CROSS-REFERENCE TO RELATED APPLICATIONS 0001 This application claims benefit of priority from U.S. Provisional Patent Application No. 60/396,903, filed Jul. 17, 2002.

FIELD OF THE INVENTION 0002 This invention provides a combination of an allosteric carboxylic inhibitor of matrix metalloproteinase-13 with celecoxib or valdecoxib, a pharmaceutical composition comprising the combination, and methods of using the combination to treat diseases characterized by connective tissue breakdown, including cartilage damage, and inflammation or pain. Such diseases include arthritis, heart failure, multiple sclerosis, atherosclerosis, and osteoporosis.

BACKGROUND OF THE INVENTION 0003 More than 23 million Americans have some form of arthritis. Among the various forms of arthritis, osteoarthritis (OA) is the most prevalent, affecting 21 million Americans. Characterized by the degeneration of joint cartilage and adjacent bone, OA is a chronic disorder that can cause pain and stiffness. Rheumatoid arthritis (RA), which affects more than 2.1 million Americans, is an autoimmune disease that affects joint lining, cartilage and bones. 0004 Aspirin and conventional nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, diclofenac, and naproxen are the primary agents used to treat OA- and RA-related pain. These agents inhibit prostaglandin release by blocking cyclooxygenase-mediated conversion of cell membrane lipids from arachidonic acid. 0005 Two forms of COX are now known, a constitutive isoform usually named cyclooxygenase-1 (COX-1) and an inducible isoform usually named cyclooxygenase-2 (COX-2), the latter of which expression is upregulated at sites of inflammation. COX-1 appears to play a physiological role and to be responsible for gastrointestinal and renal protection. On the other hand, COX-2 appears to play a pathological role and is believed to be the predominant isoform present in inflammation conditions. The therapeutic use of conventional COX inhibitors, which are typically nonselective inhibitors of both COX-1 and COX-2, is limited due to drug associated side effects, including life threatening ulceration and renal toxicity. Compounds that selectively inhibit COX-2 would exert anti-inflammatory effects without the adverse side effects associated with COX-1 inhibition. 0006 Valdecoxib is a COX-2 specific inhibitor that was approved in 2001 by the United States Food and Drug Administration (FDA) for treating the signs and symptoms of osteoarthritis (OA) and adult rheumatoid arthritis (RA); and the treatment of pain associated with menstrual cramping. Valdecoxib tablets are marketed under the tradename BEXTRA. In a combined analysis of various clinical studies with valdecoxib, valdecoxib was well tolerated with an overall upper gastrointestinal safety profile (ulcers, perforations, obstructions and GI bleeds) significantly better than the conventional NSAIDs studied such as ibuprofen, diclofenac and naproxen. 0007 Matrix metalloproteinases (MMPs) are naturally occurring enzymes found in most mammals. Stromelysin-1 and gelatinase A are members of the matrix metalloproteinases (MMP) family. Other members include fibroblast collagenase (MMP-1), neutrophil collagenase (MMP-8), gelatinase B (92 kDa gelatinase) (MMP-9), stromelysin-2 (MMP-10), stromelysin-3 (MMP-11), matrilysin (MMP-7), collagenase 3 (MMP-13), and other newly discovered membrane-associated matrix metalloproteinases. 0008 Over-expression or activation of MMPs, or an imbalance between MMPs and their endogenous inhibitors, namely tissue inhibitors of metalloproteinases (TIMPs), have been suggested as factors in the pathogenesis of diseases characterized by the breakdown of extracellular matrix or connective tissues. These diseases include 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. 0009 A major limitation on the use of currently known MMP inhibitors is their lack of specificity for any particular MMP enzyme. Recent data has established that specific MMP enzymes are associated with some diseases, with no effect on others. The MMPs are generally categorized based on their substrate specificity, and indeed the collagenase subfamily of MMP-1, MMP-8, and MMP-13 selectively cleave native interstitial collagens, and thus are associated only with diseases linked to such interstitial collagen tissue. This is evidenced by the recent discovery that MMP-13 alone is over expressed in breast carcinoma, while MMP-1 alone is over expressed in papillary carcinoma (see Chen et al., J. Am. Chem. Soc., 2000;122:9648-9654). 0010 Another major limitation of currently known MMP inhibitors related to their lack of specificity for any particular MMP enzyme is their production of undesirable side effects related to inhibition of multiple MMP enzymes and/or tumor necrosis factor-alpha converting enzyme (TACE). One example of such a side effect is musculoskeletal syndrome (MSS). 0011 There appears to be few selective inhibitors of MMP-13 reported. A compound named WAY-170523 has been reported by Chen et al., supra., 2000, and a few other compounds are reported in PCT International Patent Application Publication Number WO 01/63244 A1, as allegedly selective inhibitors of MMP-13. Further, U.S. Pat. No. 6,008,243 discloses inhibitors of MMP-13. These inhibitors contain functional groups that ligate, coordinate, or bind the catalytic zinc cation on MMP-13. However, selectivity in these cases can mean only a 5-fold or 10-fold greater inhibition of MMP-13 versus as few as one other MMP enzyme. Further, no selective or non-allosteric carboxylic inhibitor of MMP-13 has been marketed for the treatment of any disease in any mammal. 0012 Applicant has previously discovered highly selective inhibitors of MMP-13 that show promising pharmacological and pharmacokinetic activity in vivo. These inhibitors have been the subjects of previously filed patent applications. 0013 Applicant's inhibitors are more selective than prior art inhibitors for MMP-13 versus other MMP enzymes, both in terms of relative potencies and in terms of the numbers of the other MMP enzymes. For example, some of Applicant's inhibitors have shown 100-fold or greater selectivity with MMP-13 versus five or more other MMP enzymes, and further have shown efficacy in animal models of osteoarthritis. 0014 The observed selectivity of Applicant's inhibitors may be attributed to the inhibitors' binding to MMP-13 at an allosteric site and, further, to a binding mode which does not involve binding to the enzyme's catalytic zinc. Prior to Applicant's allosteric MMP-13 inhibitors, it is believed that all prior art MMP-13 inhibitors bound to an MMP enzyme's catalytic zinc and occupied the MMP enzyme's substrate binding site. This latter binding mode was erroneously believed by others to be necessary for MMP-13 inhibitor potency. 0015 Applicant's discovery that a combination of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, is particularly useful for treating diseases characterized by damage to connective tissue such as cartilage damage. All that is required to treat diseases characterized by damage to connective tissue such as cartilage damage, including osteoarthritis, heart failure, multiple sclerosis, atherosclerosis, or osteoporosis in a mammal according to the invention is to administer to the mammal in need of treatment a therapeutically effective amount of the combination, wherein the combination comprises an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. As will be discussed below, the instant combination of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, possesses many advantages over any combination of a prior art selective inhibitor of MMP-13 with a COX-2 inhibitor.

