               
               
                   
               
               
                 2/316 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/317 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =506 
               
               
                   
               
               
                 2/318 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/319 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 357 
               
               
                   
               
               
                 2/320 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 357 
               
               
                   
               
               
                 2/321 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 401 
               
               
                   
               
               
                 2/322 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B. n.d.[MH] +  = 365 
               
               
                   
               
               
                 2/323 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 346 
               
               
                   
               
               
                 2/324 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 365 
               
               
                   
               
               
                 2/325 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 351 
               
               
                   
               
               
                 2/326 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 351 
               
               
                   
               
               
                 2/327 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 368 
               
               
                   
               
               
                 2/328 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =402 
               
               
                   
               
               
                 2/329 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 368 
               
               
                   
               
               
                 2/330 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 332 
               
               
                   
               
               
                 2/331 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 376 
               
               
                   
               
               
                 2/332 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 427 
               
               
                   
               
               
                 2/333 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 381 
               
               
                   
               
               
                 2/334 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 393 
               
               
                   
               
               
                 2/335 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B. n.d.[MH] +  = 399 
               
               
                   
               
               
                 2/336 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 393 
               
               
                   
               
               
                 2/337 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =368 
               
               
                   
               
               
                 2/338 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 375 
               
               
                   
               
               
                 2/339 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 393 
               
               
                   
               
               
                 2/340 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 343 
               
               
                   
               
               
                 2/341 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 345 
               
               
                   
               
               
                 2/342 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 345 
               
               
                   
               
               
                 2/343 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 319 
               
               
                   
               
               
                 2/344 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 331 
               
               
                   
               
               
                 2/345 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =410 
               
               
                   
               
               
                 2/346 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 367 
               
               
                   
               
               
                 2/347 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 353 
               
               
                   
               
               
                 2/348 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 353 
               
               
                   
               
               
                 2/349 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 353 
               
               
                   
               
               
                 2/350 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 345 
               
               
                   
               
               
                 2/351 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 319 
               
               
                   
               
               
                 2/352 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 381 
               
               
                   
               
               
                 2/353 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =410 
               
               
                   
               
               
                 2/354 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 365 
               
               
                   
               
               
                 2/355 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =424 
               
               
                   
               
               
                 2/356 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 409 
               
               
                   
               
               
                 2/357 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =326 
               
               
                   
               
               
                 2/358 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =340 
               
               
                   
               
               
                 2/359 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =410 
               
               
                   
               
               
                 2/360 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-(TFA) 2 ] +  =423 
               
               
                   
               
               
                 2/361 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 409 
               
               
                   
               
               
                 2/362 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 333 
               
               
                   
               
               
                 2/363 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 367 
               
               
                   
               
               
                 2/364 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =315 
               
               
                   
               
               
                 2/365 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 331 
               
               
                   
               
               
                 2/366 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 317 
               
               
                   
               
               
                 2/367 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 410 
               
               
                   
               
               
                 2/368 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =394 
               
               
                   
               
               
                 2/369 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 332 
               
               
                   
               
               
                 2/370 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 374 
               
               
                   
               
               
                 2/371 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 374 
               
               
                   
               
               
                 2/372 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 389 
               
               
                   
               
               
                 2/376 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 A, 87%[MH] +  = 532 
               
               
                   
               
               
                 2/382 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 370 
               
               
                   
               
               
                 2/383 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 340 
               
               
                   
               
               
                 2/384 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 356 
               
               
                   
               
               
                 2/385 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 348 
               
               
                   
               
               
                 2/386 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 356 
               
               
                   
               
               
                 2/387 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 356 
               
               
                   
               
               
                 2/388 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 354 
               
               
                   
               
               
                 2/389 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/390 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 426 
               
               
                   
               
               
                 2/391 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 368 
               
               
                   
               
               
                 2/392 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 356 
               
               
                   
               
               
                 2/393 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 356 
               
               
                   
               
               
                 2/394 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/395 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/396 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/397 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 356 
               
               
                   
               
               
                 2/398 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 400 
               
               
                   
               
               
                 2/399 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 372 
               
               
                   
               
               
                 2/400 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 455 
               
               
                   
               
               
                 2/401 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/402 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/403 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/404 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/405 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 340 
               
               
                   
               
               
                 2/406 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 406 
               
               
                   
               
               
                 2/407 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 382 
               
               
                   
               
               
