US20100249102A1 - Heterotricyclic Metalloprotease Inhibitors - Google Patents

Heterotricyclic Metalloprotease Inhibitors Download PDF

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US20100249102A1
US20100249102A1 US12/755,326 US75532610A US2010249102A1 US 20100249102 A1 US20100249102 A1 US 20100249102A1 US 75532610 A US75532610 A US 75532610A US 2010249102 A1 US2010249102 A1 US 2010249102A1
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alkyl
aryl
cycloalkyl
heteroaryl
heterocycloalkyl
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Christian Gege
Carine Chevrier
Matthias Schneider
Harald Bluhm
Matthias Hochgürtel
Hongbo Deng
Brian M. GALLAGHER, JR.
Irving Sucholeiki
Arthur Taveras
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Alantos Pharmaceuticals Holding Inc
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Alantos Pharmaceuticals Holding Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • 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.
  • 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.
  • the ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans.
  • the ADAMTSs are extracellular, multidomain enzymes whose functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti-Inflammatory Anti-Allergy Agents 2005, 4, 251-264).
  • the mammalian MMP family has been reported to include at least 20 enzymes (Chem. Rev. 1999, 99, 2735-2776).
  • Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain.
  • MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma.
  • the principal substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).
  • the activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexed with the catalytic zinc (II) ion.
  • X-ray crystal structures of the complex between MMP-3 catalytic domain and TIMP-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.
  • MMP-3 stromelysin-1; transin-1
  • MMP-3 is another member of the MMP family (FASEB J. 1991, 5, 2145-2154).
  • Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues (Am. J. Pathol. 1989, 135, 1055-64).
  • MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers. MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may thus prevent the epidermis from healing (J. Clin. Invest. 1994, 94, 79-88).
  • MMP-3 serum protein levels are significantly elevated in patients with early and long-term rheumatoid arthritis (Arthritis Rheum. 2000, 43, 852-8) and in osteoarthritis patients (Clin. Orthop. Relat. Res. 2004, 428, 272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis (Rheumatology 2006, 45, 414-20).
  • MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatin, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, IX, X (Clin. Orthop. Relat. Res. 2004, 428, 272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity (Arthritis Res. 2001, 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).
  • MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGF ⁇ 1 from the ECM, activating TNF ⁇ , inactivating IL-1 ⁇ 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).
  • 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 & Growth Factor Rev. 2006, 17, 217-23).
  • MMP-8 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.
  • 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 & Growth Factor Rev. 2006, 17, 217-23).
  • ECM extracellular matrix
  • 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).
  • 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).
  • 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).
  • the present invention relates to a new class of azatricyclic amide containing pharmaceutical agents which inhibits metalloproteases.
  • 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.
  • the present invention provides several new classes of amide containing azatricyclic metalloprotease compounds, which are represented by the following general formula:
  • 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.
  • ocular inflammation 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'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
  • 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.
  • 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.
  • 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.
  • 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 intra
  • 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.
  • One aspect of the invention relates to a compound of Formula (I):
  • 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 heteroarylalkyl, cycloalkyl fused heteroarylalky
  • R 1 is optionally substituted one or more times, or
  • R 1 is optionally substituted by one R 16 group and optionally substituted by one or more R 9 groups;
  • 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;
  • 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) x
  • each R 4 group is optionally substituted one or more times, or
  • each R 4 group is optionally substituted by one or more R 14 groups, or
  • 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
  • R 4 groups optionally two R 4 groups together at one saturated carbon atom form ⁇ O, ⁇ S , ⁇ NR 10 or ⁇ NOR 10 ;
  • 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;
  • 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;
  • 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 11 , (C 0 -C 6 )-alkyl-NO 2 , (C 0 -C 6 )-alkyl-CN, (C 0 -C 6 )-alkyl-S(O) y R 10 , (C 0 -C 6 )-alkyl-P(O) 2 OH, (C 0 -C 6 -alkyl-S(O) y NR 10 R 11 , (C
  • each R 9 group is optionally substituted, or
  • each R 9 group is optionally substituted by one or more R 14 groups
  • 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 amino
  • 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.
  • 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 heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (i) and (i) and (i) and (i) and
  • R 17 is selected from R 1 , R 4 and R 21 ;
  • R 21 is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and
  • R 21 is optionally substituted one or more times, or
  • R 21 is optionally substituted by one or more R 9 groups
  • R 30 is selected from alkyl and (C 0 -C 6 )-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
  • 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;
  • 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
  • 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
  • L a is independently selected from CR 9 and N;
  • 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;
  • 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 10 NR 10 CO—, —CONR 10 —, —S(O) x —, —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;
  • Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected from aryl and heteroaryl,
  • 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;
  • U is selected from C(R 5 R 10 ), NR 5 , O, S, S ⁇ O and S( ⁇ O) 2 ;
  • 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 );
  • X is selected from a bond and (CR 10 R 11 ) w E(CR 10 R 11 ) w ;
  • X 1 is independently selected from O, S, NR 10 , N—CN, NCOR 10 , N—NO 2 , or N—SO 2 R 10 ;
  • g and h are independently selected from 0-2;
  • w is selected from 0-4;
  • x is selected from 0 to 2;
  • y is selected from 1 and 2;
  • the dotted line optionally represents a double bond
  • N-oxides pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof
  • 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.
  • L a is N.
  • L a is N; and L b is C.
  • the compound in another embodiment, in conjunction with any above or below embodiments, has the structure:
  • Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
  • Q′ is a fused cycloalkyl
  • Q′ is a fused heterocycloalkyl
  • Q′ is a fused heterobicycloalkyl.
  • Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
  • Q′ is a fused phenyl
  • Q′ is a fused heteroaryl
  • the compound is selected from:
  • R 8 is H
  • R 17 is selected from
  • 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 -C6)-alkyl-NR 10 CONR 11 SO 2 R 30 , (C 0 -C 6 )-
  • 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;
  • R 1 is selected from:
  • 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;
  • 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;
  • B 1 is selected from NR 10 , O and S;
  • D 2 , G 2 , L 2 , M 2 and T 2 are independently selected from CR 18 and N;
  • 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.
  • R 1 is selected from:
  • R 1 is selected from:
  • 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 12 and R 13 together form ⁇ O, ⁇ S, ⁇ NR 10 or ⁇ NOR 10 ;
  • 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;
  • 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 SO 2 R 11 , NR 10 SO 2 NR 10 R 11 , 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 ;
  • 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;
  • J and K are independently selected from CR 10 R 18 , NR 10 , O and S(O) x ;
  • a 1 is selected from NR 10 , O and S(O) x ;
  • D 2 , G 2 , J 2 , L 2 , M 2 and T 2 are independently selected from CR 18 and N.
  • R 1 is selected from:
  • R 1 is selected from:
  • 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;
  • 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 ;
  • 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;
  • L 2 , M 2 , and T 2 are independently selected from CR 18 and N;
  • D 3 , G 3 , L 3 , M 3 , and T 3 are independently selected from N, CR 18 , (i) and (ii)
  • one of L 3 , M 3 , T 3 , D 3 , and G 3 is (i) or (ii);
  • B 1 is selected from the group consisting of NR 10 , O and S(O) x ;
  • 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 .
  • R 1 is selected from:
  • R 1 is selected from:
  • R 1 is selected from:
  • the compounds in another embodiment, in conjunction with any above or below embodiments, have the structure:
  • N-oxides pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of the compound according to any of the above or below embodiments.
  • 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.
  • the disease is selected from rheumatoid arthritis, osteoarthritis, inflammation, atherosclerosis and multiple sclerosis.
  • Another aspect of the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising:
  • 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.
  • 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.
  • the metalloproteinase is selected from MMP-2, MMP-3, MMP-8, and MMP-13.
  • 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.
  • ocular inflammation 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'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
  • 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.
  • the metalloprotease mediated disease is selected from the group consisting of MMP-2, MMP-3, MMP-8 and MMP-13 mediated diseases.
  • 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.
  • 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).
  • groups halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl
  • 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.
  • 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).
  • groups halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl
  • 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.
  • alkoxy denotes an alkyl group as described above bonded through an oxygen linkage (——O——).
  • alkenyl 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.
  • 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).
  • alkynyl 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.
  • cycloalkyl 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.
  • 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.
  • bicycloalkyl 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.
  • spiroalkyl 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.
  • spiroheteroalkyl 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.
  • 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.
  • aromatic 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.
  • substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
  • 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.
  • 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,
  • 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.
  • 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.
  • heterocyclenyl may be optionally substituted by one or more substituents as defined herein.
  • the nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • “Heterocyclenyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J.
  • Exemplary monocyclic azaheterocyclenyl groups include, but are not limited to, 1,2,3,4-tetrahydrohydropyridine, 1,2-dihydropyridyl, 1,4-dihydropyridyl, 1,2,3,6-tetrahydropyridine, 1,4,5,6-tetrahydropyrimidine, 2-pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like.
  • Exemplary oxaheterocyclenyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, dihydrofuranyl, and fluorodihydrofuranyl.
  • An exemplary multicyclic oxaheterocyclenyl group is 7-oxabicyclo[2.2.1]heptenyl.
  • Heterocyclyl or “heterocycloalkyl,” denotes a non-aromatic saturated monocyclic or 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.
  • Heterocyclyl as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 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.
  • Heteroaryl denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms.
  • the “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein.
  • the designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom.
  • a nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide.
  • Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 82:5566 (1960).
  • 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,
  • 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.
  • 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.
  • 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.
  • arylalkyl denotes an aryl group as described above bonded through an alkyl, as defined above.
  • heteroarylalkyl denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
  • heterocyclylalkyl or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.
  • halogen as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
  • haloalkyl denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.
  • aminoalkyl denotes an amino group as defined above bonded through an alkyl, as defined above.
  • 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.
  • 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.
  • pharmaceutically acceptable salts refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof.
  • 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.
  • 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.
  • such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two.
  • Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • phrases “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.
  • 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.
  • 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)).
  • 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.
  • inert diluents such as celluloses, calcium or sodium carbonate, lactose, calcium or sodium phosphate
  • 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.
  • an inert solid diluent for example celluloses, lactose, calcium phosphate or kaolin
  • non-aqueous or oil medium such as glycerin, propylene glycol, polyethylene glycol, peanut oil, liquid paraffin or olive oil.
  • 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.
  • pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
  • Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol.
  • suspending agents such as sodium carboxymethylcellulose,
  • 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.
  • preservatives such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
  • coloring agents such as acetic acid, methyl and/or n-propyl p-hydroxy-benzoate
  • flavoring agents such as sucrose or saccharin.
  • sweetening agents such as sucrose or saccharin.
  • Cyclodextrins may be added as aqueous solubility enhancers.
  • Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of ⁇ -, ⁇ -, and ⁇ -cyclodextrin.
  • the amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.
  • 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.
  • the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
  • 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.
  • polymorph denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations.
  • the 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.
  • stereoisomers such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers.
  • 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.
  • 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.
  • the invention encompasses all enantiomerically-pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) and (II).
  • 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.
  • Substituted is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • a substituent is keto (i.e., ⁇ O) group, then 2 hydrogens on the atom are replaced.
  • moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted.
  • the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from:
  • 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.
  • 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.
  • R X were defined as being:
  • R X substituents may be bonded to any available ring atom.
  • R X substituents may be bonded to any available ring atom.
  • configurations such as:
  • 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.
  • 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 ⁇ M, and typically, from about 0.2 nM to about 1 ⁇ M.
  • 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 ⁇ M (Group B).
  • 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 ⁇ M, and typically, from about 10 nM to about 2 ⁇ M.
  • 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 ⁇ M (Group B).
  • 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 ⁇ M, and typically, from about 50 nM to about 2 ⁇ M.
  • 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 ⁇ M (Group B).
  • 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.
  • the compounds of Formula (I) and (II) are synthesized by the general methods shown in Scheme 1 to Scheme 3.
  • An carbonic acid and amino substituted compound e.g. 4-amino-nicotinic acid
  • is condensed e.g. EtOH/reflux
  • 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.).
  • a suitable reagent e.g. NH 4 OAc, HOAc, EtOH/80° C.
  • An ester and amino substituted compound e.g. 2-amino-benzoic acid ethyl ester
  • is condensed e.g. 4N HCl, dioxane/50° C.
  • ethyl cyanoformate as previously described e.g. in WO2005/105760, to give a 1,3-pyrimidine-4-one ethyl ester (Scheme 1).
  • An carboxamide and amino substituted compound e.g. 2-amino-benzamide
  • 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).
  • Saponification e.g. aqueous LiOH
  • 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
  • R 1 R 2 NH e.g. 6-aminomethyl-4H-benzo[1,4]oxazin-3-one
  • 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.
  • 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.
  • the Knoevenagel/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.
  • a suitable solvent e.g EtOH/50° C.
  • 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).
  • Preparative Examples are directed to intermediate compounds useful in preparing the compounds of the present invention.
  • 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 ⁇ L aliquots. 10 ⁇ L 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.
  • the assay Upon the completion of incubation, the assay is started by addition of 40 ⁇ L of a 12.5 ⁇ M 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.
  • 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 ⁇ L aliquots. 10 ⁇ L 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 ⁇ L of a 12.5 ⁇ M stock solution of NFF-3 fluorescent substrate (Calbiochem, Cat. No. 480455). 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.
  • 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 ⁇ L aliquots. 10 ⁇ L 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 ⁇ L of a 10 ⁇ M 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 an automatic plate multireader at 37° C. The IC 50 values are calculated from the initial reaction rates.
  • 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 ⁇ L aliquots. 10 ⁇ L 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 ⁇ L of a 12.5 ⁇ M 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.
  • 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 ⁇ L aliquots. 10 ⁇ L 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 ⁇ L of a 250 nM stock solution of aggrecan-IGD substrate (Invitek) and incubation at 37° C. for exact 15 min.
  • 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 ⁇ L aliquots. 10 ⁇ L of a 75 nM
  • 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 ⁇ L 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.
  • 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 are detected in supernatant, using a modification of the colorimetric DMMB (1,9-dimethylmethylene blue dye) assay (Billinghurst et al., 2000, Arthritis & Rheumatism, 43 (3), 664). 10 ⁇ L of the samples or standard are added to 190 ⁇ L of the dye reagent in microtiter plate wells, and the absorbance is measured at 525 nm immediately. All data points are performed in triplicates.
  • DMMB 1,9-dimethylmethylene blue dye
  • the assay for MMP-3 mediated activation of pro-collagenase 3 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).
  • the assay to determine the MMP-13 activity is started by addition of 40 ⁇ L of a 10 ⁇ M 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.

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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.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a continuation of U.S. patent application Ser. No. 11/986,603, filed Nov. 20, 2007, which claims the benefit of U.S. Provisional Application No. 60/860,195, filed Nov. 20, 2006, all of which are hereby incorporated by reference.
    • FIELD OF THE INVENTION
  • 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
  • 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.
  • The ADAMTSs are a group of proteases that are encoded in 19 ADAMTS genes in humans. The ADAMTSs are extracellular, multidomain enzymes whose functions include collagen processing, cleavage of the matrix proteoglycans, inhibition of angiogenesis and blood coagulation homoeostasis (Biochem. J. 2005, 386, 15-27; Arthritis Res. Ther. 2005, 7, 160-169; Curr. Med. Chem. Anti-Inflammatory Anti-Allergy Agents 2005, 4, 251-264).
  • The mammalian MMP family has been reported to include at least 20 enzymes (Chem. Rev. 1999, 99, 2735-2776). Collagenase-3 (MMP-13) is among three collagenases that have been identified. Based on identification of domain structures for individual members of the MMP family, it has been determined that the catalytic domain of the MMPs contains two zinc atoms; one of these zinc atoms performs a catalytic function and is coordinated with three histidines contained within the conserved amino acid sequence of the catalytic domain. MMP-13 is over-expressed in rheumatoid arthritis, osteoarthritis, abdominal aortic aneurysm, breast carcinoma, squamous cell carcinomas of the head and neck, and vulvar squamous cell carcinoma. The principal substrates of MMP-13 are fibrillar collagens (types I, II, III) and gelatins, proteoglycans, cytokines and other components of ECM (extracellular matrix).
  • The activation of the MMPs involves the removal of a propeptide, which features an unpaired cysteine residue complexed with the catalytic zinc (II) ion. X-ray crystal structures of the complex between MMP-3 catalytic domain and TIMP-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.
  • MMP-3 (stromelysin-1; transin-1) is another member of the MMP family (FASEB J. 1991, 5, 2145-2154). Human MMP-3 was initially isolated from cultured human synoviocytes. It is also expressed by chondrocytes and has been localized in OA cartilage and synovial tissues (Am. J. Pathol. 1989, 135, 1055-64).
  • MMP-3 is produced by basal keratinocytes in a variety of chronic ulcers. MMP-3 mRNA and Protein were detected in basal keratinocytes adjacent to but distal from the wound edge in what probably represents the sites of proliferating epidermis. MMP-3 may thus prevent the epidermis from healing (J. Clin. Invest. 1994, 94, 79-88).
  • MMP-3 serum protein levels are significantly elevated in patients with early and long-term rheumatoid arthritis (Arthritis Rheum. 2000, 43, 852-8) and in osteoarthritis patients (Clin. Orthop. Relat. Res. 2004, 428, 272-85) as well as in other inflammatory diseases like systemic lupus erythematosis and ankylosing spondylitis (Rheumatology 2006, 45, 414-20).
  • MMP-3 acts on components of the ECM as aggrecan, fibronectin, gelatin, laminin, elastin, fibrillin and others and on collagens of type III, IV, V, VII, IX, X (Clin. Orthop. Relat. Res. 2004, 428, 272-85). On collagens of type II and IX, MMP-3 exhibits telopeptidase activity (Arthritis Res. 2001, 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).
  • MMP-3 is involved in the regulation of cytokines and chemokines by releasing TGFβ1 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).
  • 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 & Growth Factor Rev. 2006, 17, 217-23).
  • 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.
  • 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 & Growth Factor Rev. 2006, 17, 217-23).
  • 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).
  • 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).
  • 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
  • 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.
  • The present invention provides several new classes of amide containing azatricyclic metalloprotease compounds, which are represented by the following general formula:
  • Figure US20100249102A1-20100930-C00001
  • wherein all variables in the preceding Formula (I) are as defined hereinbelow.
  • 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'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's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted 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's sarcoma associated virus, liver fibrosis, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, chronic periodontitis, periodontitis, peritonitis associated with continous 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.
  • 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.
  • 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.
  • 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.