                 2/408 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 396 
               
               
                   
               
               
                 2/409 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/410 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 397 
               
               
                   
               
               
                 2/411 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 397 
               
               
                   
               
               
                 2/412 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 410 
               
               
                   
               
               
                 2/413 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 450 
               
               
                   
               
               
                 2/414 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 478 
               
               
                   
               
               
                 2/415 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 394 
               
               
                   
               
               
                 2/416 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 464 
               
               
                   
               
               
                 2/417 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 468 
               
               
                   
               
               
                 2/418 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 482 
               
               
                   
               
               
                 2/419 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 482 
               
               
                   
               
               
                 2/420 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 416 
               
               
                   
               
               
                 2/421 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 490 
               
               
                   
               
               
                 2/422 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 372 
               
               
                   
               
               
                 2/423 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 351 
               
               
                   
               
               
                 2/424 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =368 
               
               
                   
               
               
                 2/425 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 390 
               
               
                   
               
               
                 2/426 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 412 
               
               
                   
               
               
                 2/427 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 412 
               
               
                   
               
               
                 2/428 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/429 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 400 
               
               
                   
               
               
                 2/430 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 400 
               
               
                   
               
               
                 2/431 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 388 
               
               
                   
               
               
                 2/432 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 368 
               
               
                   
               
               
                 2/433 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 378 
               
               
                   
               
               
                 2/434 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 342 
               
               
                   
               
               
                 2/435 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  =420/422 
               
               
                   
               
               
                 2/436 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 425 
               
               
                   
               
               
                 2/437 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 395 
               
               
                   
               
               
                 2/438 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 402 
               
               
                   
               
               
                 2/439 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 412 
               
               
                   
               
               
                 2/440 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =365 
               
               
                   
               
               
                 2/441 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 392 
               
               
                   
               
               
                 2/442 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 392 
               
               
                   
               
               
                 2/443 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 351 
               
               
                   
               
               
                 2/444 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 388 
               
               
                   
               
               
                 2/445 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 404 
               
               
                   
               
               
                 2/446 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 455 
               
               
                   
               
               
                 2/447 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/448 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 419 
               
               
                   
               
               
                 2/449 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 384 
               
               
                   
               
               
                 2/450 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =357 
               
               
                   
               
               
                 2/451 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 294 
               
               
                   
               
               
                 2/452 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 360 
               
               
                   
               
               
                 2/453 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 306 
               
               
                   
               
               
                 2/454 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 462 
               
               
                   
               
               
                 2/455 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =347 
               
               
                   
               
               
                 2/456 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 306 
               
               
                   
               
               
                 2/457 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 370 
               
               
                   
               
               
                 2/458 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 320 
               
               
                   
               
               
                 2/459 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 280 
               
               
                   
               
               
                 2/460 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 446 
               
               
                   
               
               
                 2/461 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 320 
               
               
                   
               
               
                 2/462 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 320 
               
               
                   
               
               
                 2/463 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 330 
               
               
                   
               
               
                 2/464 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 320 
               
               
                   
               
               
                 2/465 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 394 
               
               
                   
               
               
                 2/466 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 419 
               
               
                   
               
               
                 2/467 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 308 
               
               
                   
               
               
                 2/468 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 364 
               
               
                   
               
               
                 2/469 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 376 
               
               
                   
               
               
                 2/470 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 337 
               
               
                   
               
               
                 2/471 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 405 
               
               
                   
               
               
                 2/472 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  =418/420 
               
               
                   
               
               
                 2/473 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =328 
               
               
                   
               
               
                 2/474 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 294 
               
               
                   
               
               
                 2/475 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 322 
               
               
                   
               
               
                 2/476 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  =418/420 
               
               
                   
               
               
                 2/477 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =407 
               
               
                   
               
               
                 2/478 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =321 
               
               
                   
               
               
                 2/479 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 294 
               
               
                   
               
               
                 2/480 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 274 
               
               
                   
               
               
                 2/481 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 368 
               
               
                   
               
               
                 2/482 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 386 
               
               
                   
               
               
                 2/483 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =452 
               
               
                   
               
               
                 2/484 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 466 
               
               
                   
               
               
                 2/485 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 320 
               
               
                   
               
               
                 2/486 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =411 
               
               
                   
               
               
                 2/487 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =411 
               
               
                   
               
               
                 2/488 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  =404/406 
               
               
                   