  • 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
  • One aspect of the invention relates to a compound of Formula (I):
  • Figure US20100249102A1-20100930-C00002
  • wherein
  • R1 in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,
  • wherein R1 is optionally substituted one or more times, or
  • wherein R1 is optionally substituted by one R16 group and optionally substituted by one or more R9 groups;
  • R2 is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
  • R4 in each occurrence is independently selected from R10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF3, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, C(0-C6)-alkyl-S(O)xR10, C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0_C6)-alkyl-C(O)NR10SO2R11, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x-(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10-(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10-C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR10, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl,
  • wherein each R4 group is optionally substituted one or more times, or
  • wherein each R4 group is optionally substituted by one or more R14 groups, or
  • wherein optionally two R4 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 NR50 and which is optionally substituted one or more times, or
  • optionally two R4 groups together at one saturated carbon atom form ═O, ═S , ═NR10 or ═NOR10;
  • R5 is independently selected from hydrogen, alkyl, C(O)NR10R11, aryl, arylalkyl, SO2NR10R11 and C(O)OR10 wherein alkyl, aryl and arylalkyl are optionally substituted one or more times;
  • R8 is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R10 and NR10R11 wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted one or more times;
  • R9 in each occurrence is independently selected from R10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF2, CF3, OR10, SR10, COOR10, CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10 , (C 0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-heteroaryl, C(O)NR10, (C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-heteroaryl, (C0-C6)-alkyl-C(O)-NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6-alkyl-heteroaryl,
  • wherein each R9 group is optionally substituted, or
  • wherein each R9 group is optionally substituted by one or more R14 groups;
  • R10 and R11 in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R10 and R11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
  • R14 is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times.
  • R16 is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):
  • Figure US20100249102A1-20100930-C00003
  • 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;
  • R17 is selected from R1, R4 and R21;
  • R21 is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and
  • wherein R21 is optionally substituted one or more times, or
  • wherein R21 is optionally substituted by one or more R9 groups;
  • R30 is selected from alkyl and (C0-C6)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
  • R50 in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R80, C(O)NR80R81, SO2R80 and SO2NR80R81, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;
  • R80 and R81 in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R80 and R81 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)x, —NH, and —N(alkyl) and which is optionally substituted one or more times;
  • E is selected from a bond, CR10R11, O, NR5, S, S═O, S(═O)2, C(═O), N(R10)(C═O), (C═O)N(R10), N(R10)S(═O)2, S(═O)2N(R10), C═N—OR11, —C(R10R11)C(R10R11)—, —CH2—W1— and
  • Figure US20100249102A1-20100930-C00004
  • La is independently selected from CR9 and N;
  • Lb is independently selected from C and N with the proviso, that both Lb are not N, and that the bond between Lb and Lb is optionally a double bond only if both Lb are C;
  • Lc 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—, NR10 NR10CO—, —CONR10—, —S(O)x—, —SO2NR10—, —NR10SO2—, NR10SO2NR10—, —NR10CONR10—, —OC(O)NR10—, —NR10C(O(O—, which replace a corresponding number of non-adjacent carbon atoms, and wherein the hydrocarbon chain is optionally substituted one or more times;
  • Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected from aryl and heteroaryl,
  • wherein Q is optionally substituted one or more times, or
  • wherein Q is optionally substituted one or more times with R4, or
  • 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;
  • U is selected from C(R5R10), NR5, O, S, S═O and S(═O)2;
  • W1 is selected from O, NR5, S, S═O, S(═O)2, N(R10)( C═O), N(R10)S(═O)2 and S(═O)2N(R10);
  • X is selected from a bond and (CR10R11)wE(CR10R11)w;
  • X1 is independently selected from O, S, NR10, N—CN, NCOR10, N—NO2, or N—SO2R10;
  • g and h are independently selected from 0-2;
  • w is selected from 0-4;
  • x is selected from 0 to 2;
  • y is selected from 1 and 2;
  • the dotted line optionally represents a double bond; and
  • N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof
  • 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.
  • In another embodiment, in conjunction with any above or below embodiments, La is N.
  • In another embodiment, in conjunction with any above or below embodiments, La is N; and Lb is C.
  • In another embodiment, in conjunction with any above or below embodiments, the compound has the structure:
  • Figure US20100249102A1-20100930-C00005
  • wherein Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
  • In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused cycloalkyl.
  • In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heterocycloalkyl.
  • In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heterobicycloalkyl.
  • In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, aryl or heteroaryl.
  • In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused phenyl.
  • In another embodiment, in conjunction with any above or below embodiments, Q′ is a fused heteroaryl.
  • In another embodiment, in conjunction with any above or below embodiments, the compound is selected from:
  • Figure US20100249102A1-20100930-C00006
    Figure US20100249102A1-20100930-C00007
    Figure US20100249102A1-20100930-C00008
  • In another embodiment, in conjunction with any above or below embodiments, R8 is H.
  • In another embodiment, in conjunction with any above or below embodiments, R17 is selected from
  • Figure US20100249102A1-20100930-C00009
  • wherein:
  • R6 is selected from R9, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OR10 CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-heteroaryl, C(O)NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-heteroaryl, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, C(0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl, wherein each R6 group is optionally substituted by one or more R14 groups;
  • R9 is independently selected from hydrogen, alkyl, halo, CHF2, CF3, OR10, NR10R11, NO2, and CN, wherein alkyl is optionally substituted one or more times;
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00010
  • wherein:
  • R18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times;
  • R25 is selected from hydrogen, alkyl, cycloalkyl, C(O)NR10R11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
  • B1 is selected from NR10, O and S;
  • D2, G2, L2, M2 and T2 are independently selected from CR18 and N; and
  • 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.
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00011
    Figure US20100249102A1-20100930-C00012
    Figure US20100249102A1-20100930-C00013
    Figure US20100249102A1-20100930-C00014
    Figure US20100249102A1-20100930-C00015
    Figure US20100249102A1-20100930-C00016
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00017
  • wherein:
  • R12 and R13 are independently selected from hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R12 and R13 together form ═O, ═S, ═NR10 or ═NOR10;
  • R18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
  • R19 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R19 groups together at one carbon atom form ═O, ═S, ═NR10 or ═NOR10;
  • R25 is selected from hydrogen, alkyl, cycloalkyl, C(O)NR10R11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
  • J and K are independently selected from CR10R18, NR10, O and S(O)x;
  • A1 is selected from NR10, O and S(O)x; and
  • D2, G2, J2, L2, M2 and T2 are independently selected from CR18 and N.
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00018
    Figure US20100249102A1-20100930-C00019
    Figure US20100249102A1-20100930-C00020
    Figure US20100249102A1-20100930-C00021
    Figure US20100249102A1-20100930-C00022
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00023
    Figure US20100249102A1-20100930-C00024
  • wherein:
  • R18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
  • R19 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R19 groups together at one carbon atom form ═O, ═S , ═NR10 or ═NOR10;
  • R25 is selected from hydrogen, alkyl, cycloalkyl, CONR10R11 and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;
  • L2, M2, and T2 are independently selected from CR18 and N;
  • D3, G3, L3, M3, and T3 are independently selected from N, CR18, (i) and (ii)
  • Figure US20100249102A1-20100930-C00025
  • with the proviso that one of L3, M3, T3, D3, and G3 is (i) or (ii);
  • B1 is selected from the group consisting of NR10, O and S(O)x; and
  • Q2 is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R19.
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00026
    Figure US20100249102A1-20100930-C00027
    Figure US20100249102A1-20100930-C00028
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00029
    Figure US20100249102A1-20100930-C00030
    Figure US20100249102A1-20100930-C00031
    Figure US20100249102A1-20100930-C00032
  • In another embodiment, in conjunction with any above or below embodiments, R1 is selected from:
  • Figure US20100249102A1-20100930-C00033
  • In another embodiment, in conjunction with any above or below embodiments, the compounds have the structure:
  • Figure US20100249102A1-20100930-C00034
    Figure US20100249102A1-20100930-C00035
    Figure US20100249102A1-20100930-C00036
    Figure US20100249102A1-20100930-C00037
    Figure US20100249102A1-20100930-C00038
    Figure US20100249102A1-20100930-C00039
  • N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof
  • 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.
  • 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.
  • In another embodiment, in conjunction with any above or below embodiments, the disease is selected from rheumatoid arthritis, osteoarthritis, inflammation, atherosclerosis and multiple sclerosis.
  • Another aspect of the invention relates to a pharmaceutical composition comprising:
  • 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.
  • 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.
  • 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.
  • 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'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's disease, chronic bronchitis, chronic inflammation, chronic pancreatitis, chronic sinusitis, crystal induced arthritis, cystic fibrosis, delayted 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's sarcoma associated virus, lupus, malaria, meningitis, multi-organ dysfunction, necrotizing enterocolitis, osteoporosis, chronic periodontitis, periodontitis, peritonitis associated with continous 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.
  • 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.
  • 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.
  • 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.
  • The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (——COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2——CO——), substituted carbamoyl ((R10)(R11)N——CO—— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (——SH).
  • The terms “alkyl” or “alk”, as used herein alone or as part of another group, denote optionally substituted, straight and branched chain saturated hydrocarbon groups, preferably having 1 to 10 carbons in the normal chain, most preferably lower alkyl groups. Exemplary unsubstituted such groups include methyl, ethyl, propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl, hexyl, isohexyl, heptyl, 4,4-dimethylpentyl, octyl, 2,2,4-trimethylpentyl, nonyl, decyl, undecyl, dodecyl and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkenyl, alkynyl, aryl (e.g., to form a benzyl group), cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (——COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2——CO——), substituted carbamoyl ((R10)(R11)N——CO—— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (——SH).
  • The terms “lower alk” or “lower alkyl” as used herein, denote such optionally substituted groups as described above for alkyl having 1 to 4 carbon atoms in the normal chain.
  • The term “alkoxy” denotes an alkyl group as described above bonded through an oxygen linkage (——O——).
  • The term “alkenyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon double bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include ethenyl, propenyl, isobutenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (——COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2——CO——), substituted carbamoyl ((R10)(R11)N——CO—— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (——SH).
  • The term “alkynyl”, as used herein alone or as part of another group, denotes optionally substituted, straight and branched chain hydrocarbon groups containing at least one carbon to carbon triple bond in the chain, and preferably having 2 to 10 carbons in the normal chain. Exemplary unsubstituted such groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl, and the like. Exemplary substituents may include, but are not limited to, one or more of the following groups: halo, alkoxy, alkylthio, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, hydroxy or protected hydroxy, carboxyl (——COOH), alkyloxycarbonyl, alkylcarbonyloxy, alkylcarbonyl, carbamoyl (NH2——CO——), substituted carbamoyl ((R10)(R11)N——CO—— wherein R10 or R11 are as defined below, except that at least one of R10 or R11 is not hydrogen), amino, heterocyclo, mono- or dialkylamino, or thiol (——SH).
  • The term “cycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic hydrocarbon ring systems, containing one ring with 3 to 9 carbons. Exemplary unsubstituted such groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, and cyclododecyl. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • The term “bicycloalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated cyclic bridged hydrocarbon ring systems, desirably containing 2 or 3 rings and 3 to 9 carbons per ring. Exemplary unsubstituted such groups include, but are not limited to, adamantyl, bicyclo[2.2.2]octane, bicyclo[2.2.1]heptane and cubane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • The term “spiroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom. Exemplary unsubstituted such groups include, but are not limited to, spiro[3.5]nonane, spiro[4.5]decane or spiro[2.5]octane. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • The term “spiroheteroalkyl”, as used herein alone or as part of another group, denotes optionally substituted, saturated hydrocarbon ring systems, wherein two rings of 3 to 9 carbons per ring are bridged via one carbon atom and at least one carbon atom is replaced by a heteroatom independently selected from N, O and S. The nitrogen and sulfur heteroatoms may optionally be oxidized. Exemplary unsubstituted such groups include, but are not limited to, 1,3-diaza-spiro[4.5]decane-2,4-dione. Exemplary substituents include, but are not limited to, one or more alkyl groups as described above, or one or more groups described above as alkyl substituents.
  • The terms “ar” or “aryl”, as used herein alone or as part of another group, denote optionally substituted, homocyclic aromatic groups, preferably containing 1 or 2 rings and 6 to 12 ring carbons. Exemplary unsubstituted such groups include, but are not limited to, phenyl, biphenyl, and naphthyl. Exemplary substituents include, but are not limited to, one or more nitro groups, alkyl groups as described above or groups described above as alkyl substituents.
  • The term “heterocycle” or “heterocyclic system” denotes a heterocyclyl, heterocyclenyl, or heteroaryl group as described herein, which contains carbon atoms and from 1 to 4 heteroatoms independently selected from N, O and S and including any bicyclic or tricyclic group in which any of the above-defined heterocyclic rings is fused to one or more heterocycle, aryl or cycloalkyl groups. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom.
  • Examples of heterocycles include, but are not limited to, 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.
  • 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.
  • “Heterocyclenyl” denotes a non-aromatic monocyclic or multicyclic hydrocarbon ring system of about 3 to about 10 atoms, desirably about 4 to about 8 atoms, in which one or more of the carbon atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur atoms, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. Ring sizes of rings of the ring system may include 5 to 6 ring atoms. The designation of the aza, oxa or thia as a prefix before heterocyclenyl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. The heterocyclenyl may be optionally substituted by one or more substituents as defined herein. The nitrogen or sulphur atom of the heterocyclenyl may also be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. “Heterocyclenyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 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.
  • “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.
  • “Heterocyclyl” as used herein includes by way of example and not limitation those described in Paquette, Leo A.; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 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.
  • “Heteroaryl” denotes an aromatic monocyclic or multicyclic ring system of about 5 to about 10 atoms, in which one or more of the atoms in the ring system is/are hetero element(s) other than carbon, for example nitrogen, oxygen or sulfur. Ring sizes of rings of the ring system include 5 to 6 ring atoms. The “heteroaryl” may also be substituted by one or more substituents which may be the same or different, and are as defined herein. The designation of the aza, oxa or thia as a prefix before heteroaryl define that at least a nitrogen, oxygen or sulfur atom is present respectively as a ring atom. A nitrogen atom of a heteroaryl may be optionally oxidized to the corresponding N-oxide. Heteroaryl as used herein includes by way of example and not limitation those described in Paquette, Leo A. ; “Principles of Modern Heterocyclic Chemistry” (W. A. Benjamin, New York, 1968), particularly Chapters 1, 3, 4, 6, 7, and 9; “The Chemistry of Heterocyclic Compounds, A series of Monographs” (John Wiley & Sons, New York, 1950 to present), in particular Volumes 13, 14, 16, 19, and 28; and “J. Am. Chem. Soc.”, 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.
  • 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.
  • The term “amino” denotes the radical -NH2 wherein one or both of the hydrogen atoms may be replaced by an optionally substituted hydrocarbon group. Exemplary amino groups include, but are not limited to, n-butylamino, tert-butylamino, methylpropylamino and ethyldimethylamino.
  • The term “cycloalkylalkyl” denotes a cycloalkyl-alkyl group wherein a cycloalkyl as described above is bonded through an alkyl, as defined above. Cycloalkylalkyl groups may contain a lower alkyl moiety. Exemplary cycloalkylalkyl groups include, but are not limited to, cyclopropylmethyl, cyclopentylmethyl, cyclohexylmethyl, cyclopropylethyl, cyclopentylethyl, cyclohexylpropyl, cyclopropylpropyl, cyclopentylpropyl, and cyclohexylpropyl.
  • The term “arylalkyl” denotes an aryl group as described above bonded through an alkyl, as defined above.
  • The term “heteroarylalkyl” denotes a heteroaryl group as described above bonded through an alkyl, as defined above.
  • The term “heterocyclylalkyl,” or “heterocycloalkylalkyl,” denotes a heterocyclyl group as described above bonded through an alkyl, as defined above.
  • The terms “halogen”, “halo”, or “hal”, as used herein alone or as part of another group, denote chlorine, bromine, fluorine, and iodine.
  • The term “haloalkyl” denotes a halo group as described above bonded though an alkyl, as defined above. Fluoroalkyl is an exemplary group.
  • The term “aminoalkyl” denotes an amino group as defined above bonded through an alkyl, as defined above.
  • The phrase “bicyclic fused ring system wherein at least one ring is partially saturated” denotes an 8- to 13-membered fused bicyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-4 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, indanyl, tetrahydronaphthyl, tetrahydroquinolyl and benzocycloheptyl.
  • The phrase “tricyclic fused ring system wherein at least one ring is partially saturated” denotes a 9- to 18-membered fused tricyclic ring group in which at least one of the rings is non-aromatic. The ring group has carbon atoms and optionally 1-7 heteroatoms independently selected from N, O and S. Illustrative examples include, but are not limited to, fluorene, 10,11-dihydro-5H-dibenzo[a,d]cycloheptene and 2,2a,7,7a-tetrahydro-1H-cyclobuta[a]indene.
  • The term “pharmaceutically acceptable salts” refers to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. Examples therefore may be, but are not limited to, sodium, potassium, choline, lysine, arginine or N-methyl-glucamine salts, and the like.
  • The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as, but not limited to, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as, but not limited to, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Organic solvents include, but are not limited to, nonaqueous media like ethers, ethyl acetate, ethanol, isopropanol, or acetonitrile. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa., 1990, p. 1445, the disclosure of which is hereby incorporated by reference.
  • The phrase “pharmaceutically acceptable” denotes those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.
  • The phrase “pharmaceutically acceptable carrier” denotes media generally accepted in the art for the delivery of biologically active agents to mammals, e.g., humans. Such carriers are generally formulated according to a number of factors well within the purview of those of ordinary skill in the art to determine and account for. These include, without limitation: the type and nature of the active agent being formulated; the subject to which the agent-containing composition is to be administered; the intended route of administration of the composition; and, the therapeutic indication being targeted. Pharmaceutically acceptable carriers include both aqueous and non-aqueous liquid media, as well as a variety of solid and semi-solid dosage forms. Such carriers can include a number of different ingredients and additives in addition to the active agent, such additional ingredients being included in the formulation for a variety of reasons, e.g., stabilization of the active agent, well known to those of ordinary skill in the art. Non-limiting examples of a pharmaceutically acceptable carrier are hyaluronic acid and salts thereof, and microspheres (including, but not limited to poly(D,L)-lactide-co-glycolic acid copolymer (PLGA), poly(L-lactic acid) (PLA), poly(caprolactone (PCL) and bovine serum albumin (BSA)). Descriptions of suitable pharmaceutically acceptable carriers, and factors involved in their selection, are found in a variety of readily available sources, e.g., Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, the contents of which are incorporated herein by reference.
  • 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.
  • 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.
  • The compositions of the invention may also be formulated as suspensions including a compound of the present invention in admixture with at least one pharmaceutically acceptable excipient suitable for the manufacture of a suspension. In yet another embodiment, pharmaceutical compositions of the invention may be formulated as dispersible powders and granules suitable for preparation of a suspension by the addition of suitable excipients.