               
               
                 2/489 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 348 
               
               
                   
               
               
                 2/490 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 315 
               
               
                   
               
               
                 2/491 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =355 
               
               
                   
               
               
                 2/492 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 292 
               
               
                   
               
               
                 2/493 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 368 
               
               
                   
               
               
                 2/494 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 462 
               
               
                   
               
               
                 2/495 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  =422/424 
               
               
                   
               
               
                 2/496 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 342 
               
               
                   
               
               
                 2/497 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 399 
               
               
                   
               
               
                 2/498 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 362 
               
               
                   
               
               
                 2/499 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 362 
               
               
                   
               
               
                 2/500 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 306 
               
               
                   
               
               
                 2/501 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 306 
               
               
                   
               
               
                 2/502 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 292 
               
               
                   
               
               
                 2/503 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 292 
               
               
                   
               
               
                 2/504 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =375 
               
               
                   
               
               
                 2/505 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =319 
               
               
                   
               
               
                 2/506 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 447 
               
               
                   
               
               
                 2/507 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =333 
               
               
                   
               
               
                 2/508 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 390 
               
               
                   
               
               
                 2/509 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =423 
               
               
                   
               
               
                 2/510 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 336 
               
               
                   
               
               
                 2/511 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/512 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/513 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 333 
               
               
                   
               
               
                 2/514 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 358 
               
               
                   
               
               
                 2/515 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 433 
               
               
                   
               
               
                 2/516 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 304 
               
               
                   
               
               
                 2/517 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 318 
               
               
                   
               
               
                 2/518 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =345 
               
               
                   
               
               
                 2/519 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =328 
               
               
                   
               
               
                 2/520 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 447 
               
               
                   
               
               
                 2/521 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =330 
               
               
                   
               
               
                 2/522 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 382 
               
               
                   
               
               
                 2/523 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 410 
               
               
                   
               
               
                 2/524 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 410 
               
               
                   
               
               
                 2/525 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 410 
               
               
                   
               
               
                 2/526 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 390 
               
               
                   
               
               
                 2/527 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-(TFA) 2 ] +  =396 
               
               
                   
               
               
                 2/528 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-(TFA) 2 ] +  =428 
               
               
                   
               
               
                 2/529 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-(TFA) 2 ] +  =412 
               
               
                   
               
               
                 2/530 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 419 
               
               
                   
               
               
                 2/531 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 358 
               
               
                   
               
               
                 2/532 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 358 
               
               
                   
               
               
                 2/533 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 346 
               
               
                   
               
               
                 2/534 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 358 
               
               
                   
               
               
                 2/535 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 340 
               
               
                   
               
               
                 2/536 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[M-TFA] +  =349 
               
               
                   
               
               
                 2/537 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 415 
               
               
                   
               
               
                 2/538 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 459 
               
               
                   
               
               
                 2/539 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 411 
               
               
                   
               
               
                 2/540 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 415 
               
               
                   
               
               
                 2/541 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 433 
               
               
                   
               
               
                 2/542 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 411 
               
               
                   
               
               
                 2/543 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 436 
               
               
                   
               
               
                 2/544 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 454 
               
               
                   
               
               
                 2/545 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 383 
               
               
                   
               
               
                 2/546 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 426 
               
               
                   
               
               
                 2/547 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 B, n.d.[MH] +  = 416 
               
               
                   
               
             
          
         
       
     
       Example 3 
       [0311]    
       
                 
         
             
             
         
       
     
       Step A 
       [0312]    To a solution of the title compound from Step A above (200 mg) in THF (3 mL) was added 1M aqueous LiOH (1,2 mL). The resulting mixture was stirred at room temperature 3 h, concentrated and suspended in 1M aqueous HCl. The residue was filtered off and used without further purification (150 mg, 80%). [MH] + =469. 
       Examples 4/4-4/19 
       [0313]    Following a similar procedure as described in Example 3, except using the ester indicated in Table 11.2 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE II.2 
               
               
                   
               
             
             
               
                 Ex. # 
                 Ester 
               
               
                   
               
               
                 4/4  
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/9  
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 4/19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. # 
                 product 
                 yield 
               
               
                   
               
               
                 4/4  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 70%[MH] +  = 441 
               
               
                   
               
               
                 4/9  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 66%[MH] +  = 606 
               
               
                   
               
               