  • Carriers suitable for use in connection with suspensions include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gum acacia, dispersing or wetting agents such as a naturally occurring phosphatide (e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethyleneoxycethanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate); and thickening agents, such as carbomer, beeswax, hard paraffin or cetyl alcohol. The suspensions may also contain one or more preservatives such as acetic acid, methyl and/or 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.
  • Cyclodextrins may be added as aqueous solubility enhancers. Preferred cyclodextrins include hydroxypropyl, hydroxyethyl, glucosyl, maltosyl and maltotriosyl derivatives of α-, β-, and γ-cyclodextrin. The amount of solubility enhancer employed will depend on the amount of the compound of the present invention in the composition.
  • The term “formulation” denotes a product comprising the active ingredient(s) and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical formulations of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutical carrier.
  • The term “N-oxide” denotes compounds that can be obtained in a known manner by reacting a compound of the present invention including a nitrogen atom (such as in a pyridyl group) with hydrogen peroxide or a peracid, such as 3-chloroperoxy-benzoic acid, in an inert solvent, such as dichloromethane, at a temperature between about −10-80° C., desirably about 0° C.
  • The term “polymorph” denotes a form of a chemical compound in a particular crystalline arrangement. Certain polymorphs may exhibit enhanced thermodynamic stability and may be more suitable than other polymorphic forms for inclusion in pharmaceutical formulations.
  • The compounds of the invention can contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as double-bond isomers (i.e., geometric isomers), enantiomers, or diastereomers. According to the invention, the chemical structures depicted herein, and therefore the compounds of the invention, encompass all of the corresponding enantiomers and stereoisomers, that is, both the stereomerically pure form (e.g., geometrically pure, enantiomerically pure, or diastereomerically pure) and enantiomeric and stereoisomeric mixtures.
  • The term “racemic mixture” denotes a mixture that is about 50% of one enantiomer and about 50% of the corresponding enantiomer relative to all chiral centers in the molecule. Thus, the invention encompasses all enantiomerically-pure, enantiomerically-enriched, and racemic mixtures of compounds of Formulas (I) and (II).
  • 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 & Sons, Inc.), and Stereoselective Synthesis A Practical Approach, Mihaly Nogradi (1995 VCH Publishers, Inc., NY, N.Y.). Enantiomers and stereoisomers can also be obtained from stereomerically- or enantiomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • “Substituted” is intended to indicate that one or more hydrogens on the atom indicated in the expression using “substituted” is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., ═O) group, then 2 hydrogens on the atom are replaced.
  • Unless moieties of a compound of the present invention are defined as being unsubstituted, the moieties of the compound may be substituted. In addition to any substituents provided above, the moieties of the compounds of the present invention may be optionally substituted with one or more groups independently selected from:
  • C1-C4 alkyl;
  • C2-C4 alkenyl;
  • C2-C4 alkynyl;
  • CF3;
  • halo;
  • OH;
  • O—(C1-C4 alkyl);
  • OCH2F;
  • OCHF2;
  • OCF3;
  • ONO2;
  • OC(O)—(C1-C4 alkyl);
  • OC(O)—(C1-C4 alkyl);
  • OC(O)NH—(C1-C4 alkyl);
  • OC(O)N(C1-C4 alkyl)2;
  • OC(S)NH—(C1-C4 alkyl);
  • OC(S)N(C1-C4 alkyl)2;
  • SH;
  • S—(C1-C4 alkyl);
  • S(O)—(C1-C4 alkyl);
  • S(O)2—(C1-C4 alkyl);
  • SC(O)—(C1-C4 alkyl);
  • SC(O)O—(C1-C4 alkyl);
  • NH2;
  • N(H)—(C1-C4 alkyl);
  • N(C1-C4 alkyl)2;
  • N(H)C(O)—(C1-C4 alkyl);
  • N(CH3)C(O)—(C1-C4 alkyl);
  • N(H)C(O)—CF3;
  • N(CH3)C(O)—CF3;
  • N(H)C(S)—(C1-C4 alkyl);
  • N(CH3)C(S)—(C1-C4 alkyl);
  • N(H)S(O)2—(C1-C4 alkyl);
  • N(H)C(O)NH2;
  • N(H)C(O)NH—(C1-C4 alkyl);
  • N(CH3)C(O)NH—(C1-C4 alkyl);
  • N(H)C(O)N(C1-C4 alkyl)2;
  • N(CH3)C(O)N(C1-C4 alkyl)2;
  • N(H)S(O)2NH2);
  • N(H)S(O)2NH—(C1-C4 alkyl);
  • N(CH3)S(O)2NH—(C1-C4 alkyl);
  • N(H)S(O)2N(C1-C4 alkyl)2;
  • N(CH3)S(O)2N(C1-C4 alkyl)2;
  • N(H)C(O)O—(C1-C4 alkyl);
  • N(CH3)C(O)O—(C1-C4 alkyl);
  • N(H)S(O)2O—(C1-C4 alkyl);
  • N(CH3)S(O)2O—(C1-C4 alkyl);
  • N(CH3)C(S)NH—(C1-C4 alkyl);
  • N(CH3)C(S)N(C1-C4 alkyl)2;
  • N(CH3)C(S)O—(C1-C4 alkyl);
  • N(H)C(S)NH2;
  • NO2;
  • CO2H;
  • CO2—(C1-C4 alkyl);
  • C(O)N(H)OH;
  • C(O)N(CH3)OH:
  • C(O)N(CH3)OH;
  • C(O)N(CH3)O—(C1-C4 alkyl);
  • C(O)N(H)—(C1-C4 alkyl);
  • C(O)N(C1-C4 alkyl)2;
  • C(S)N(H)—(C1-C4 alkyl);
  • C(S)N(C1-C4 alkyl)2;
  • C(NH)N(H)—(C1-C4 alkyl);
  • C(NH)N(C1-C4 alkyl)2;
  • C(NCH3)N(H)—(C1-C4 alkyl);
  • C(NCH3)N(C1-C4 alkyl)2;
  • C(O)—(C1-C4 alkyl);
  • C(NH)—(C1-C4 alkyl);
  • C(NCH3)—(C1-C4 alkyl);
  • C(NOH)—(C1-C4 alkyl);
  • C(NOCH3)—(C1-C4 alkyl);
  • CN;
  • CHO;
  • CH2OH;
  • CH2O—(C1-C4 alkyl);
  • CH2NH2;
  • CH2N(H)—(C1-C4 alkyl);
  • CH2N(C1-C4 alkyl)2;
  • aryl;
  • heteroaryl;
  • cycloalkyl; and
  • heterocyclyl.
  • In some cases, a ring substituent may be shown as being connected to the ring by a bond extending from the center of the ring. The number of such substituents present on a ring is indicated in subscript by a number. Moreover, the substituent may be present on any available ring atom, the available ring atom being any ring atom which bears a hydrogen which the ring substituent may replace. For illustrative purposes, if variable RX were defined as being:
  • Figure US20100249102A1-20100930-C00040
  • this would indicate a cyclohexyl ring bearing five RX substituents. The RX substituents may be bonded to any available ring atom. For example, among the configurations encompassed by this are configurations such as:
  • Figure US20100249102A1-20100930-C00041
  • These configurations are illustrative and are not meant to limit the scope of the invention in any way.
    • Biological Activity
  • 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.
  • The heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-13 inhibition activity (IC50 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).
  • 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
  • Some heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-8 inhibition activity (IC50 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).
  • 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
  • Some heterocyclic metalloprotease inhibiting compounds of the invention have an MMP-3 inhibition activity (IC50 MMP-3) ranging from below 10 nM to about 20 μM, and typically, from about 50 nM to about 2 μM. 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).
  • 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
  • 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
  • Provided below are schemes according to which compounds of the present invention may be prepared.
  • In some embodiments the compounds of Formula (I) and (II) are synthesized by the general methods shown in Scheme 1 to Scheme 3.
  • Figure US20100249102A1-20100930-C00042
    • Route A
  • 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. NH4OAc, HOAc, EtOH/80° C.). For example, when ring Q is a pyridine ring. the compound can be obtained according this route A.
    • Route B
  • 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).
    • Route C
  • 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).
  • Figure US20100249102A1-20100930-C00043
  • 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 R1R2NH (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.
  • Figure US20100249102A1-20100930-C00044
  • 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, Et2NH, EtOH/50° C.) as previously described e.g. in J. prakt. Chem. 1973, 315, 39-43 or Monatsh. Chem. 2001, 132, 279-293.
  • The Knoevenagel/cyclisation step can be combined by stirring the ketone with ethyl cyanoacetate, sulphur and a base (e.g. Et3N) 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.
  • In compounds, where the one Lb in formula (I) is a nitrogen atom, the following procedure can be applied (Scheme 4).
  • Figure US20100249102A1-20100930-C00045
  • 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 SeO2 and then oxone).
  • 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&Sons), e.g. palladium catalyzed halogen-cyanide exchange or nucleophilic substitution.
    • Examples and Methods
  • All reagents and solvents were obtained from commercial sources and used without further purification. Proton spectra (1H-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.
  • Preparative Examples are directed to intermediate compounds useful in preparing the compounds of the present invention.
    • Preparative Example 4
  • Figure US20100249102A1-20100930-C00046
    • Step A
  • 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
  • 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.
  • TABLE I.2
    Ex. # amine product yield
    5/7
    Figure US20100249102A1-20100930-C00047
    Figure US20100249102A1-20100930-C00048
         		59% [MH]+ = 275
    5/10
    Figure US20100249102A1-20100930-C00049
    Figure US20100249102A1-20100930-C00050
         		n.d. [MH]+ = 294
    5/35
    Figure US20100249102A1-20100930-C00051
    Figure US20100249102A1-20100930-C00052
         		74% [MH]+ = 306
    5/36
    Figure US20100249102A1-20100930-C00053
    Figure US20100249102A1-20100930-C00054
         		36% [MH]+ = 322
    5/41
    Figure US20100249102A1-20100930-C00055
    Figure US20100249102A1-20100930-C00056
         		88% [MH]+ = 329
    5/43
    Figure US20100249102A1-20100930-C00057
    Figure US20100249102A1-20100930-C00058
         		46% [MH]+ = 357
    5/45
    Figure US20100249102A1-20100930-C00059
    Figure US20100249102A1-20100930-C00060
         		89% [MH]+ = 337
    5/47
    Figure US20100249102A1-20100930-C00061
    Figure US20100249102A1-20100930-C00062
         		100% [MH]+ = 293
    5/48
    Figure US20100249102A1-20100930-C00063
    Figure US20100249102A1-20100930-C00064
         		27% [MH]+ = 297
    5/49
    Figure US20100249102A1-20100930-C00065
    Figure US20100249102A1-20100930-C00066
         		100% [MH]+ = 283
    5/51
    Figure US20100249102A1-20100930-C00067
    Figure US20100249102A1-20100930-C00068
         		95% [MH]+ = 307
    5/53
    Figure US20100249102A1-20100930-C00069
    Figure US20100249102A1-20100930-C00070
         		100% [MH]+ = 297
    5/59
    Figure US20100249102A1-20100930-C00071
    Figure US20100249102A1-20100930-C00072
         		84% [MH]+ = 331
    5/60
    Figure US20100249102A1-20100930-C00073
    Figure US20100249102A1-20100930-C00074
         		96% [MH]+ = 355
    5/63
    Figure US20100249102A1-20100930-C00075
    Figure US20100249102A1-20100930-C00076
         		7% [MH]+ = 281
    5/64
    Figure US20100249102A1-20100930-C00077
    Figure US20100249102A1-20100930-C00078
         		28% [MH]+ = 394
    5/69
    Figure US20100249102A1-20100930-C00079
    Figure US20100249102A1-20100930-C00080
         		n.d. [MH]+ = 406
    5/71
    Figure US20100249102A1-20100930-C00081
    Figure US20100249102A1-20100930-C00082
         		97% [MH]+ = 351
    5/72
    Figure US20100249102A1-20100930-C00083
    Figure US20100249102A1-20100930-C00084
         		96% [MH]+ = 337
    5/73
    Figure US20100249102A1-20100930-C00085
    Figure US20100249102A1-20100930-C00086
         		35% [MH]+ = 295
    5/74
    Figure US20100249102A1-20100930-C00087
    Figure US20100249102A1-20100930-C00088
         		30% (cryst from, CH2Cl2- cyclohexane) [MH]+ = 311
    5/76
    Figure US20100249102A1-20100930-C00089
    Figure US20100249102A1-20100930-C00090
         		38% [MH]+ = 365
    5/87
    Figure US20100249102A1-20100930-C00091
    Figure US20100249102A1-20100930-C00092
         		100% [MH]+ = 351
    5/88
    Figure US20100249102A1-20100930-C00093
    Figure US20100249102A1-20100930-C00094
         		69% [MH]+ = 351
    5/89
    Figure US20100249102A1-20100930-C00095
    Figure US20100249102A1-20100930-C00096
         		n.d. [MH]+ = 323
    5/91
    Figure US20100249102A1-20100930-C00097
    Figure US20100249102A1-20100930-C00098
         		100% [MH]+ = 351
    5/95
    Figure US20100249102A1-20100930-C00099
     Synthesis US6387912
    Figure US20100249102A1-20100930-C00100
         		35% [MH]+ = 400
    5/106
    Figure US20100249102A1-20100930-C00101
    Figure US20100249102A1-20100930-C00102
         		n.d. [MH]+ = n.d.
    • Preparative Example 9
  • Figure US20100249102A1-20100930-C00103
    • Step A
  • 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
  • A solution of the intermediate from Step A above (800 mg), xantphos (36 mg), Pd2(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
  • 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.
  • TABLE I.4
    Ex. # aniline product yield
    10/4
    Figure US20100249102A1-20100930-C00104
    Figure US20100249102A1-20100930-C00105
         		10% [MH]+ = 259
    • Preparative Example 11
  • Figure US20100249102A1-20100930-C00106
    • Step A
  • 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
  • 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.
  • TABLE I.5
    Ex. # ester product yield
    12/9
    Figure US20100249102A1-20100930-C00107
    Figure US20100249102A1-20100930-C00108
         		>99% [MH]+ = 247
    12/12
    Figure US20100249102A1-20100930-C00109
    Figure US20100249102A1-20100930-C00110
         		n.d. [MH]+ = 266
    12/13
    Figure US20100249102A1-20100930-C00111
    Figure US20100249102A1-20100930-C00112
         		83% [MH]+ = 251
    12/43
    Figure US20100249102A1-20100930-C00113
    Figure US20100249102A1-20100930-C00114
         		n.d. [MH]+ = 278
    12/44
    Figure US20100249102A1-20100930-C00115
    Figure US20100249102A1-20100930-C00116
         		92% [MH]+ = 294
    12/49
    Figure US20100249102A1-20100930-C00117
    Figure US20100249102A1-20100930-C00118
         		31% [MH]+ = 301
    12/51
    Figure US20100249102A1-20100930-C00119
    Figure US20100249102A1-20100930-C00120
         		78% [MH]+ = 329
    12/54
    Figure US20100249102A1-20100930-C00121
    Figure US20100249102A1-20100930-C00122
         		56% [MH]+ = 309
    12/56
    Figure US20100249102A1-20100930-C00123
    Figure US20100249102A1-20100930-C00124
         		68% [MH]+ = 265
    12/57
    Figure US20100249102A1-20100930-C00125
    Figure US20100249102A1-20100930-C00126
         		100% [MH]+ = 269
    12/58
    Figure US20100249102A1-20100930-C00127
    Figure US20100249102A1-20100930-C00128
         		69% [MH]+ = 255
    12/60
    Figure US20100249102A1-20100930-C00129
    Figure US20100249102A1-20100930-C00130
         		84% [MH]+ = 279
    12/62
    Figure US20100249102A1-20100930-C00131
    Figure US20100249102A1-20100930-C00132
         		65% [MH]+ = 269
    12/68
    Figure US20100249102A1-20100930-C00133
    Figure US20100249102A1-20100930-C00134
         		89% [MH]+ = 303
    12/69
    Figure US20100249102A1-20100930-C00135
    Figure US20100249102A1-20100930-C00136
         		100% [MH]+ = 327
    12/73
    Figure US20100249102A1-20100930-C00137
    Figure US20100249102A1-20100930-C00138
         		100% [MH]+ = 253
    12/77
    Figure US20100249102A1-20100930-C00139
    Figure US20100249102A1-20100930-C00140
         		45% [MH]+ = 366
    12/84
    Figure US20100249102A1-20100930-C00141
    Figure US20100249102A1-20100930-C00142
         		n.d. [MH]+ = 378
    12/85
    Figure US20100249102A1-20100930-C00143
    Figure US20100249102A1-20100930-C00144
         		63% [MH]+ = 323
    12/86
    Figure US20100249102A1-20100930-C00145
    Figure US20100249102A1-20100930-C00146
         		18% [MH]+ = 309
    12/87
    Figure US20100249102A1-20100930-C00147
    Figure US20100249102A1-20100930-C00148
         		74% [MH]+ = 267
    12/89
    Figure US20100249102A1-20100930-C00149
    Figure US20100249102A1-20100930-C00150
         		93% [MH]+ = 283
    12/91
    Figure US20100249102A1-20100930-C00151
    Figure US20100249102A1-20100930-C00152
         		63% [MH]+ = 337
    12/92
    Figure US20100249102A1-20100930-C00153
    Figure US20100249102A1-20100930-C00154
         		91% [MH]+ = 323
    12/93
    Figure US20100249102A1-20100930-C00155
    Figure US20100249102A1-20100930-C00156
         		70% [MH]+ = 323
    12/94
    Figure US20100249102A1-20100930-C00157
    Figure US20100249102A1-20100930-C00158
         		21% (2 steps) [MH]+ = 295
    12/96
    Figure US20100249102A1-20100930-C00159
    Figure US20100249102A1-20100930-C00160
         		47% [MH]+ = 323
    12/97
    Figure US20100249102A1-20100930-C00161
    Figure US20100249102A1-20100930-C00162
         		68% [MH]+ = 352
    12/104
    Figure US20100249102A1-20100930-C00163
    Figure US20100249102A1-20100930-C00164
         		92% [MH]+ = 372
    • Preparative Example 13
  • Figure US20100249102A1-20100930-C00165
    • Step A
  • 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(PPh3)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 CH2Cl2/MeOH (1:1), filtered through an silica pad and concentrated to yield a yellow solid (5.68 g, 89%). [MH]+=175.
    • Step B
  • To an ice cooled solution of the title compound from Step A above (5.6 g), di-tert-butyl dicarbonate (14.06 g) and NiCl2.6H2O (1.53 g) in MeOH, NaBH4 (8.51 g 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 NaHCO3 and saturated aqueous NaCl, dried (MgSO4), concentrated to afford the title compound as an off-white solid (7.91 g, 88%). [M+Na]+=397.