                 4/10 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 68%[MH] +  = 574 
               
               
                   
               
               
                 4/11 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 99%[MH] +  = 455 
               
               
                   
               
               
                 4/14 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 65%[MH] +  = 520 
               
               
                   
               
               
                 4/15 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 65%[MH] +  = 441 
               
               
                   
               
               
                 4/17 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 40%[MH] +  = 455 
               
               
                   
               
               
                 4/18 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 72%[MH] +  = 455 
               
               
                   
               
               
                 4/19 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 66%[MH] +  = 467 
               
               
                   
               
             
          
         
       
     
       Example 15 
       [0314]    
       
                 
         
             
             
         
       
     
       Step A 
       [0315]    To the title compound from Step A above (55 mg) was added a 4M solution of HCl in 1,4-dioxane (3 mL). The reaction mixture was stirred at room temperature overnight and concentrated to afford the title compound (29 mg, 58%). [MH] + =526. 
       Examples 15/2-15/5 
       [0316]    Following a similar procedure as described in the Example 15, except using the protected product indicated in Table 11.7 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE II.7 
               
               
                   
               
             
             
               
                 Ex. # 
                 educt 
               
               
                   
               
               
                 15/2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15/3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15/4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 15/5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. # 
                 product  
                 Yield 
               
               
                   
               
               
                 15/2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 50%[MH] +  = 498 
               
               
                   
               
               
                 15/3 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 16%[MH] +  = 426 
               
               
                   
               
               
                 15/4 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 69%[MH] +  = 426 
               
               
                   
               
               
                 15/5 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 46%[MH] +  = 412 
               
               
                   
               
             
          
         
       
     
       Example 19 
       [0317]    
       
                 
         
             
             
         
       
     
       Step A 
       [0318]    To DMF (5 mL) was added 2M oxalylchloride in dichloromethane (250 μL) at 0° C. Then a solution of the title compound from Example 2/166 (200 mg) in DMF (2 mL) was added and the mixture was stirred for 6 h at 0° C. After adding pyridine (150 μL) the mixture was stirred for additional 2 h at room temperature. The mixture was concentrated and the remaining residue was suspended in 1M HCl and filtered to afford the title compound as an off white solid (192 mg, 99%). [MH] + =422. 
       Example 22 
       [0319]    
       
                 
         
             
             
         
       
     
       Step A 
       [0320]    The title compound from example 2/119 (9 mg) was placed in a mixture acetic acid/acetic acid anhydride (1:1). Hydrogen peroxide (6 μL) was added and the reaction mixture was heated at 100° C. for 4 h and then stirred at room temperature overnight. After evaporation, water was added and the residual product was filtrated and dried to afford the title compound (7 mg, 72%). [MH] + =461. 
       Example 22/1 and 22/2 
       [0321]    Following a similar procedure as described in Example 22, except using the educt indicated in Table II.9 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE II.9 
               
               
                   
               
             
             
               
                 Ex. # 
                 educt 
               
               
                   
               
               
                 22/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 22/2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. # 
                 product 
                 Yield 
               
               
                   
               
               
                 22/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 80%[MH] +  = 475 
               
               
                   
               
               
                 22/2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 89%[MH] +  = 461 
               
               
                   
               
             
          
         
       
     
       Example 26 
       [0322]    
       
                 
         
             
             
         
       
     
       Step A 
       [0323]    The title compound from Example 2/218 (15.8 mg) was dissolved in DMSO, then H 2 O 2  (˜1 mL) was added and the mixture was stirred at room temperature for 3 h, evaporated, slurried with water and filtered to afford the title compound (13.8 mg, 84%) as a colourless solid. [MH] + =459. 
       Example 28 
       [0324]    
       
                 
         
             
             
         
       
     
       Step A 
       [0325]    To a solution of 9-oxo-8,9-dihydro-1,3-dioxa-6,8-diaza-cyclopenta[a]naphthalene-7-carboxylic acid ethyl ester (32 mg) in ethanol (1 mL) were added triethyl amine (40 μL) and the title compound from the Preparative Example 13 (30 mg). The mixture was heated at 180° C. in a microwave oven for 1 h and then concentrated. The remaining residue was purified by silica gel chromatography (10% methanol in methylene chloride) to give a yellow solid (45 mg, 95%). [MH] + =395. 
       Example 39/7 and 39/20 
       [0326]    Following similar procedures as described in Examples 28 except using the amines and the ester indicated in Table II.14 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE II.14 
               