    • Step C
  • 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 Et2O, filtered and dried to afford the title compound as an off-white solid (5.81 g, 96%). [M-NH3Cl]+=162.
    • Preparative Example 14
  • Figure US20100249102A1-20100930-C00166
    • Step A
  • A solution of commercially available 7-cyano-1,2,3,4-tetrahydroisoquinoline (2.75 g), K2CO3 (3.60 g) and benzylchloroformate (2.7 mL) in THF/H2O was stirred overnight and then concentrated. The residue was diluted with EtOAc, washed with 10% aqueous citric acid, saturated aqueous NaHCO3 and brine, dried (MgSO4) and concentrated. The residue was dissolved in MeOH (100 mL) and di-tert-butyl dicarbonate (7.60 g) and NiCl2.6H2O (400 mg) was added. The solution was cooled to 0° C. and NaBH4 (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 NaHCO3 and saturated aqueous NaCl, dried (MgSO4), concentrated and purified by chromatography (silica, CH2Cl2/MeOH) to afford the title compound as a colorless oil (1.81 g, 26%). [MH]+=397.
    • Preparative Example 15
  • Figure US20100249102A1-20100930-C00167
    • Step A
  • 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 NEt3 (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 NH3 in H2O (100 mL) was added. The mixture was stirred for 3 h, concentrated, slurried in H2O, 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 Et2O, filtered and dried to afford the title compound as an off-white solid (1.08 g, 92%). [M-Cl]+=258.
    • Preparative Example 16
  • Figure US20100249102A1-20100930-C00168
    • Step A
  • 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
  • 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.
  • TABLE I.6
    Ex. # Ketone product yield
    17/1
    Figure US20100249102A1-20100930-C00169
    Figure US20100249102A1-20100930-C00170
         		27% [MH]+ = 212
    17/2
    Figure US20100249102A1-20100930-C00171
    Figure US20100249102A1-20100930-C00172
         		n.d [MH]+ = 309
    17/5
    Figure US20100249102A1-20100930-C00173
    Figure US20100249102A1-20100930-C00174
         		n.d [MH]+ = n.d.
    17/7
    Figure US20100249102A1-20100930-C00175
    Figure US20100249102A1-20100930-C00176
         		93% [MH]+ = 266
    17/8
    Figure US20100249102A1-20100930-C00177
    Figure US20100249102A1-20100930-C00178
         		83% [MH]+ = 252
    17/9
    Figure US20100249102A1-20100930-C00179
    Figure US20100249102A1-20100930-C00180
         		37% [MH]+ = 210
    17/10
    Figure US20100249102A1-20100930-C00181
    Figure US20100249102A1-20100930-C00182
         		n.d. [MH]+ = 226
    17/12
    Figure US20100249102A1-20100930-C00183
    Figure US20100249102A1-20100930-C00184
         		n.d. [MH]+ = 280
    17/13
    Figure US20100249102A1-20100930-C00185
    Figure US20100249102A1-20100930-C00186
         		40% [MH]+ = 266
    17/14
    Figure US20100249102A1-20100930-C00187
    Figure US20100249102A1-20100930-C00188
         		n.d. [MH]+ = 266
    17/15
    Figure US20100249102A1-20100930-C00189
    Figure US20100249102A1-20100930-C00190
         		n.d. [MH]+ = 238
    17/17
    Figure US20100249102A1-20100930-C00191
    Figure US20100249102A1-20100930-C00192
         		41% [MH]+ = 266
    17/20
    Figure US20100249102A1-20100930-C00193
    Figure US20100249102A1-20100930-C00194
         		n.d. [MH]+ = n.d.
    • Preparative Example 18
  • Figure US20100249102A1-20100930-C00195
    • Step A
  • 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.
    • Reparative Examples 18/1 to 18/21
  • 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.
  • TABLE I.7
    Ex. # adduct product yield
    18/1
    Figure US20100249102A1-20100930-C00196
    Figure US20100249102A1-20100930-C00197
         		43% [MH]+ = 244
    18/2
    Figure US20100249102A1-20100930-C00198
    Figure US20100249102A1-20100930-C00199
         		62% (2 steps) [MH]+ = 341
    18/5
    Figure US20100249102A1-20100930-C00200
    Figure US20100249102A1-20100930-C00201
         		98% (2 steps) [MH]+ = 353
    18/7
    Figure US20100249102A1-20100930-C00202
    Figure US20100249102A1-20100930-C00203
         		82% [MH]+ = 298
    18/8
    Figure US20100249102A1-20100930-C00204
    Figure US20100249102A1-20100930-C00205
         		65% [MH]+ = 284
    18/9
    Figure US20100249102A1-20100930-C00206
    Figure US20100249102A1-20100930-C00207
         		80% [MH]+ = 242
    18/10
    Figure US20100249102A1-20100930-C00208
    Figure US20100249102A1-20100930-C00209
         		92% (2 steps) [MH]+ = 258
    18/12
    Figure US20100249102A1-20100930-C00210
    Figure US20100249102A1-20100930-C00211
         		47% (2 steps) [MH]+ = 312
    18/13
    Figure US20100249102A1-20100930-C00212
    Figure US20100249102A1-20100930-C00213
         		79% [MH]+ = 298
    18/14
    Figure US20100249102A1-20100930-C00214
    Figure US20100249102A1-20100930-C00215
         		38% (2 steps) [MH]+ = 298
    18/15
    Figure US20100249102A1-20100930-C00216
    Figure US20100249102A1-20100930-C00217
         		62% (2 steps) [MH]+ = 270
    18/17
    Figure US20100249102A1-20100930-C00218
    Figure US20100249102A1-20100930-C00219
         		61% [MH]+ = 298
    18/21
    Figure US20100249102A1-20100930-C00220
    Figure US20100249102A1-20100930-C00221
         		30% (2 steps). [MH]+ = 347
    • Preparative Example 19
  • Figure US20100249102A1-20100930-C00222
    • Step A
  • 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
  • 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
  • Figure US20100249102A1-20100930-C00223
    • Step A
  • 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
  • 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.
  • TABLE I.13
    Ex. # Educt product yield
    20/1
    Figure US20100249102A1-20100930-C00224
    Figure US20100249102A1-20100930-C00225
         		76% [MH]+ = 143
    • Example 1
  • Figure US20100249102A1-20100930-C00226
    • Step A
  • To a solution of the title compound from Preparative Example 11 above (30 mg), EDCl (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
  • Figure US20100249102A1-20100930-C00227
    • Step A
  • 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/H2O) to afford the title compound. [MH]+=305.
    • Examples 2/24-2/547
  • Following similar procedures as described in the Examples 1 (method A) or 1a (method B), except using the amines and acids indicated in Table II.1 below, the following compounds were prepared.
  • TABLE II.1
    method,
    Ex. # amine, acid product yield
    2/24
    Figure US20100249102A1-20100930-C00228
    Figure US20100249102A1-20100930-C00229
    Figure US20100249102A1-20100930-C00230
         		A, 95% [MH]+ = 407
    2/25
    Figure US20100249102A1-20100930-C00231
    Figure US20100249102A1-20100930-C00232
    Figure US20100249102A1-20100930-C00233
         		A, 26% [MH]+ = 407
    2/29
    Figure US20100249102A1-20100930-C00234
    Figure US20100249102A1-20100930-C00235
    Figure US20100249102A1-20100930-C00236
         		A, 12% [MH]+ = 426
    2/30
    Figure US20100249102A1-20100930-C00237
    Figure US20100249102A1-20100930-C00238
    Figure US20100249102A1-20100930-C00239
         		A, n.d. [MH]+ = 426
    2/33
    Figure US20100249102A1-20100930-C00240
    Figure US20100249102A1-20100930-C00241
    Figure US20100249102A1-20100930-C00242
         		A, 29% [MH]+ = 411
    2/34
    Figure US20100249102A1-20100930-C00243
    Figure US20100249102A1-20100930-C00244
    Figure US20100249102A1-20100930-C00245
         		A, 77% [MH]+ = 411
    2/52
    Figure US20100249102A1-20100930-C00246
    Figure US20100249102A1-20100930-C00247
    Figure US20100249102A1-20100930-C00248
         		A, 85% [MH]+ = 476
    2/67
    Figure US20100249102A1-20100930-C00249
    Figure US20100249102A1-20100930-C00250
    Figure US20100249102A1-20100930-C00251
         		A, 76% [MH]+ = 486
    2/89
    Figure US20100249102A1-20100930-C00252
    Figure US20100249102A1-20100930-C00253
    Figure US20100249102A1-20100930-C00254
         		A, 27% [MH]+ = 438
    2/90
    Figure US20100249102A1-20100930-C00255
    Figure US20100249102A1-20100930-C00256
    Figure US20100249102A1-20100930-C00257
         		A, 63% [MH]+ = 517
    2/94
    Figure US20100249102A1-20100930-C00258
    Figure US20100249102A1-20100930-C00259
    Figure US20100249102A1-20100930-C00260
         		A, 83% [MH]+ = 454
    2/95
    Figure US20100249102A1-20100930-C00261
    Figure US20100249102A1-20100930-C00262
    Figure US20100249102A1-20100930-C00263
         		A, 70% [MH]+ = 533
    2/103
    Figure US20100249102A1-20100930-C00264
    Figure US20100249102A1-20100930-C00265
    Figure US20100249102A1-20100930-C00266
         		A, 81% [MH]+ = 461
    2/104
    Figure US20100249102A1-20100930-C00267
    Figure US20100249102A1-20100930-C00268
    Figure US20100249102A1-20100930-C00269
         		A, 64% [MH]+ = 540
    2/107
    Figure US20100249102A1-20100930-C00270
    Figure US20100249102A1-20100930-C00271
         		A, 85% [MH]+ = 489
    2/108
    Figure US20100249102A1-20100930-C00272
    Figure US20100249102A1-20100930-C00273
    Figure US20100249102A1-20100930-C00274
         		A, quant. [MH]+ = 489
    2/113
    Figure US20100249102A1-20100930-C00275
    Figure US20100249102A1-20100930-C00276
    Figure US20100249102A1-20100930-C00277
         		A, 40% [MH]+ = 469
    2/114
    Figure US20100249102A1-20100930-C00278
    Figure US20100249102A1-20100930-C00279
    Figure US20100249102A1-20100930-C00280
         		A, 88% [MH]+ = 548
    2/117
    Figure US20100249102A1-20100930-C00281
    Figure US20100249102A1-20100930-C00282
    Figure US20100249102A1-20100930-C00283
         		A, 93% [MH]+ = 425
    2/118
    Figure US20100249102A1-20100930-C00284
    Figure US20100249102A1-20100930-C00285
    Figure US20100249102A1-20100930-C00286
         		A, 98% [MH]+ = 504
    2/119
    Figure US20100249102A1-20100930-C00287
    Figure US20100249102A1-20100930-C00288
    Figure US20100249102A1-20100930-C00289
         		A, 65% [MH]+ = 429
    2/120
    Figure US20100249102A1-20100930-C00290
    Figure US20100249102A1-20100930-C00291
    Figure US20100249102A1-20100930-C00292
         		A, 76% [MH]+ = 508
    2/121
    Figure US20100249102A1-20100930-C00293
    Figure US20100249102A1-20100930-C00294
    Figure US20100249102A1-20100930-C00295
         		A, 86% [MH]+ = 415
    2/122
    Figure US20100249102A1-20100930-C00296
    Figure US20100249102A1-20100930-C00297
    Figure US20100249102A1-20100930-C00298
         		A, 91% [MH]+ = 494
    2/125
    Figure US20100249102A1-20100930-C00299
    Figure US20100249102A1-20100930-C00300
    Figure US20100249102A1-20100930-C00301
         		A, 68% [MH]+ = 439
    2/126
    Figure US20100249102A1-20100930-C00302
    Figure US20100249102A1-20100930-C00303
    Figure US20100249102A1-20100930-C00304
         		A, 43% [MH]+ = 518
    2/129
    Figure US20100249102A1-20100930-C00305
    Figure US20100249102A1-20100930-C00306
    Figure US20100249102A1-20100930-C00307
         		A, 31% [MH]+ = 420
    2/130
    Figure US20100249102A1-20100930-C00308
    Figure US20100249102A1-20100930-C00309
    Figure US20100249102A1-20100930-C00310
         		A, 10% [MH]+ = 422
    2/131
    Figure US20100249102A1-20100930-C00311
    Figure US20100249102A1-20100930-C00312
    Figure US20100249102A1-20100930-C00313
         		A, 77% [MH]+ = 429
    2/132
    Figure US20100249102A1-20100930-C00314
    Figure US20100249102A1-20100930-C00315
    Figure US20100249102A1-20100930-C00316
         		A, 31% [MH]+ = 508
    2/143
    Figure US20100249102A1-20100930-C00317
    Figure US20100249102A1-20100930-C00318
    Figure US20100249102A1-20100930-C00319
         		A, 80% [MH]+ = 463
    2/144
    Figure US20100249102A1-20100930-C00320
    Figure US20100249102A1-20100930-C00321
    Figure US20100249102A1-20100930-C00322
         		A, 5% [MH]+ = 542
    2/145
    Figure US20100249102A1-20100930-C00323
    Figure US20100249102A1-20100930-C00324
    Figure US20100249102A1-20100930-C00325
         		A, 27% [MH]+ = 487
    2/146
    Figure US20100249102A1-20100930-C00326
    Figure US20100249102A1-20100930-C00327
    Figure US20100249102A1-20100930-C00328
         		A, 74% [MH]+ = 566
    2/152
    Figure US20100249102A1-20100930-C00329
    Figure US20100249102A1-20100930-C00330
    Figure US20100249102A1-20100930-C00331
         		A, 45% [MH]+ = 413
    2/153
    Figure US20100249102A1-20100930-C00332
    Figure US20100249102A1-20100930-C00333
    Figure US20100249102A1-20100930-C00334
         		A, 60% [MH]+ = 492
    2/166
    Figure US20100249102A1-20100930-C00335
    Figure US20100249102A1-20100930-C00336
         		A, 75% [MH]+ = 440
    2/167
    Figure US20100249102A1-20100930-C00337
    Figure US20100249102A1-20100930-C00338
    Figure US20100249102A1-20100930-C00339
         		A, 99% [MH]+ = 530
    2/168
    Figure US20100249102A1-20100930-C00340
    Figure US20100249102A1-20100930-C00341
    Figure US20100249102A1-20100930-C00342
         		A, 40% [MH]+ = 620
    2/169
    Figure US20100249102A1-20100930-C00343
    Figure US20100249102A1-20100930-C00344
    Figure US20100249102A1-20100930-C00345
         		A, 34% [MH]+ = 587
    2/170
    Figure US20100249102A1-20100930-C00346
    Figure US20100249102A1-20100930-C00347
    Figure US20100249102A1-20100930-C00348
         		A, 50% [MH]+ = 608
    2/171
    Figure US20100249102A1-20100930-C00349
    Figure US20100249102A1-20100930-C00350
    Figure US20100249102A1-20100930-C00351
         		A, 78% [MH]+ = 526
    2/172
    Figure US20100249102A1-20100930-C00352
    Figure US20100249102A1-20100930-C00353
         		A, 26% [MH]+ = 454
    2/173
    Figure US20100249102A1-20100930-C00354
    Figure US20100249102A1-20100930-C00355
    Figure US20100249102A1-20100930-C00356
         		A, 23% [MH]+ = 468
    2/174
    Figure US20100249102A1-20100930-C00357
    Figure US20100249102A1-20100930-C00358
    Figure US20100249102A1-20100930-C00359
         		A, 80% [MH]+ = 548
    2/175
    Figure US20100249102A1-20100930-C00360
    Figure US20100249102A1-20100930-C00361
    Figure US20100249102A1-20100930-C00362
         		A, 39% [MH]+ = 544
    2/176
    Figure US20100249102A1-20100930-C00363
    Figure US20100249102A1-20100930-C00364
    Figure US20100249102A1-20100930-C00365
         		A, 36% [MH]+ = 562
    2/177
    Figure US20100249102A1-20100930-C00366
    Figure US20100249102A1-20100930-C00367
    Figure US20100249102A1-20100930-C00368
         		A, 86% [MH]+ = 562
    2/178
    Figure US20100249102A1-20100930-C00369
    Figure US20100249102A1-20100930-C00370
    Figure US20100249102A1-20100930-C00371
         		A, 76% [MH]+ = 562
    2/188
    Figure US20100249102A1-20100930-C00372
    Figure US20100249102A1-20100930-C00373
    Figure US20100249102A1-20100930-C00374
         		A, n.d. [MH]+ = 538
    2/208
    Figure US20100249102A1-20100930-C00375
    Figure US20100249102A1-20100930-C00376
    Figure US20100249102A1-20100930-C00377
         		A, 25% [MH]+ = 483
    2/209
    Figure US20100249102A1-20100930-C00378
    Figure US20100249102A1-20100930-C00379
    Figure US20100249102A1-20100930-C00380
         		A, 22% [MH]+ = 562
    2/210
    Figure US20100249102A1-20100930-C00381
    Figure US20100249102A1-20100930-C00382
    Figure US20100249102A1-20100930-C00383
         		A, 7% [MH]+ = 469
    2/211
    Figure US20100249102A1-20100930-C00384
    Figure US20100249102A1-20100930-C00385
    Figure US20100249102A1-20100930-C00386
         		A, 79% [MH]+ = 427
    2/212
    Figure US20100249102A1-20100930-C00387
    Figure US20100249102A1-20100930-C00388
    Figure US20100249102A1-20100930-C00389
         		A, 87% [MH]+ = 506
    2/218
    Figure US20100249102A1-20100930-C00390
    Figure US20100249102A1-20100930-C00391
    Figure US20100249102A1-20100930-C00392
         		A, 66% [MH]+ = 443
    2/219
    Figure US20100249102A1-20100930-C00393
    Figure US20100249102A1-20100930-C00394
    Figure US20100249102A1-20100930-C00395
         		A, 56% [MH]+ = 522
    2/223
    Figure US20100249102A1-20100930-C00396
    Figure US20100249102A1-20100930-C00397
    Figure US20100249102A1-20100930-C00398
         		A, 61% [MH]+ = 478
    2/224
    Figure US20100249102A1-20100930-C00399
    Figure US20100249102A1-20100930-C00400
    Figure US20100249102A1-20100930-C00401
         		A, 58% [MH]+ = 554
    2/225
    Figure US20100249102A1-20100930-C00402
    Figure US20100249102A1-20100930-C00403
    Figure US20100249102A1-20100930-C00404
         		A, 34% [MH]+ = 482
    2/230
    Figure US20100249102A1-20100930-C00405
    Figure US20100249102A1-20100930-C00406
    Figure US20100249102A1-20100930-C00407
         		A, 48% [MH]+ = 534
    2/231
    Figure US20100249102A1-20100930-C00408
    Figure US20100249102A1-20100930-C00409
    Figure US20100249102A1-20100930-C00410
         		A, 87% [MH]+ = 496
    2/232
    Figure US20100249102A1-20100930-C00411
    Figure US20100249102A1-20100930-C00412
         		A, 70% [MH]+ = 519
    2/236
    Figure US20100249102A1-20100930-C00413
    Figure US20100249102A1-20100930-C00414
    Figure US20100249102A1-20100930-C00415
         		A, 98% [MH]+ = 497
    2/237
    Figure US20100249102A1-20100930-C00416
    Figure US20100249102A1-20100930-C00417
         		A, 78% [MH]+ = 482
    2/238
    Figure US20100249102A1-20100930-C00418
    Figure US20100249102A1-20100930-C00419
    Figure US20100249102A1-20100930-C00420
         		A, 80% [MH]+ = 582
    2/239
    Figure US20100249102A1-20100930-C00421
    Figure US20100249102A1-20100930-C00422
    Figure US20100249102A1-20100930-C00423
         		A, 79% [MH]+ = 468
    2/240
    Figure US20100249102A1-20100930-C00424
    Figure US20100249102A1-20100930-C00425
         		A, 69% [MH]+ = 468
    2/245
    Figure US20100249102A1-20100930-C00426
    Figure US20100249102A1-20100930-C00427
    Figure US20100249102A1-20100930-C00428
         		A, 26% [MH]+ = 391
    2/246
    Figure US20100249102A1-20100930-C00429
    Figure US20100249102A1-20100930-C00430
    Figure US20100249102A1-20100930-C00431
         		A, 10% [MH]+ = 391
    2/249
    Figure US20100249102A1-20100930-C00432
    Figure US20100249102A1-20100930-C00433
    Figure US20100249102A1-20100930-C00434
         		A, 67% [MH]+ = 526
    2/250
    Figure US20100249102A1-20100930-C00435
    Figure US20100249102A1-20100930-C00436
    Figure US20100249102A1-20100930-C00437
         		A, 69% [MH]+ = 526
    2/251
    Figure US20100249102A1-20100930-C00438
    Figure US20100249102A1-20100930-C00439
    Figure US20100249102A1-20100930-C00440
         		A, 90% [MH]+ = 506
    2/252
    Figure US20100249102A1-20100930-C00441
    Figure US20100249102A1-20100930-C00442
    Figure US20100249102A1-20100930-C00443
         		A, 96% [MH]+ = 483
    2/253
    Figure US20100249102A1-20100930-C00444
    Figure US20100249102A1-20100930-C00445
         		A, 16% [MH]+ = 454
    2/254
    Figure US20100249102A1-20100930-C00446
    Figure US20100249102A1-20100930-C00447
         		A, 26% [MH]+ = 468
    2/255
    Figure US20100249102A1-20100930-C00448
    Figure US20100249102A1-20100930-C00449
         		A, 25% [MH]+ = 497
    2/256
    Figure US20100249102A1-20100930-C00450
    Figure US20100249102A1-20100930-C00451
         		A, 86% [MH]+ = 525
    2/257
    Figure US20100249102A1-20100930-C00452
    Figure US20100249102A1-20100930-C00453
    Figure US20100249102A1-20100930-C00454
         		A, 85% [MH]+ = 483
    2/258
    Figure US20100249102A1-20100930-C00455
    Figure US20100249102A1-20100930-C00456
         		A, 43% [MH]+ = 454
    2/259
    Figure US20100249102A1-20100930-C00457
    Figure US20100249102A1-20100930-C00458
         		A, 20% [MH]+ = 468
    2/260
    Figure US20100249102A1-20100930-C00459
    Figure US20100249102A1-20100930-C00460
         		A, 30% [MH]+ = 482
    2/261
    Figure US20100249102A1-20100930-C00461
    Figure US20100249102A1-20100930-C00462
    Figure US20100249102A1-20100930-C00463
         		A, 14% [MH]+ = 492
    2/262
    Figure US20100249102A1-20100930-C00464
    Figure US20100249102A1-20100930-C00465
         		A, 78% [MH]+ = 454
    2/263
    Figure US20100249102A1-20100930-C00466
    Figure US20100249102A1-20100930-C00467
         		A, 60% [MH]+ = 468
    2/264
    Figure US20100249102A1-20100930-C00468
    Figure US20100249102A1-20100930-C00469
    Figure US20100249102A1-20100930-C00470
         		A, 23% [MH]+ = 455
    2/266
    Figure US20100249102A1-20100930-C00471
    Figure US20100249102A1-20100930-C00472
    Figure US20100249102A1-20100930-C00473
         		A, 95% [MH]+ = 483
    2/267
    Figure US20100249102A1-20100930-C00474
    Figure US20100249102A1-20100930-C00475
         		A, 96% [MH]+ = 468
    2/268
    Figure US20100249102A1-20100930-C00476
    Figure US20100249102A1-20100930-C00477
         		A, 57% [MH]+ = 482
    2/269
    Figure US20100249102A1-20100930-C00478
    Figure US20100249102A1-20100930-C00479
         		A, 72% [MH]+ = 496
    2/270
    Figure US20100249102A1-20100930-C00480
    Figure US20100249102A1-20100930-C00481
    Figure US20100249102A1-20100930-C00482
         		A, 85% [MH]+ = 512
    2/289
    Figure US20100249102A1-20100930-C00483
    Figure US20100249102A1-20100930-C00484
    Figure US20100249102A1-20100930-C00485
         		B, n.d. [MH]+ = 315
    2/290
    Figure US20100249102A1-20100930-C00486
    Figure US20100249102A1-20100930-C00487
    Figure US20100249102A1-20100930-C00488
         		B, n.d. [MH]+ = 343
    2/291
    Figure US20100249102A1-20100930-C00489
    Figure US20100249102A1-20100930-C00490
    Figure US20100249102A1-20100930-C00491
         		B, n.d. [MH]+ = 289
    2/292
    Figure US20100249102A1-20100930-C00492
    Figure US20100249102A1-20100930-C00493
    Figure US20100249102A1-20100930-C00494
         		B, n.d. [MH]+ = 343
    2/293
    Figure US20100249102A1-20100930-C00495
    Figure US20100249102A1-20100930-C00496
    Figure US20100249102A1-20100930-C00497
         		B, n.d. [MH]+ = 303
    2/294
    Figure US20100249102A1-20100930-C00498
    Figure US20100249102A1-20100930-C00499
    Figure US20100249102A1-20100930-C00500
         		B, n.d. [MH]+ = 277
    2/295
    Figure US20100249102A1-20100930-C00501
    Figure US20100249102A1-20100930-C00502
    Figure US20100249102A1-20100930-C00503
         		B, n.d. [MH]+ = 303
    2/296
    Figure US20100249102A1-20100930-C00504
    Figure US20100249102A1-20100930-C00505
    Figure US20100249102A1-20100930-C00506
         		B, n.d. [MH]+ = 325
    2/297
    Figure US20100249102A1-20100930-C00507
    Figure US20100249102A1-20100930-C00508
    Figure US20100249102A1-20100930-C00509
         		B, n.d. [MH]+ = 331
    2/298
    Figure US20100249102A1-20100930-C00510
    Figure US20100249102A1-20100930-C00511
    Figure US20100249102A1-20100930-C00512
         		B, n.d. [MH]+ = 334
    2/299
    Figure US20100249102A1-20100930-C00513
    Figure US20100249102A1-20100930-C00514
    Figure US20100249102A1-20100930-C00515
         		B, n.d. [MH]+ = 263
    2/300
    Figure US20100249102A1-20100930-C00516
    Figure US20100249102A1-20100930-C00517
    Figure US20100249102A1-20100930-C00518
         		B, n.d. [MH]+ = 317
    2/301
    Figure US20100249102A1-20100930-C00519
    Figure US20100249102A1-20100930-C00520
    Figure US20100249102A1-20100930-C00521
         		B, n.d. [M − TFA]+ = 306
    2/302
    Figure US20100249102A1-20100930-C00522
    Figure US20100249102A1-20100930-C00523
    Figure US20100249102A1-20100930-C00524
         		B, n.d. [MH]+ = 403
    2/303
    Figure US20100249102A1-20100930-C00525
    Figure US20100249102A1-20100930-C00526
    Figure US20100249102A1-20100930-C00527
         		B, n.d. [MH]+ = 249
    2/304
    Figure US20100249102A1-20100930-C00528
    Figure US20100249102A1-20100930-C00529
    Figure US20100249102A1-20100930-C00530
         		B, n.d. [MH]+ = 339
    2/305
    Figure US20100249102A1-20100930-C00531
    Figure US20100249102A1-20100930-C00532
    Figure US20100249102A1-20100930-C00533
         		B, n.d. [MH]+ = 357
    2/306
    Figure US20100249102A1-20100930-C00534
    Figure US20100249102A1-20100930-C00535
    Figure US20100249102A1-20100930-C00536
         		B, n.d. [M − TFA]+ = 318
    2/307
    Figure US20100249102A1-20100930-C00537
    Figure US20100249102A1-20100930-C00538
    Figure US20100249102A1-20100930-C00539
         		B, n.d. [MH]+ = 365
    2/308
    Figure US20100249102A1-20100930-C00540
    Figure US20100249102A1-20100930-C00541
    Figure US20100249102A1-20100930-C00542
         		B, n.d. [MH]+ = 292
    2/309
    Figure US20100249102A1-20100930-C00543
    Figure US20100249102A1-20100930-C00544
    Figure US20100249102A1-20100930-C00545
         		B, n.d. [M − TFA]+ = 326
    2/310
    Figure US20100249102A1-20100930-C00546
    Figure US20100249102A1-20100930-C00547
    Figure US20100249102A1-20100930-C00548
         		B, n.d. [MH]+ = 339
    2/311
    Figure US20100249102A1-20100930-C00549
    Figure US20100249102A1-20100930-C00550
    Figure US20100249102A1-20100930-C00551
         		B, n.d. [MH]+ = 339
    2/312
    Figure US20100249102A1-20100930-C00552
    Figure US20100249102A1-20100930-C00553
    Figure US20100249102A1-20100930-C00554
         		B, n.d. [MH]+ = 318
    2/313
    Figure US20100249102A1-20100930-C00555
    Figure US20100249102A1-20100930-C00556
    Figure US20100249102A1-20100930-C00557
         		B, n.d. [MH]+ = 357
    2/314
    Figure US20100249102A1-20100930-C00558
    Figure US20100249102A1-20100930-C00559
    Figure US20100249102A1-20100930-C00560
         		B, n.d. [MH]+ = 404
    2/315
    Figure US20100249102A1-20100930-C00561
    Figure US20100249102A1-20100930-C00562
    Figure US20100249102A1-20100930-C00563
         		B, n.d. [MH]+ = 409
    2/316
    Figure US20100249102A1-20100930-C00564
    Figure US20100249102A1-20100930-C00565
    Figure US20100249102A1-20100930-C00566
         		B, n.d. [MH]+ = 383
    2/317
    Figure US20100249102A1-20100930-C00567
    Figure US20100249102A1-20100930-C00568
    Figure US20100249102A1-20100930-C00569
         		B, n.d. [M − TFA]+ = 506
    2/318
    Figure US20100249102A1-20100930-C00570
    Figure US20100249102A1-20100930-C00571
    Figure US20100249102A1-20100930-C00572
         		B, n.d. [MH]+ = 383
    2/319
    Figure US20100249102A1-20100930-C00573
    Figure US20100249102A1-20100930-C00574
    Figure US20100249102A1-20100930-C00575
         		B, n.d. [MH]+ = 357
    2/320
    Figure US20100249102A1-20100930-C00576
    Figure US20100249102A1-20100930-C00577
    Figure US20100249102A1-20100930-C00578
         		B, n.d. [MH]+ = 357
    2/321
    Figure US20100249102A1-20100930-C00579
    Figure US20100249102A1-20100930-C00580
    Figure US20100249102A1-20100930-C00581
         		B, n.d. [MH]+ = 401
    2/322
    Figure US20100249102A1-20100930-C00582
    Figure US20100249102A1-20100930-C00583
    Figure US20100249102A1-20100930-C00584
         		B, n.d. [MH]+ = 365
    2/323
    Figure US20100249102A1-20100930-C00585
    Figure US20100249102A1-20100930-C00586
    Figure US20100249102A1-20100930-C00587
         		B, n.d. [MH]+ = 346
    2/324
    Figure US20100249102A1-20100930-C00588
    Figure US20100249102A1-20100930-C00589
    Figure US20100249102A1-20100930-C00590
         		B, n.d. [MH]+ = 365
    2/325
    Figure US20100249102A1-20100930-C00591
    Figure US20100249102A1-20100930-C00592
    Figure US20100249102A1-20100930-C00593
         		B, n.d. [MH]+ = 351
    2/326
    Figure US20100249102A1-20100930-C00594
    Figure US20100249102A1-20100930-C00595
    Figure US20100249102A1-20100930-C00596
         		B, n.d. [MH]+ = 351
    2/327
    Figure US20100249102A1-20100930-C00597
    Figure US20100249102A1-20100930-C00598
    Figure US20100249102A1-20100930-C00599
         		B, n.d. [MH]+ = 368
    2/328
    Figure US20100249102A1-20100930-C00600
    Figure US20100249102A1-20100930-C00601
    Figure US20100249102A1-20100930-C00602
         		B, n.d. [M − TFA]+ = 402
    2/329
    Figure US20100249102A1-20100930-C00603
    Figure US20100249102A1-20100930-C00604
    Figure US20100249102A1-20100930-C00605
         		B, n.d. [MH]+ = 368
    2/330
    Figure US20100249102A1-20100930-C00606
    Figure US20100249102A1-20100930-C00607
    Figure US20100249102A1-20100930-C00608
         		B, n.d. [MH]+ = 332
    2/331
    Figure US20100249102A1-20100930-C00609
    Figure US20100249102A1-20100930-C00610
    Figure US20100249102A1-20100930-C00611
         		B, n.d. [MH]+ = 376
    2/332
    Figure US20100249102A1-20100930-C00612
    Figure US20100249102A1-20100930-C00613
    Figure US20100249102A1-20100930-C00614
         		B, n.d. [MH]+ = 427
    2/333
    Figure US20100249102A1-20100930-C00615
    Figure US20100249102A1-20100930-C00616
    Figure US20100249102A1-20100930-C00617
         		B, n.d. [MH]+ = 381
    2/334
    Figure US20100249102A1-20100930-C00618
    Figure US20100249102A1-20100930-C00619
    Figure US20100249102A1-20100930-C00620
         		B, n.d. [MH]+ = 393
    2/335
    Figure US20100249102A1-20100930-C00621
    Figure US20100249102A1-20100930-C00622
    Figure US20100249102A1-20100930-C00623
         		B, n.d. [MH]+ = 399
    2/336
    Figure US20100249102A1-20100930-C00624
    Figure US20100249102A1-20100930-C00625
    Figure US20100249102A1-20100930-C00626
         		B, n.d. [MH]+ = 393
    2/337
    Figure US20100249102A1-20100930-C00627
    Figure US20100249102A1-20100930-C00628
    Figure US20100249102A1-20100930-C00629
         		B, n.d. [M − TFA]+ = 368
    2/338
    Figure US20100249102A1-20100930-C00630
    Figure US20100249102A1-20100930-C00631
    Figure US20100249102A1-20100930-C00632
         		B, n.d. [MH]+ = 375
    2/339
    Figure US20100249102A1-20100930-C00633
    Figure US20100249102A1-20100930-C00634
    Figure US20100249102A1-20100930-C00635
         		B, n.d. [MH]+ = 393
    2/340
    Figure US20100249102A1-20100930-C00636
    Figure US20100249102A1-20100930-C00637
    Figure US20100249102A1-20100930-C00638
         		B, n.d. [MH]+ = 343
    2/341
    Figure US20100249102A1-20100930-C00639
    Figure US20100249102A1-20100930-C00640
    Figure US20100249102A1-20100930-C00641
         		B, n.d. [MH]+ = 345
    2/342
    Figure US20100249102A1-20100930-C00642
    Figure US20100249102A1-20100930-C00643
    Figure US20100249102A1-20100930-C00644
         		B, n.d. [MH]+ = 345
    2/343
    Figure US20100249102A1-20100930-C00645
    Figure US20100249102A1-20100930-C00646
    Figure US20100249102A1-20100930-C00647
         		B, n.d. [MH]+ = 319
    2/344
    Figure US20100249102A1-20100930-C00648
    Figure US20100249102A1-20100930-C00649
    Figure US20100249102A1-20100930-C00650
         		B, n.d. [MH]+ = 331
    2/345
    Figure US20100249102A1-20100930-C00651
    Figure US20100249102A1-20100930-C00652
    Figure US20100249102A1-20100930-C00653
         		B, n.d. [M − TFA]+ = 410
    2/346
    Figure US20100249102A1-20100930-C00654
    Figure US20100249102A1-20100930-C00655
    Figure US20100249102A1-20100930-C00656
         		B, n.d. [MH]+ = 367
    2/347
    Figure US20100249102A1-20100930-C00657
    Figure US20100249102A1-20100930-C00658
    Figure US20100249102A1-20100930-C00659
         		B, n.d. [MH]+ = 353
    2/348
    Figure US20100249102A1-20100930-C00660
    Figure US20100249102A1-20100930-C00661
    Figure US20100249102A1-20100930-C00662
         		B, n.d. [MH]+ = 353
    2/349
    Figure US20100249102A1-20100930-C00663
    Figure US20100249102A1-20100930-C00664
    Figure US20100249102A1-20100930-C00665
         		B, n.d. [MH]+ = 353
    2/350
    Figure US20100249102A1-20100930-C00666
    Figure US20100249102A1-20100930-C00667
    Figure US20100249102A1-20100930-C00668
         		B, n.d. [MH]+ = 345
    2/351
    Figure US20100249102A1-20100930-C00669
    Figure US20100249102A1-20100930-C00670
    Figure US20100249102A1-20100930-C00671
         		B, n.d. [MH]+ = 319
    2/352
    Figure US20100249102A1-20100930-C00672
    Figure US20100249102A1-20100930-C00673
    Figure US20100249102A1-20100930-C00674
         		B, n.d. [MH]+ = 381
    2/353
    Figure US20100249102A1-20100930-C00675