               
                   
               
             
             
               
                 Ex. # 
                 amine; ester 
               
               
                   
               
               
                 39/7  
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 39/20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. # 
                 product 
                 Yield 
               
               
                   
               
               
                 39/7  
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 20%[MH] +  = 428 
               
               
                   
               
               
                 39/20 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 19%[MH] +  = 401 
               
               
                   
               
             
          
         
       
     
       Example 41 
       [0327]    
       
                 
         
             
             
         
       
     
       Step A 
       [0328]    The title compound from Example 2/376 above was stirred in a solution of HBr in glacial acid (33 wt %) at room temperature for 2 h. Evaporation afford the title compound. [MH] 30 =398. 
       Example 42 
       [0329]    
       
                 
         
             
             
         
       
     
       Step A 
       [0330]    To a solution of the title compound from Example 41 (9.6 mg) in pyridine (200 μL) was added acetyl chloride (3 μL) at room temperature. The mixture was stirred for 2 h at room temperature and evaporated. The resulting residue was purified by HPLC to afford the title compound. (2.2 mg; 25%, [MH] + =440). 
       Example 42/1 and 42/2 
       [0331]    Following a similar procedure as described in Example 42 above, except using amines and acid chlorides as indicated in the Table 11.15 below, the following compounds were prepared. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE II.15 
               
               
                   
               
             
             
               
                 Ex. # 
                 amine; acid chloride 
               
               
                   
               
               
                 42/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
               
                 42/2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. # 
                 product 
                 Yield 
               
               
                   
               
               
                 42/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                  9%[MH] +  = 508 
               
               
                   
               
               
                 42/2 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 29%[MH] +  = 476 
               
               
                   
               
             
          
         
       
     
       Example 43 
       [0332]    
       
                 
         
             
             
         
       
     
       Step A 
       [0333]    To a solution of the title compound from Example 41 (15 mg) above in DMA (500 μL) was added 2-bromo-pyrimidine (10 mg). The mixture was heated in a sealed tube at 100° C. (microwave) for 5 min. Purification by HPLC afforded the title compound. (6.1 mg; 33%, [MH] + =476). 
       Example 43/1 
       [0334]    Following a similar procedure as described in Example 43 above, except using amine and benzyl bromide as indicated in the Table 11.16 below, the following compound was prepared. 
         [0000]    
       
         
               
               
             
               
               
               
             
           
               
                 TABLE II.16 
               
               
                   
               
             
             
               
                 Ex. # 
                 amine; benzyl bromide 
               
               
                   
               
               
                 43/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
               
               
                   
               
             
          
           
               
                 Ex. # 
                 product 
                 yield 
               
               
                   
               
               
                 43/1 
                 
                   
                             
                     
                         
                         
                     
                   
                 
                 14%[MH] +  = 488 
               
               
                   
               
             
          
         
       
     