    Figure US20100249102A1-20100930-C00676
    Figure US20100249102A1-20100930-C00677
         		B, n.d. [M − TFA]+ = 410
    2/354
    Figure US20100249102A1-20100930-C00678
    Figure US20100249102A1-20100930-C00679
    Figure US20100249102A1-20100930-C00680
         		B, n.d. [MH]+ = 365
    2/355
    Figure US20100249102A1-20100930-C00681
    Figure US20100249102A1-20100930-C00682
    Figure US20100249102A1-20100930-C00683
         		B, n.d. [M − TFA]+ = 424
    2/356
    Figure US20100249102A1-20100930-C00684
    Figure US20100249102A1-20100930-C00685
    Figure US20100249102A1-20100930-C00686
         		B, n.d. [MH]+ = 409
    2/357
    Figure US20100249102A1-20100930-C00687
    Figure US20100249102A1-20100930-C00688
    Figure US20100249102A1-20100930-C00689
         		B, n.d. [M − TFA]+ = 326
    2/358
    Figure US20100249102A1-20100930-C00690
    Figure US20100249102A1-20100930-C00691
    Figure US20100249102A1-20100930-C00692
         		B, n.d. [M − TFA]+ = 340
    2/359
    Figure US20100249102A1-20100930-C00693
    Figure US20100249102A1-20100930-C00694
    Figure US20100249102A1-20100930-C00695
         		B, n.d. [M − TFA]+ = 410
    2/360
    Figure US20100249102A1-20100930-C00696
    Figure US20100249102A1-20100930-C00697
    Figure US20100249102A1-20100930-C00698
         		B, n.d. [M − (TFA)2]+ = 423
    2/361
    Figure US20100249102A1-20100930-C00699
    Figure US20100249102A1-20100930-C00700
    Figure US20100249102A1-20100930-C00701
         		B, n.d. [MH]+ = 409
    2/362
    Figure US20100249102A1-20100930-C00702
    Figure US20100249102A1-20100930-C00703
    Figure US20100249102A1-20100930-C00704
         		B, n.d. [MH]+ = 333
    2/363
    Figure US20100249102A1-20100930-C00705
    Figure US20100249102A1-20100930-C00706
    Figure US20100249102A1-20100930-C00707
         		B, n.d. [MH]+ = 367
    2/364
    Figure US20100249102A1-20100930-C00708
    Figure US20100249102A1-20100930-C00709
    Figure US20100249102A1-20100930-C00710
         		B, n.d. [M − TFA]+ = 315
    2/365
    Figure US20100249102A1-20100930-C00711
    Figure US20100249102A1-20100930-C00712
    Figure US20100249102A1-20100930-C00713
         		B, n.d. [MH]+ = 331
    2/366
    Figure US20100249102A1-20100930-C00714
    Figure US20100249102A1-20100930-C00715
    Figure US20100249102A1-20100930-C00716
         		B, n.d. [MH]+ = 317
    2/367
    Figure US20100249102A1-20100930-C00717
    Figure US20100249102A1-20100930-C00718
    Figure US20100249102A1-20100930-C00719
         		B, n.d. [MH]+ = 410
    2/368
    Figure US20100249102A1-20100930-C00720
    Figure US20100249102A1-20100930-C00721
    Figure US20100249102A1-20100930-C00722
         		B, n.d. [M − TFA]+ = 394
    2/369
    Figure US20100249102A1-20100930-C00723
    Figure US20100249102A1-20100930-C00724
    Figure US20100249102A1-20100930-C00725
         		B, n.d. [MH]+ = 332
    2/370
    Figure US20100249102A1-20100930-C00726
    Figure US20100249102A1-20100930-C00727
    Figure US20100249102A1-20100930-C00728
         		B, n.d. [MH]+ = 374
    2/371
    Figure US20100249102A1-20100930-C00729
    Figure US20100249102A1-20100930-C00730
    Figure US20100249102A1-20100930-C00731
         		B, n.d. [MH]+ = 374
    2/372
    Figure US20100249102A1-20100930-C00732
    Figure US20100249102A1-20100930-C00733
    Figure US20100249102A1-20100930-C00734
         		B, n.d. [MH]+ = 389
    2/376
    Figure US20100249102A1-20100930-C00735
    Figure US20100249102A1-20100930-C00736
    Figure US20100249102A1-20100930-C00737
         		A, 87% [MH]+ = 532
    2/382
    Figure US20100249102A1-20100930-C00738
    Figure US20100249102A1-20100930-C00739
    Figure US20100249102A1-20100930-C00740
         		B, n.d. [MH]+ = 370
    2/383
    Figure US20100249102A1-20100930-C00741
    Figure US20100249102A1-20100930-C00742
    Figure US20100249102A1-20100930-C00743
         		B, n.d. [MH]+ = 340
    2/384
    Figure US20100249102A1-20100930-C00744
    Figure US20100249102A1-20100930-C00745
    Figure US20100249102A1-20100930-C00746
         		B, n.d. [MH]+ = 356
    2/385
    Figure US20100249102A1-20100930-C00747
    Figure US20100249102A1-20100930-C00748
    Figure US20100249102A1-20100930-C00749
         		B, n.d. [MH]+ = 348
    2/386
    Figure US20100249102A1-20100930-C00750
    Figure US20100249102A1-20100930-C00751
    Figure US20100249102A1-20100930-C00752
         		B, n.d. [MH]+ = 356
    2/387
    Figure US20100249102A1-20100930-C00753
    Figure US20100249102A1-20100930-C00754
    Figure US20100249102A1-20100930-C00755
         		B, n.d. [MH]+ = 356
    2/388
    Figure US20100249102A1-20100930-C00756
    Figure US20100249102A1-20100930-C00757
    Figure US20100249102A1-20100930-C00758
         		B, n.d. [MH]+ = 354
    2/389
    Figure US20100249102A1-20100930-C00759
    Figure US20100249102A1-20100930-C00760
    Figure US20100249102A1-20100930-C00761
         		B, n.d. [MH]+ = 384
    2/390
    Figure US20100249102A1-20100930-C00762
    Figure US20100249102A1-20100930-C00763
    Figure US20100249102A1-20100930-C00764
         		B, n.d. [MH]+ = 426
    2/391
    Figure US20100249102A1-20100930-C00765
    Figure US20100249102A1-20100930-C00766
    Figure US20100249102A1-20100930-C00767
         		B, n.d. [MH]+ = 368
    2/392
    Figure US20100249102A1-20100930-C00768
    Figure US20100249102A1-20100930-C00769
    Figure US20100249102A1-20100930-C00770
         		B, n.d. [MH]+ = 356
    2/393
    Figure US20100249102A1-20100930-C00771
    Figure US20100249102A1-20100930-C00772
    Figure US20100249102A1-20100930-C00773
         		B, n.d. [MH]+ = 356
    2/394
    Figure US20100249102A1-20100930-C00774
    Figure US20100249102A1-20100930-C00775
    Figure US20100249102A1-20100930-C00776
         		B, n.d. [MH]+ = 384
    2/395
    Figure US20100249102A1-20100930-C00777
    Figure US20100249102A1-20100930-C00778
    Figure US20100249102A1-20100930-C00779
         		B, n.d. [MH]+ = 384
    2/396
    Figure US20100249102A1-20100930-C00780
    Figure US20100249102A1-20100930-C00781
    Figure US20100249102A1-20100930-C00782
         		B, n.d. [MH]+ = 384
    2/397
    Figure US20100249102A1-20100930-C00783
    Figure US20100249102A1-20100930-C00784
    Figure US20100249102A1-20100930-C00785
         		B, n.d. [MH]+ = 356
    2/398
    Figure US20100249102A1-20100930-C00786
    Figure US20100249102A1-20100930-C00787
    Figure US20100249102A1-20100930-C00788
         		B, n.d. [MH]+ = 400
    2/399
    Figure US20100249102A1-20100930-C00789
    Figure US20100249102A1-20100930-C00790
    Figure US20100249102A1-20100930-C00791
         		B, n.d. [MH]+ = 372
    2/400
    Figure US20100249102A1-20100930-C00792
    Figure US20100249102A1-20100930-C00793
    Figure US20100249102A1-20100930-C00794
         		B, n.d. [MH]+ = 455
    2/401
    Figure US20100249102A1-20100930-C00795
    Figure US20100249102A1-20100930-C00796
    Figure US20100249102A1-20100930-C00797
         		B, n.d. [MH]+ = 384
    2/402
    Figure US20100249102A1-20100930-C00798
    Figure US20100249102A1-20100930-C00799
    Figure US20100249102A1-20100930-C00800
         		B, n.d. [MH]+ = 384
    2/403
    Figure US20100249102A1-20100930-C00801
    Figure US20100249102A1-20100930-C00802
    Figure US20100249102A1-20100930-C00803
         		B, n.d. [MH]+ = 383
    2/404
    Figure US20100249102A1-20100930-C00804
    Figure US20100249102A1-20100930-C00805
    Figure US20100249102A1-20100930-C00806
         		B, n.d. [MH]+ = 383
    2/405
    Figure US20100249102A1-20100930-C00807
    Figure US20100249102A1-20100930-C00808
    Figure US20100249102A1-20100930-C00809
         		B, n.d. [MH]+ = 340
    2/406
    Figure US20100249102A1-20100930-C00810
    Figure US20100249102A1-20100930-C00811
    Figure US20100249102A1-20100930-C00812
         		B, n.d. [MH]+ = 406
    2/407
    Figure US20100249102A1-20100930-C00813
    Figure US20100249102A1-20100930-C00814
    Figure US20100249102A1-20100930-C00815
         		B, n.d. [MH]+ = 382
    2/408
    Figure US20100249102A1-20100930-C00816
    Figure US20100249102A1-20100930-C00817
    Figure US20100249102A1-20100930-C00818
         		B, n.d. [MH]+ = 396
    2/409
    Figure US20100249102A1-20100930-C00819
    Figure US20100249102A1-20100930-C00820
    Figure US20100249102A1-20100930-C00821
         		B, n.d. [MH]+ = 383
    2/410
    Figure US20100249102A1-20100930-C00822
    Figure US20100249102A1-20100930-C00823
    Figure US20100249102A1-20100930-C00824
         		B, n.d. [MH]+ = 397
    2/411
    Figure US20100249102A1-20100930-C00825
    Figure US20100249102A1-20100930-C00826
         		B, n.d. [MH]+ = 397
    2/412
    Figure US20100249102A1-20100930-C00827
    Figure US20100249102A1-20100930-C00828
         		B, n.d. [MH]+ = 410
    2/413
    Figure US20100249102A1-20100930-C00829
    Figure US20100249102A1-20100930-C00830
    Figure US20100249102A1-20100930-C00831
         		B, n.d. [MH]+ = 450
    2/414
    Figure US20100249102A1-20100930-C00832
    Figure US20100249102A1-20100930-C00833
         		B, n.d. [MH]+ = 478
    2/415
    Figure US20100249102A1-20100930-C00834
    Figure US20100249102A1-20100930-C00835
    Figure US20100249102A1-20100930-C00836
         		B, n.d. [MH]+ = 394
    2/416
    Figure US20100249102A1-20100930-C00837
    Figure US20100249102A1-20100930-C00838
    Figure US20100249102A1-20100930-C00839
         		B, n.d. [MH]+ = 464
    2/417
    Figure US20100249102A1-20100930-C00840
    Figure US20100249102A1-20100930-C00841
    Figure US20100249102A1-20100930-C00842
         		B, n.d. [MH]+ = 468
    2/418
    Figure US20100249102A1-20100930-C00843
    Figure US20100249102A1-20100930-C00844
    Figure US20100249102A1-20100930-C00845
         		B, n.d. [MH]+ = 482
    2/419
    Figure US20100249102A1-20100930-C00846
    Figure US20100249102A1-20100930-C00847
    Figure US20100249102A1-20100930-C00848
         		B, n.d. [MH]+ = 482
    2/420
    Figure US20100249102A1-20100930-C00849
    Figure US20100249102A1-20100930-C00850
    Figure US20100249102A1-20100930-C00851
         		B, n.d. [MH]+ = 416
    2/421
    Figure US20100249102A1-20100930-C00852
    Figure US20100249102A1-20100930-C00853
    Figure US20100249102A1-20100930-C00854
         		B, n.d. [MH]+ = 490
    2/422
    Figure US20100249102A1-20100930-C00855
    Figure US20100249102A1-20100930-C00856
    Figure US20100249102A1-20100930-C00857
         		B, n.d. [MH]+ = 372
    2/423
    Figure US20100249102A1-20100930-C00858
    Figure US20100249102A1-20100930-C00859
    Figure US20100249102A1-20100930-C00860
         		B, n.d. [MH]+ = 351
    2/424
    Figure US20100249102A1-20100930-C00861
    Figure US20100249102A1-20100930-C00862
    Figure US20100249102A1-20100930-C00863
         		B, n.d. [M − TFA]+ = 368
    2/425
    Figure US20100249102A1-20100930-C00864
    Figure US20100249102A1-20100930-C00865
    Figure US20100249102A1-20100930-C00866
         		B, n.d. [MH]+ = 390
    2/426
    Figure US20100249102A1-20100930-C00867
    Figure US20100249102A1-20100930-C00868
    Figure US20100249102A1-20100930-C00869
         		B, n.d. [MH]+ = 412
    2/427
    Figure US20100249102A1-20100930-C00870
    Figure US20100249102A1-20100930-C00871
    Figure US20100249102A1-20100930-C00872
         		B, n.d. [MH]+ = 412
    2/428
    Figure US20100249102A1-20100930-C00873
    Figure US20100249102A1-20100930-C00874
    Figure US20100249102A1-20100930-C00875
         		B, n.d. [MH]+ = 384
    2/429
    Figure US20100249102A1-20100930-C00876
    Figure US20100249102A1-20100930-C00877
    Figure US20100249102A1-20100930-C00878
         		B, n.d. [MH]+ = 400
    2/430
    Figure US20100249102A1-20100930-C00879
    Figure US20100249102A1-20100930-C00880
    Figure US20100249102A1-20100930-C00881
         		B, n.d. [MH]+ = 400
    2/431
    Figure US20100249102A1-20100930-C00882
    Figure US20100249102A1-20100930-C00883
    Figure US20100249102A1-20100930-C00884
         		B, n.d. [MH]+ = 388
    2/432
    Figure US20100249102A1-20100930-C00885
    Figure US20100249102A1-20100930-C00886
    Figure US20100249102A1-20100930-C00887
         		B, n.d. [MH]+ = 368
    2/433
    Figure US20100249102A1-20100930-C00888
    Figure US20100249102A1-20100930-C00889
    Figure US20100249102A1-20100930-C00890
         		B, n.d. [MH]+ = 378
    2/434
    Figure US20100249102A1-20100930-C00891
    Figure US20100249102A1-20100930-C00892
    Figure US20100249102A1-20100930-C00893
         		B, n.d. [MH]+ = 342
    2/435
    Figure US20100249102A1-20100930-C00894
    Figure US20100249102A1-20100930-C00895
    Figure US20100249102A1-20100930-C00896
         		B, n.d. [MH]+ = 420/422
    2/436
    Figure US20100249102A1-20100930-C00897
    Figure US20100249102A1-20100930-C00898
    Figure US20100249102A1-20100930-C00899
         		B, n.d. [MH]+ = 425
    2/437
    Figure US20100249102A1-20100930-C00900
    Figure US20100249102A1-20100930-C00901
    Figure US20100249102A1-20100930-C00902
         		B, n.d. [MH]+ = 395
    2/438
    Figure US20100249102A1-20100930-C00903
    Figure US20100249102A1-20100930-C00904
    Figure US20100249102A1-20100930-C00905
         		B, n.d. [MH]+ = 402
    2/439
    Figure US20100249102A1-20100930-C00906
    Figure US20100249102A1-20100930-C00907
    Figure US20100249102A1-20100930-C00908
         		B, n.d. [MH]+ = 412
    2/440
    Figure US20100249102A1-20100930-C00909
    Figure US20100249102A1-20100930-C00910
    Figure US20100249102A1-20100930-C00911
         		B, n.d. [M − TFA]+ = 365
    2/441
    Figure US20100249102A1-20100930-C00912
    Figure US20100249102A1-20100930-C00913
    Figure US20100249102A1-20100930-C00914
         		B, n.d. [MH]+ = 392
    2/442
    Figure US20100249102A1-20100930-C00915
    Figure US20100249102A1-20100930-C00916
    Figure US20100249102A1-20100930-C00917
         		B, n.d. [MH]+ = 392
    2/443
    Figure US20100249102A1-20100930-C00918
    Figure US20100249102A1-20100930-C00919
    Figure US20100249102A1-20100930-C00920
         		B, n.d. [MH]+ = 351
    2/444
    Figure US20100249102A1-20100930-C00921
    Figure US20100249102A1-20100930-C00922
    Figure US20100249102A1-20100930-C00923
         		B, n.d. [MH]+ = 388
    2/445
    Figure US20100249102A1-20100930-C00924
    Figure US20100249102A1-20100930-C00925
    Figure US20100249102A1-20100930-C00926
         		B, n.d. [MH]+ = 404
    2/446
    Figure US20100249102A1-20100930-C00927
    Figure US20100249102A1-20100930-C00928
    Figure US20100249102A1-20100930-C00929
         		B, n.d. [MH]+ = 455
    2/447
    Figure US20100249102A1-20100930-C00930
    Figure US20100249102A1-20100930-C00931
    Figure US20100249102A1-20100930-C00932
         		B, n.d. [MH]+ = 384
    2/448
    Figure US20100249102A1-20100930-C00933
    Figure US20100249102A1-20100930-C00934
    Figure US20100249102A1-20100930-C00935
         		B, n.d. [MH]+ = 419
    2/449
    Figure US20100249102A1-20100930-C00936
    Figure US20100249102A1-20100930-C00937
    Figure US20100249102A1-20100930-C00938
         		B, n.d. [MH]+ = 384
    2/450
    Figure US20100249102A1-20100930-C00939
    Figure US20100249102A1-20100930-C00940
    Figure US20100249102A1-20100930-C00941
         		B, n.d. [M − TFA]+ = 357
    2/451
    Figure US20100249102A1-20100930-C00942
    Figure US20100249102A1-20100930-C00943
         		B, n.d. [MH]+ = 294
    2/452
    Figure US20100249102A1-20100930-C00944
    Figure US20100249102A1-20100930-C00945
    Figure US20100249102A1-20100930-C00946
         		B, n.d. [MH]+ = 360
    2/453
    Figure US20100249102A1-20100930-C00947
    Figure US20100249102A1-20100930-C00948
    Figure US20100249102A1-20100930-C00949
         		B, n.d. [MH]+ = 306
    2/454
    Figure US20100249102A1-20100930-C00950
    Figure US20100249102A1-20100930-C00951
    Figure US20100249102A1-20100930-C00952
         		B, n.d. [MH]+ = 462
    2/455
    Figure US20100249102A1-20100930-C00953
    Figure US20100249102A1-20100930-C00954
    Figure US20100249102A1-20100930-C00955
         		B, n.d. [M − TFA]+ = 347
    2/456
    Figure US20100249102A1-20100930-C00956
    Figure US20100249102A1-20100930-C00957
    Figure US20100249102A1-20100930-C00958
         		B, n.d. [MH]+ = 306
    2/457
    Figure US20100249102A1-20100930-C00959
    Figure US20100249102A1-20100930-C00960
    Figure US20100249102A1-20100930-C00961
         		B, n.d. [MH]+ = 370
    2/458
    Figure US20100249102A1-20100930-C00962
    Figure US20100249102A1-20100930-C00963
    Figure US20100249102A1-20100930-C00964
         		B, n.d. [MH]+ = 320
    2/459
    Figure US20100249102A1-20100930-C00965
    Figure US20100249102A1-20100930-C00966
    Figure US20100249102A1-20100930-C00967
         		B, n.d. [MH]+ = 280
    2/460
    Figure US20100249102A1-20100930-C00968
    Figure US20100249102A1-20100930-C00969
    Figure US20100249102A1-20100930-C00970
         		B, n.d. [MH]+ = 446
    2/461
    Figure US20100249102A1-20100930-C00971
    Figure US20100249102A1-20100930-C00972
    Figure US20100249102A1-20100930-C00973
         		B, n.d. [MH]+ = 320
    2/462
    Figure US20100249102A1-20100930-C00974
    Figure US20100249102A1-20100930-C00975
    Figure US20100249102A1-20100930-C00976
         		B, n.d. [MH]+ = 320
    2/463
    Figure US20100249102A1-20100930-C00977
    Figure US20100249102A1-20100930-C00978
    Figure US20100249102A1-20100930-C00979
         		B, n.d. [MH]+ = 330
    2/464
    Figure US20100249102A1-20100930-C00980
    Figure US20100249102A1-20100930-C00981
    Figure US20100249102A1-20100930-C00982
         		B, n.d. [MH]+ = 320
    2/465
    Figure US20100249102A1-20100930-C00983
    Figure US20100249102A1-20100930-C00984
    Figure US20100249102A1-20100930-C00985
         		B, n.d. [MH]+ = 394
    2/466
    Figure US20100249102A1-20100930-C00986
    Figure US20100249102A1-20100930-C00987
    Figure US20100249102A1-20100930-C00988
         		B, n.d. [MH]+ = 419
    2/467
    Figure US20100249102A1-20100930-C00989
    Figure US20100249102A1-20100930-C00990
    Figure US20100249102A1-20100930-C00991
         		B, n.d. [MH]+ = 308
    2/468
    Figure US20100249102A1-20100930-C00992
    Figure US20100249102A1-20100930-C00993
    Figure US20100249102A1-20100930-C00994
         		B, n.d. [MH]+ = 364
    2/469
    Figure US20100249102A1-20100930-C00995
    Figure US20100249102A1-20100930-C00996
    Figure US20100249102A1-20100930-C00997
         		B, n.d. [MH]+ = 376
    2/470
    Figure US20100249102A1-20100930-C00998
    Figure US20100249102A1-20100930-C00999
    Figure US20100249102A1-20100930-C01000
         		B, n.d. [MH]+ = 337
    2/471
    Figure US20100249102A1-20100930-C01001
    Figure US20100249102A1-20100930-C01002
    Figure US20100249102A1-20100930-C01003
         		B, n.d. [MH]+ = 405
    2/472
    Figure US20100249102A1-20100930-C01004
    Figure US20100249102A1-20100930-C01005
    Figure US20100249102A1-20100930-C01006
         		B, n.d. [MH]+ = 418/420
    2/473
    Figure US20100249102A1-20100930-C01007
    Figure US20100249102A1-20100930-C01008
    Figure US20100249102A1-20100930-C01009
         		B, n.d. [M − TFA]+ = 328
    2/474
    Figure US20100249102A1-20100930-C01010
    Figure US20100249102A1-20100930-C01011
    Figure US20100249102A1-20100930-C01012
         		B, n.d. [MH]+ = 294
    2/475
    Figure US20100249102A1-20100930-C01013
    Figure US20100249102A1-20100930-C01014
    Figure US20100249102A1-20100930-C01015
         		B, n.d. [MH]+ = 322
    2/476
    Figure US20100249102A1-20100930-C01016
    Figure US20100249102A1-20100930-C01017
    Figure US20100249102A1-20100930-C01018
         		B, n.d. [MH]+ = 418/420
    2/477
    Figure US20100249102A1-20100930-C01019
    Figure US20100249102A1-20100930-C01020
    Figure US20100249102A1-20100930-C01021
         		B, n.d. [M − TFA]+ = 407
    2/478
    Figure US20100249102A1-20100930-C01022
    Figure US20100249102A1-20100930-C01023
    Figure US20100249102A1-20100930-C01024
         		B, n.d. [M − TFA]+ = 321
    2/479
    Figure US20100249102A1-20100930-C01025
    Figure US20100249102A1-20100930-C01026
    Figure US20100249102A1-20100930-C01027
         		B, n.d. [MH]+ = 294
    2/480
    Figure US20100249102A1-20100930-C01028
    Figure US20100249102A1-20100930-C01029
    Figure US20100249102A1-20100930-C01030
         		B, n.d. [MH]+ = 274
    2/481
    Figure US20100249102A1-20100930-C01031
    Figure US20100249102A1-20100930-C01032
    Figure US20100249102A1-20100930-C01033
         		B, n.d. [MH]+ = 368
    2/482
    Figure US20100249102A1-20100930-C01034
    Figure US20100249102A1-20100930-C01035
    Figure US20100249102A1-20100930-C01036
         		B, n.d. [MH]+ = 386
    2/483
    Figure US20100249102A1-20100930-C01037
    Figure US20100249102A1-20100930-C01038
    Figure US20100249102A1-20100930-C01039
         		B, n.d. [M − TFA]+ = 452
    2/484
    Figure US20100249102A1-20100930-C01040
    Figure US20100249102A1-20100930-C01041
    Figure US20100249102A1-20100930-C01042
         		B, n.d. [MH]+ = 466
    2/485
    Figure US20100249102A1-20100930-C01043
    Figure US20100249102A1-20100930-C01044
    Figure US20100249102A1-20100930-C01045
         		B, n.d. [MH]+ = 320
    2/486
    Figure US20100249102A1-20100930-C01046
    Figure US20100249102A1-20100930-C01047
    Figure US20100249102A1-20100930-C01048
         		B, n.d. [M − TFA]+ = 411
    2/487
    Figure US20100249102A1-20100930-C01049
    Figure US20100249102A1-20100930-C01050
    Figure US20100249102A1-20100930-C01051
         		B, n.d. [M − TFA]+ = 411
    2/488
    Figure US20100249102A1-20100930-C01052
    Figure US20100249102A1-20100930-C01053
    Figure US20100249102A1-20100930-C01054
         		B, n.d. [MH]+ = 404/406
    2/489
    Figure US20100249102A1-20100930-C01055
    Figure US20100249102A1-20100930-C01056
    Figure US20100249102A1-20100930-C01057
         		B, n.d. [MH]+ = 348
    2/490
    Figure US20100249102A1-20100930-C01058
    Figure US20100249102A1-20100930-C01059
    Figure US20100249102A1-20100930-C01060
         		B, n.d. [MH]+ = 315
    2/491
    Figure US20100249102A1-20100930-C01061
    Figure US20100249102A1-20100930-C01062
    Figure US20100249102A1-20100930-C01063
         		B, n.d. [M − TFA]+ = 355
    2/492
    Figure US20100249102A1-20100930-C01064
    Figure US20100249102A1-20100930-C01065
    Figure US20100249102A1-20100930-C01066
         		B, n.d. [MH]+ = 292
    2/493
    Figure US20100249102A1-20100930-C01067
    Figure US20100249102A1-20100930-C01068
    Figure US20100249102A1-20100930-C01069
         		B, n.d. [MH]+ = 368
    2/494
    Figure US20100249102A1-20100930-C01070
    Figure US20100249102A1-20100930-C01071
    Figure US20100249102A1-20100930-C01072
         		B, n.d. [MH]+ = 462
    2/495
    Figure US20100249102A1-20100930-C01073
    Figure US20100249102A1-20100930-C01074
    Figure US20100249102A1-20100930-C01075
         		B, n.d. [MH]+ = 422/424
    2/496
    Figure US20100249102A1-20100930-C01076
    Figure US20100249102A1-20100930-C01077
    Figure US20100249102A1-20100930-C01078
         		B, n.d. [MH]+ = 342
    2/497
    Figure US20100249102A1-20100930-C01079
    Figure US20100249102A1-20100930-C01080
    Figure US20100249102A1-20100930-C01081
         		B, n.d. [MH]+ = 399
    2/498
    Figure US20100249102A1-20100930-C01082
    Figure US20100249102A1-20100930-C01083
    Figure US20100249102A1-20100930-C01084
         		B, n.d. [MH]+ = 362
    2/499
    Figure US20100249102A1-20100930-C01085
    Figure US20100249102A1-20100930-C01086
    Figure US20100249102A1-20100930-C01087
         		B, n.d. [MH]+ = 362
    2/500
    Figure US20100249102A1-20100930-C01088
    Figure US20100249102A1-20100930-C01089
    Figure US20100249102A1-20100930-C01090
         		B, n.d. [MH]+ = 306
    2/501
    Figure US20100249102A1-20100930-C01091
    Figure US20100249102A1-20100930-C01092
    Figure US20100249102A1-20100930-C01093
         		B, n.d. [MH]+ = 306
    2/502
    Figure US20100249102A1-20100930-C01094
    Figure US20100249102A1-20100930-C01095
    Figure US20100249102A1-20100930-C01096
         		B, n.d. [MH]+ = 292
    2/503
    Figure US20100249102A1-20100930-C01097
    Figure US20100249102A1-20100930-C01098
    Figure US20100249102A1-20100930-C01099
         		B, n.d. [MH]+ = 292
    2/504
    Figure US20100249102A1-20100930-C01100
    Figure US20100249102A1-20100930-C01101
    Figure US20100249102A1-20100930-C01102
         		B, n.d. [M − TFA]+ = 375
    2/505
    Figure US20100249102A1-20100930-C01103
    Figure US20100249102A1-20100930-C01104
    Figure US20100249102A1-20100930-C01105
         		B, n.d. [M − TFA]+ = 319
    2/506
    Figure US20100249102A1-20100930-C01106
    Figure US20100249102A1-20100930-C01107
    Figure US20100249102A1-20100930-C01108
         		B, n.d. [MH]+ = 447
    2/507
    Figure US20100249102A1-20100930-C01109
    Figure US20100249102A1-20100930-C01110
    Figure US20100249102A1-20100930-C01111
         		B, n.d. [M − TFA]+ = 333
    2/508
    Figure US20100249102A1-20100930-C01112
    Figure US20100249102A1-20100930-C01113
    Figure US20100249102A1-20100930-C01114
         		B, n.d. [MH]+ = 390
    2/509
    Figure US20100249102A1-20100930-C01115
    Figure US20100249102A1-20100930-C01116
    Figure US20100249102A1-20100930-C01117
         		B, n.d. [M − TFA]+ = 423
    2/510
    Figure US20100249102A1-20100930-C01118
    Figure US20100249102A1-20100930-C01119
    Figure US20100249102A1-20100930-C01120
         		B, n.d. [MH]+ = 336
    2/511
    Figure US20100249102A1-20100930-C01121
    Figure US20100249102A1-20100930-C01122
    Figure US20100249102A1-20100930-C01123
         		B, n.d. [MH]+ = 383
    2/512
    Figure US20100249102A1-20100930-C01124
    Figure US20100249102A1-20100930-C01125
    Figure US20100249102A1-20100930-C01126
         		B, n.d. [MH]+ = 383
    2/513
    Figure US20100249102A1-20100930-C01127
    Figure US20100249102A1-20100930-C01128
    Figure US20100249102A1-20100930-C01129
         		B, n.d. [MH]+ = 333
    2/514
    Figure US20100249102A1-20100930-C01130
    Figure US20100249102A1-20100930-C01131
    Figure US20100249102A1-20100930-C01132
         		B, n.d. [MH]+ = 358
    2/515
    Figure US20100249102A1-20100930-C01133
    Figure US20100249102A1-20100930-C01134
    Figure US20100249102A1-20100930-C01135
         		B, n.d. [MH]+ = 433
    2/516
    Figure US20100249102A1-20100930-C01136
    Figure US20100249102A1-20100930-C01137
    Figure US20100249102A1-20100930-C01138
         		B, n.d. [MH]+ = 304
    2/517
    Figure US20100249102A1-20100930-C01139
    Figure US20100249102A1-20100930-C01140
    Figure US20100249102A1-20100930-C01141
         		B, n.d. [MH]+ = 318
    2/518
    Figure US20100249102A1-20100930-C01142
    Figure US20100249102A1-20100930-C01143
    Figure US20100249102A1-20100930-C01144
         		B, n.d. [M − TFA]+ = 345
    2/519
    Figure US20100249102A1-20100930-C01145
    Figure US20100249102A1-20100930-C01146
    Figure US20100249102A1-20100930-C01147
         		B, n.d. [M − TFA]+ = 328
    2/520
    Figure US20100249102A1-20100930-C01148
    Figure US20100249102A1-20100930-C01149
    Figure US20100249102A1-20100930-C01150
         		B, n.d. [MH]+ = 447
    2/521
    Figure US20100249102A1-20100930-C01151
    Figure US20100249102A1-20100930-C01152
    Figure US20100249102A1-20100930-C01153
         		B, n.d. [M − TFA]+ = 330
    2/522
    Figure US20100249102A1-20100930-C01154
    Figure US20100249102A1-20100930-C01155
    Figure US20100249102A1-20100930-C01156
         		B, n.d. [MH]+ = 382
    2/523
    Figure US20100249102A1-20100930-C01157
    Figure US20100249102A1-20100930-C01158
    Figure US20100249102A1-20100930-C01159
         		B, n.d. [MH]+ = 410
    2/524
    Figure US20100249102A1-20100930-C01160
    Figure US20100249102A1-20100930-C01161
    Figure US20100249102A1-20100930-C01162
         		B, n.d. [MH]+ = 410
    2/525
    Figure US20100249102A1-20100930-C01163
    Figure US20100249102A1-20100930-C01164
    Figure US20100249102A1-20100930-C01165
         		B, n.d. [MH]+ = 410
    2/526
    Figure US20100249102A1-20100930-C01166
    Figure US20100249102A1-20100930-C01167
    Figure US20100249102A1-20100930-C01168
         		B, n.d. [MH]+ = 390
    2/527
    Figure US20100249102A1-20100930-C01169
    Figure US20100249102A1-20100930-C01170
    Figure US20100249102A1-20100930-C01171
         		B, n.d. [M − (TFA)2]+ = 396
    2/528
    Figure US20100249102A1-20100930-C01172
    Figure US20100249102A1-20100930-C01173
    Figure US20100249102A1-20100930-C01174
         		B, n.d. [M − (TFA)2]+ = 428
    2/529
    Figure US20100249102A1-20100930-C01175
    Figure US20100249102A1-20100930-C01176
    Figure US20100249102A1-20100930-C01177
         		B, n.d. [M − (TFA)2]+ = 412
    2/530
    Figure US20100249102A1-20100930-C01178
    Figure US20100249102A1-20100930-C01179
    Figure US20100249102A1-20100930-C01180
         		B, n.d. [MH]+ = 419
    2/531
    Figure US20100249102A1-20100930-C01181
    Figure US20100249102A1-20100930-C01182
    Figure US20100249102A1-20100930-C01183
         		B, n.d. [MH]+ = 358
    2/532
    Figure US20100249102A1-20100930-C01184
    Figure US20100249102A1-20100930-C01185
    Figure US20100249102A1-20100930-C01186
         		B, n.d. [MH]+ = 358
    2/533
    Figure US20100249102A1-20100930-C01187
    Figure US20100249102A1-20100930-C01188
    Figure US20100249102A1-20100930-C01189
         		B, n.d. [MH]+ = 346
    2/534
    Figure US20100249102A1-20100930-C01190
    Figure US20100249102A1-20100930-C01191
    Figure US20100249102A1-20100930-C01192
         		B, n.d. [MH]+ = 358
    2/535
    Figure US20100249102A1-20100930-C01193
    Figure US20100249102A1-20100930-C01194
    Figure US20100249102A1-20100930-C01195
         		B, n.d. [MH]+ = 340
    2/536
    Figure US20100249102A1-20100930-C01196
    Figure US20100249102A1-20100930-C01197
    Figure US20100249102A1-20100930-C01198
         		B, n.d. [M − TFA]+ = 349
    2/537
    Figure US20100249102A1-20100930-C01199
    Figure US20100249102A1-20100930-C01200
    Figure US20100249102A1-20100930-C01201
         		B, n.d. [MH]+ = 415
    2/538
    Figure US20100249102A1-20100930-C01202
    Figure US20100249102A1-20100930-C01203
    Figure US20100249102A1-20100930-C01204
         		B, n.d. [MH]+ = 459
    2/539
    Figure US20100249102A1-20100930-C01205
    Figure US20100249102A1-20100930-C01206
    Figure US20100249102A1-20100930-C01207
         		B, n.d. [MH]+ = 411
    2/540
    Figure US20100249102A1-20100930-C01208
    Figure US20100249102A1-20100930-C01209
    Figure US20100249102A1-20100930-C01210
         		B, n.d. [MH]+ = 415
    2/541
    Figure US20100249102A1-20100930-C01211
    Figure US20100249102A1-20100930-C01212
    Figure US20100249102A1-20100930-C01213
         		B, n.d. [MH]+ = 433
    2/542
    Figure US20100249102A1-20100930-C01214
    Figure US20100249102A1-20100930-C01215
    Figure US20100249102A1-20100930-C01216
         		B, n.d. [MH]+ = 411
    2/543
    Figure US20100249102A1-20100930-C01217
    Figure US20100249102A1-20100930-C01218
    Figure US20100249102A1-20100930-C01219
         		B, n.d. [MH]+ = 436
    2/544
    Figure US20100249102A1-20100930-C01220
    Figure US20100249102A1-20100930-C01221
    Figure US20100249102A1-20100930-C01222
         		B, n.d. [MH]+ = 454
    2/545
    Figure US20100249102A1-20100930-C01223
    Figure US20100249102A1-20100930-C01224
    Figure US20100249102A1-20100930-C01225
         		B, n.d. [MH]+ = 383
    2/546
    Figure US20100249102A1-20100930-C01226
    Figure US20100249102A1-20100930-C01227
    Figure US20100249102A1-20100930-C01228
         		B, n.d. [MH]+ = 426
    2/547
    Figure US20100249102A1-20100930-C01229
    Figure US20100249102A1-20100930-C01230
    Figure US20100249102A1-20100930-C01231
         		B, n.d. [MH]+ = 416
    • Example 3
  • Figure US20100249102A1-20100930-C01232
    • Step A
  • 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
  • Following a similar procedure as described in Example 3, except using the ester indicated in Table II.2 below, the following compounds were prepared.