       Example 1700 
     Assay for Determining MMP-13 Inhibition 
       [0335]    The typical assay for MMP-13 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2  and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of catalytic domain of MMP-13 enzyme (produced by Alantos or commercially available from Invitek (Berlin), Cat.# 30100812) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 GAL of a 12.5 μM stock solution of MMP-13 fluorescent substrate (Calbiochem, Cat. No. 444235). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader. The IC 50  values are calculated from the initial reaction rates. 
       Example 1701 
     Assay for Determining MMP-3 Inhibition 
       [0336]    The typical assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl 2  and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 100 nM stock solution of the catalytic domain of MMP-3 enzyme (Biomol, Cat. No. SE-109) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of NFF-3 fluorescent substrate (Calbiochem, Cat. No. 480-455). The time-dependent increase in fluorescence is measured at the 330 nm excitation and 390 nm emission by an automatic plate multireader. The IC 50  values are calculated from the initial reaction rates. 
       Example 1702 
     Assay for Determining MMP-8 Inhibition 
       [0337]    The typical assay for MMP-8 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2  and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of activated MMP-8 enzyme (Calbiochem, Cat. No. 444229) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at 37° C. Upon the completion of incubation, the assay is started by addition of 40 μL of a 10 μM stock solution of OmmiMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by an automatic plate multireader at 37° C. The IC 50  values are calculated from the initial reaction rates. 
       Example 1703 
     Assay for Determining MMP-12 Inhibition 
       [0338]    The typical assay for MMP-12 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2  and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 50 nM stock solution of the catalytic domain of MMP-12 enzyme (Biomol, Cat. No. SE-138) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed and incubated for 10 min at room temperature. Upon the completion of incubation, the assay is started by addition of 40 μL of a 12.5 μM stock solution of OmniMMP fluorescent substrate (Biomol, Cat. No. P-126). The time-dependent increase in fluorescence is measured at the 320 nm excitation and 390 nm emission by automatic plate multireader at 37° C. The IC 50  values are calculated from the initial reaction rates. 
       Example 1704 
     Assay for Determining Aggrecanase-1 Inhibition 
       [0339]    The typical assay for aggrecanase-1 activity is carried out in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2  and 0.05% Brij-35. Different concentrations of tested compounds are prepared in assay buffer in 50 μL aliquots. 10 μL of a 75 nM stock solution of aggrecanase-1 (Invitek) is added to the compound solution. The mixture of enzyme and compound in assay buffer is thoroughly mixed. The reaction is started by addition of 40 μL of a 250 nM stock solution of aggrecan-IGD substrate (Invitek) and incubation at 37° C. for exact 15 min. The reaction is stopped by addition of EDTA and the samples are analysed by using aggrecanase ELISA (Invitek, InviLISA, Cat. No. 30510111) according to the protocol of the supplier. Shortly: 100 μL of each proteolytic reaction are incubated in a pre-coated micro plate for 90 min at room temperature. After 3 times washing, antibody-peroxidase conjugate is added for 90 min at room temperature. After 5 times washing, the plate is incubated with TMB solution for 3 min at room temperature. The peroxidase reaction is stopped with sulfurous acid and the absorbance is red at 450 nm. The IC 50  values are calculated from the absorbance signal corresponding to residual aggrecanase activity. 
       Example 1705 
     Assay for Determining Inhibition of MMP-3 Mediated Proteoglycan Degradation 
       [0340]    The assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl 2  and 0.05% Brij-35. Articular cartilage is isolated fresh from the first phalanges of adult cows and cut into pieces (˜3 mg). Bovine cartilage is incubated with 50 nM human MMP-3 (Chemikon, cat.# 25020461) in presence or absence of inhibitor for 24 h at 37° C. Sulfated glycosaminoglycan (aggrecan) degradation products (sGAG) are detected in supernatant, using a modification of the colorimetric DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurst et al., 2000, Arthritis &amp; Rheumatism, 43 (3), 664). 10 μL of the samples or standard are added to 190 μL of the dye reagent in microtiter plate wells, and the absorbance is measured at 525 nm immediately. All data points are performed in triplicates. 
       Example 1706 
     Assay for Determining Inhibition of MMP-3 Mediated Pro-Collagenase 3 Activation 
       [0341]    The assay for MMP-3 mediated activation of pro-collagenase 3 (pro-MMP-13) is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 and 0.05% Brij-35 (Nagase;  J. Biol. Chem.  1994 Aug. 19; 269(33):20952-7). 
         [0342]    Different concentrations of tested compounds are prepared in assay buffer in 5 μL aliquots. 10 μL of a 100 nM stock solution of trypsin-activated (Knäuper V., et al., 1996  J. Biol. Chem.  271 1544-1550) human pro-MMP-3 (Chemicon; CC1035) is added to the compound solution. To this mixture, 35 μL of a 286 nM stock solution of pro-collagenase 3 (Invitek; 30100803) is added to the mixture of enzyme and compound. The mixture is thoroughly mixed and incubated for 5 h at 37° C. Upon the completion of incubation, 10 μL of the incubation mixture is added to 50 μL assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2  and 0.05% Brij-35 and the mixture is thoroughly mixed. 
         [0343]    The assay to determine the MMP-13 activity is started by addition of 40 μL of a 10 μM stock solution of MMP-13 fluorogenic substrate (Calbiochem, Cat. No. 444235) in assay buffer comprised of 50 mM Tris, pH 7.5, 150 mM NaCl, 5 mM CaCl 2  and 0.05% Brij-35 (Knauper, V., et al., 1996 . J. Biol. Chem.  271, 1544-1550). The time-dependent increase in fluorescence is measured at 320 nm excitation and 390 nm emission by an automatic plate multireader at room temperature. The IC 50  values are calculated from the initial reaction rates.