  • TABLE 11.2
    Ex. # Ester product yield
    4/4
    Figure US20100249102A1-20100930-C01233
    Figure US20100249102A1-20100930-C01234
         		70% [MH]+ = 441
    4/9
    Figure US20100249102A1-20100930-C01235
    Figure US20100249102A1-20100930-C01236
         		66% [MH]+ = 606
    4/10
    Figure US20100249102A1-20100930-C01237
    Figure US20100249102A1-20100930-C01238
         		68% [MH]+ = 574
    4/11
    Figure US20100249102A1-20100930-C01239
    Figure US20100249102A1-20100930-C01240
         		99% [MH]+ = 455
    4/14
    Figure US20100249102A1-20100930-C01241
    Figure US20100249102A1-20100930-C01242
         		65% [MH]+ = 520
    4/15
    Figure US20100249102A1-20100930-C01243
    Figure US20100249102A1-20100930-C01244
         		65% [MH]+ = 441
    4/17
    Figure US20100249102A1-20100930-C01245
    Figure US20100249102A1-20100930-C01246
         		40% [MH]+ = 455
    4/18
    Figure US20100249102A1-20100930-C01247
    Figure US20100249102A1-20100930-C01248
         		72% [MH]+ = 455
    4/19
    Figure US20100249102A1-20100930-C01249
    Figure US20100249102A1-20100930-C01250
         		66% [MH]+ = 467
    • Example 15
  • Figure US20100249102A1-20100930-C01251
    • Step A
  • 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
  • Following a similar procedure as described in the Example 15, except using the protected product indicated in Table II.7 below, the following compounds were prepared.
  • TABLE 11.7
    Ex. # educt product Yield
    15/2
    Figure US20100249102A1-20100930-C01252
    Figure US20100249102A1-20100930-C01253
         		50% [MH]+ = 498
    15/3
    Figure US20100249102A1-20100930-C01254
    Figure US20100249102A1-20100930-C01255
         		16% [MH]+ = 426
    15/4
    Figure US20100249102A1-20100930-C01256
    Figure US20100249102A1-20100930-C01257
         		69% [MH]+ = 426
    15/5
    Figure US20100249102A1-20100930-C01258
    Figure US20100249102A1-20100930-C01259
         		46% [MH]+ = 412
    • Example 19
  • Figure US20100249102A1-20100930-C01260
    • Step A
  • 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
  • Figure US20100249102A1-20100930-C01261
    • Step A
  • 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
  • Following a similar procedure as described in Example 22, except using the educt indicated in Table II.9 below, the following compounds were prepared.
  • TABLE 11.9
    Ex. # educt product Yield
    22/1
    Figure US20100249102A1-20100930-C01262
    Figure US20100249102A1-20100930-C01263
         		80% [MH]+ = 475
    22/2
    Figure US20100249102A1-20100930-C01264
    Figure US20100249102A1-20100930-C01265
         		89% [MH]+ = 461
    • Example 26
  • Figure US20100249102A1-20100930-C01266
    • Step A
  • The title compound from Example 2/218 (15.8 mg) was dissolved in DMSO, then H2O2 (˜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
  • Figure US20100249102A1-20100930-C01267
    • Step A
  • 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
  • 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.
  • TABLE 11.14
    Ex. # amine; ester product Yield
    39/7
    Figure US20100249102A1-20100930-C01268
    Figure US20100249102A1-20100930-C01269
         		20% [MH]+ = 428
    39/20
    Figure US20100249102A1-20100930-C01270
    Figure US20100249102A1-20100930-C01271
         		19% [MH]+ = 401
    • Example 41
  • Figure US20100249102A1-20100930-C01272
    • Step A
  • The title compound from Example 2/376 above was stirred in a solution of HBr in glacial acid (33wt %) at room temperature for 2 h. Evaporation afford the title compound. [MH]+=398.
    • Example 42
  • Figure US20100249102A1-20100930-C01273
    • Step A
  • 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
  • Following a similar procedure as described in Example 42 above, except using amines and acid chlorides as indicated in the Table II.15 below, the following compounds were prepared.
  • TABLE 11.15
    Ex. # amine; acid chloride product Yield
    42/1
    Figure US20100249102A1-20100930-C01274
    Figure US20100249102A1-20100930-C01275
         		9% [MH]+ = 508
    42/2
    Figure US20100249102A1-20100930-C01276
    Figure US20100249102A1-20100930-C01277
         		29% [MH]+ = 476
    • Example 43
  • Figure US20100249102A1-20100930-C01278
    • Step A
  • 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
  • Following a similar procedure as described in Example 43 above, except using amine and benzyl bromide as indicated in the Table II.16 below, the following compound was prepared.
  • TABLE 11.16
    Ex. # amine; benzyl bromide product yield
    43/1
    Figure US20100249102A1-20100930-C01279
    Figure US20100249102A1-20100930-C01280
         		14% [MH]+ = 488
    • Example 1700 Assay for Determining MMP-13 Inhibition
  • 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 CaCl2 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 μL 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 IC50 values are calculated from the initial reaction rates.
    • Example 1701 Assay for Determining MMP-3 Inhibition
  • The typical assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 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. 480455). The time-dependent increase in fluorescence is measured at the 330 nm excitation and 390 nm emission by an automatic plate multireader. The IC50 values are calculated from the initial reaction rates.
    • Example 1702 Assay for Determining MMP-8 Inhibition
  • 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 CaCl2 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 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 an automatic plate multireader at 37° C. The IC50 values are calculated from the initial reaction rates.
    • Example 1703 Assay for Determining MMP-12 Inhibition
  • 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 CaCl2 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 IC50 values are calculated from the initial reaction rates.
    • Example 1704 Assay for Determining Aggrecanase-1 Inhibition
  • 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 CaCl2 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 IC50 values are calculated from the absorbance signal corresponding to residual aggrecanase activity.
    • Example 1705
  • Assay for Determining Inhibition of MMP-3 Mediated Proteoglycan Degradation
  • The assay for MMP-3 activity is carried out in assay buffer comprised of 50 mM MES, pH 6.0, 10 mM CaCl2 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 & 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
  • 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).
  • 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 CaCl2 and 0.05% Brij-35 and the mixture is thoroughly mixed.
  • 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 CaCl2 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 IC50 values are calculated from the initial reaction rates.

Claims (20)

1. A compound having Formula (I):
Figure US20100249102A1-20100930-C01281
wherein
R1 in each occurrence is independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, and heterocycloalkyl fused heteroarylalkyl,
wherein R1 is optionally substituted one or more times, or
wherein R1 is optionally substituted by one R16 group and optionally substituted by one or more R9 groups;
R2 is selected from hydrogen and alkyl, wherein alkyl is optionally substituted one or more times or R1 and R2 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
R4 in each occurrence is independently selected from R10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, haloalkyl, CF3, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x-(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR10, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl,
wherein each R4 group is optionally substituted one or more times, or
wherein each R4 group is optionally substituted by one or more R14 groups, or
wherein optionally two R4 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 NR50 and which is optionally substituted one or more times, or
optionally two R4 groups together at one saturated carbon atom form ═O, ═S , ═NR10 or ═NOR10;
R5 is independently selected from hydrogen, alkyl, C(O)NR10R11, aryl, arylalkyl, SO2NR10R11 and C(O)OR10 wherein alkyl, aryl and arylalkyl are optionally substituted one or more times;
R8 is independently selected from hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, R10 and NR10R11 wherein alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl is optionally substituted one or more times;
R9 in each occurrence is independently selected from R10, hydrogen, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, halo, CHF2, CF3, OR10, SR10, COOR10, CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6)-alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-heteroaryl, C(O)NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-heteraryl, (C0-C6)-alkyl-C(O)—NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl,
wherein each R9 group is optionally substituted, or
wherein each R9 group is optionally substituted by one or more R14 groups;
R10 and R11 in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted one or more times, or R10 and R11 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing a heteroatom selected from O, S(O)x, or NR50 and which is optionally substituted one or more times;
R14 is independently selected from hydrogen, alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl, heterocyclylalkyl and halo, wherein alkyl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocyclylalkyl are optionally substituted one or more times.
R16 is selected from cycloalkyl, heterocycloalkyl, bicycloalkyl, heterobicycloalkyl, spiroalkyl, spiroheteroalkyl, aryl, heteroaryl, cycloalkyl fused aryl, heterocycloalkyl fused aryl, cycloalkyl fused heteroaryl, heterocycloalkyl fused heteroaryl, cycloalkylalkyl, heterocycloalkylalkyl, bicycloalkylalkyl, heterobicycloalkylalkyl, spiroalkylalkyl, spiroheteroalkylalkyl, arylalkyl, heteroarylalkyl, cycloalkyl fused arylalkyl, heterocycloalkyl fused arylalkyl, cycloalkyl fused heteroarylalkyl, heterocycloalkyl fused heteroarylalkyl, (i) and (ii):
Figure US20100249102A1-20100930-C01282
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;
R17 is selected from R1, R4 and R21;
R21 is a bicyclic or tricyclic fused ring system, wherein at least one ring is partially saturated, and
wherein R21 is optionally substituted one or more times, or
wherein R21 is optionally substituted by one or more R9 groups;
R30 is selected from alkyl and (C0-C6)-alkyl-aryl, wherein alkyl and aryl are optionally substituted;
R50 in each occurrence is independently selected from hydrogen, alkyl, aryl, heteroaryl, C(O)R80, C(O)NR80R81, SO2R80 and SO2NR80R81, wherein alkyl, aryl, and heteroaryl are optionally substituted one or more times;
R80 and R81 in each occurrence are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, haloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl, wherein alkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, fluoroalkyl, heterocycloalkylalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl and aminoalkyl are optionally substituted, or R80 and R81 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally a heteroatom selected from O, S(O)x, —NH, and —N(alkyl) and which is optionally substituted one or more times;
E is selected from a bond, CR10R11, O, NR5, S, S═O, S(═O)2, C(═O), N(R10)(C═O), (C═O)N(R10), N(R10)S(═O)2, S(═O)2N(R10), C═N—OR11, —C(R10R11)C(R10R11)—, —CH2—W1— and
Figure US20100249102A1-20100930-C01283
La is independently selected from CR9 and N;
Lb is independently selected from C and N with the proviso, that both Lb are not N, and that the bond between Lb and Lb is optionally a double bond only if both Lb are C;
Lc 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—, NR10, NR10CO—, —CONR10—, —S(O)x—, —SO2NR10—, —NR10SO2—, NR10SO2N10—, —NR10CONR10—, —OC(O)NR10—, —NR10C(O)O—, which replace a corresponding number of non-adjacent carbon atoms, and wherein the hydrocarbon chain is optionally substituted one or more times;
Q is a 4- to 8-membered ring selected from cycloalkyl, heterocycloalkyl or a 5- or 6-membered ring selected from aryl and heteroaryl,
wherein Q is optionally substituted one or more times, or
wherein Q is optionally substituted one or more times with R4, or
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;
U is selected from C(R5R10), NR5, O, S, S═O and S(═O)2;
W1 is selected from O, NR5, S, S═O, S(═O)2, N(R10)(C═O), N(R10)S(═O)2 and S(═O)2N(R10);
X is selected from a bond and (CR10R11)wE(CR10R11)w;
X1 is independently selected from O, S, NR10, N—CN, NCOR10, N—NO2, or N—SO2R10;
g and h are independently selected from 0-2;
w is selected from 0-4;
x is selected from 0 to 2;
y is selected from 1 and 2;
the dotted line optionally represents a double bond; and
N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof.
2. A compound according to claim 1, wherein 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.
3. A compound according to claim 2, wherein La is N.
4. A compound according to claim 2, wherein:
La is N; and
Lb is C.
5. A compound according to claim 1, selected from:
Figure US20100249102A1-20100930-C01284
Figure US20100249102A1-20100930-C01285
Figure US20100249102A1-20100930-C01286
6. A compound according to claim 5, wherein R8 is H.
7. A compound according to claim 5, wherein R17 is selected from
Figure US20100249102A1-20100930-C01287
wherein:
R6 is selected from R9, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, C(O)OR10 CH(CH3)CO2H, (C0-C6)-alkyl-COR10, (C0-C6)-alkyl-OR10, (C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NO2, (C0-C6)-alkyl-CN, (C0-C6)-alkyl-S(O)yOR10, (C0-C6)-alkyl-P(O)2OH, (C0-C6 0alkyl-S(O)yNR10R11, (C0-C6)-alkyl-NR10CONR11SO2R30, (C0-C6)-alkyl-S(O)xR10, (C0-C6)-alkyl-OC(O)R10, (C0-C6)-alkyl-OC(O)NR10R11, (C0-C6)-alkyl-C(═NR10)NR10R11, (C0-C6)-alkyl-NR10C(═NR11)NR10R11, (C0-C6)-alkyl-NR10C(═N—CN)NR10R11, (C0-C6)-alkyl-C(═N—CN)NR10R11, (C0-C6)-alkyl-NR10C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(═N—NO2)NR10R11, (C0-C6)-alkyl-C(O)OR10, (C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10SO2R11, C(O)NR10—(C0-C6)-alkyl-heteroaryl, C(O)NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-aryl, S(O)2NR10—(C0-C6)-alkyl-heteroaryl, S(O)2NR10-alkyl, S(O)2—(C0-C6)-alkyl-aryl, S(O)2—(C0-C6)-alkyl-heteroaryl, (C0-C6)-alkyl-C(O)-NR11—CN, O—(C0-C6)-alkyl-C(O)NR10R11, S(O)x—(C0-C6)-alkyl-C(O)OR10, S(O)x—(C0-C6)-alkyl-C(O)NR10R11, (C0-C6)-alkyl-C(O)NR10—(C0-C6)-alkyl-NR10R11, (C0-C6)-alkyl-NR10—C(O)R10, (C0-C6)-alkyl-NR10—C(O)OR10, (C0-C6)-alkyl-NR10—C(O)—NR10R11, (C0-C6)-alkyl-NR10—S(O)yNR10R11, (C0-C6)-alkyl-NR10—S(O)yR11, O—(C0-C6)-alkyl-aryl and O—(C0-C6)-alkyl-heteroaryl, wherein each R6 group is optionally substituted by one or more R14 groups;
R9 is independently selected from hydrogen, alkyl, halo, CHF2, CF3, OR10, NR10R11, NO2, and CN, wherein alkyl is optionally substituted one or more times;
8. A compound according to claim 5, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01288
wherein:
R18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl are optionally substituted one or more times;
R25 is selected from hydrogen, alkyl, cycloalkyl, C(O)NR10R11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
B1 is selected from NR10, O and S;
D2, G2, L2, M2 and T2 are independently selected from CR18 and N; and
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.
9. The compound according to claim 6, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01289
Figure US20100249102A1-20100930-C01290
Figure US20100249102A1-20100930-C01291
Figure US20100249102A1-20100930-C01292
Figure US20100249102A1-20100930-C01293
Figure US20100249102A1-20100930-C01294
10. A compound according to claim 5, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01295
Figure US20100249102A1-20100930-C01296
wherein:
R12 and R13 are independently selected from hydrogen, alkyl and halo, wherein alkyl is optionally substituted one or more times, or optionally R12 and R13 together form ═O, ═S, ═NR10 or ═NOR10;
R18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
R19 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R19 groups together at one carbon atom form ═O, ═S , ═NR10 or ═NOR10;
R25 is selected from hydrogen, alkyl, cycloalkyl, C(O)NR10R11 and haloalkyl, wherein alkyl, cycloalkyl, and haloalkyl are optionally substituted one or more times;
J and K are independently selected from CR10R18 NR10, O and S(O)x;
A1 is selected from NR10, O and S(O)x; and
D2, G2, J2, L2, M2 and T2 are independently selected from CR18 and N.
11. A compound according to claim 6, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01297
Figure US20100249102A1-20100930-C01298
Figure US20100249102A1-20100930-C01299
Figure US20100249102A1-20100930-C01300
12. A compound according to claim 5, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01301
Figure US20100249102A1-20100930-C01302
wherein:
R18 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times;
R19 is independently selected from hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, heteroaryl, OH, halo, CN, C(O)NR10R11, CO2R10, OR10, OCF3, OCHF2, NR10CONR10R11, NR10COR11, NR10SO2R11, NR10SO2NR10R11, SO2NR10R11 and NR10R11, wherein alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, alkynyl, aryl, and heteroaryl are optionally substituted one or more times, or optionally two R19 groups together at one carbon atom form ═O, ═S, ═NR10 or ═NOR10;
R25 is selected from hydrogen, alkyl, cycloalkyl, CONR10R11 and haloalkyl, wherein alkyl, cycloalkyl and haloalkyl are optionally substituted one or more times;
L2, M2, and T2 are independently selected from CR18 and N;
D3, G3, L3, M3, and T3 are independently selected from N, CR18, (i) and (ii)
Figure US20100249102A1-20100930-C01303
with the proviso that one of L3, M3, T3, D3, and G3 is (i) or (ii);
B1 is selected from the group consisting of NR10, O and S(O)x; and
Q2 is a 5- to 8-membered ring selected from cycloalkyl, heterocycloalkyl, aryl, and heteroaryl, which is optionally substituted one or more times with R19.
13. A compound according to claim 6, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01304
Figure US20100249102A1-20100930-C01305
Figure US20100249102A1-20100930-C01306
14. A compound according to claim 6, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01307
Figure US20100249102A1-20100930-C01308
Figure US20100249102A1-20100930-C01309
Figure US20100249102A1-20100930-C01310
15. A compound according to claim 6, wherein R1 is selected from:
Figure US20100249102A1-20100930-C01311
16. A compound according to claim 1, having the structure:
Figure US20100249102A1-20100930-C01312
Figure US20100249102A1-20100930-C01313
Figure US20100249102A1-20100930-C01314
Figure US20100249102A1-20100930-C01315
Figure US20100249102A1-20100930-C01316
Figure US20100249102A1-20100930-C01317
N-oxides, pharmaceutically acceptable salts, prodrugs, formulations, polymorphs, tautomers, racemic mixtures and stereoisomers thereof
17. A pharmaceutical composition comprising an effective amount of a compound according to claim 1.
18. 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 claim 1.
19. The method according to claim 16, wherein the disease is selected from rheumatoid arthritis, osteoarthritis, inflammation, atherosclerosis and multiple sclerosis.
20. A pharmaceutical composition comprising:
A) an effective amount of a compound selected from: a compound according to claim 1;
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.
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