SUMMARY OF THE INVENTION 0016 This invention provides a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. 0017 Another invention embodiment is a combination, comprising celecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 0018 Other invention embodiments are described below: 0019 1. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula I 1

0020 or a pharmaceutically acceptable salt thereof, 0021 wherein: 0022 - - - is absent or is a bond; 0023 X is O, S, SO, SO2, CH2, CO, CHOH, NH, or NR5; 0024 Y is O or S; 0025 R1 is H, (O)nC1-C6 alkyl, (O)n substituted C1-C6 alkyl, NO2, NR5R6, CHO, or halo; 0026 R2, R3, and R4 independently are hydrogen, halo, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C6 alkenyl, substituted C2-C6 alkenyl, C2-C10alkynyl, substituted C2-C10alkynyl, (CH2)m OH, (CH2)m OR5, (CH2)m cycloalkyl, (CH2)m substituted cycloalkyl, CHOH(CH2)m aryl, CHOH (CH2)m substituted aryl, CHOH(CH2)m heteroaryl, CHOH(CH2)m substituted heteroaryl, (CO2)n(CH2)m aryl, (CO2)n(CH2)m substituted aryl, (CO2)n(CH2)m heteroaryl, (CO2)n(CH2)m substituted heteroaryl, (CO2)n(CH2)m carbocycle, (CO2)n(CH2)m substituted carbocycle, (CO2)n(CH2)m heterocycle, (CO2)n(CH2)m substituted heterocycle, (CO2)n(CH2)m NR5R6, CH(C1-6 alkyl)-aryl, (CH2)m N(H)C(O)aryl, (CH2)mS(O)0-2(CH2)n-aryl, CH(C1-C6 alkyl)-substituted aryl, (CH2)mN(H)C(O) substituted aryl, (CH2)mS(O)0-2(CH2)n substituted aryl, 0027 C(O)N(R5)(CH2)m aryl, C(O)N(R5)(CH2)m substituted aryl, C(O)N(R5)(CH2)m heteroaryl, C(O)N(R5)(CH2)m substituted heteroaryl, CC(CH2)m aryl, CC(CH2)m substituted aryl, CC(CH2)m-heteroaryl, CC(CH2)m substituted heteroaryl, CC(CH2)m carbocycle, CC(CH2)m substituted carbocycle, (CH2)mO-aryl, (CH2)mO-substituted aryl, (CH2)m COR5, 2

0028 or (CH2)m CO2R5; 0029 m is an integer from 0 to 6; 0030 R5 and R6 independently are hydrogen, C1-C6 alkyl, substituted C1-C6 alkyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl or (CH2)m substituted heteroaryl, or R5 and R6 are taken together with the nitrogen atom to which they are attached complete a 3- to 7-membered ring; containing carbon atoms, the nitrogen atom bearing R5 and R6, and optionally 1 or 2 heteroatoms independently selected form O, S, and NR2, wherein R2 is as defined above and; 0031 n is 0 or 1; with the proviso that R2 and R4 are not both selected from hydrogen and C1-C6 alkyl. 0032 2. The combination according to Embodiment 1, wherein the compound of Formula I is a compound of Formula III 3

0033 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined above for Embodiment 1. 0034 3. The combination according to Embodiment 2, wherein the compound of Formula III is selected from: 0035 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carbothioic acid benzylamide; 0036 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carbothioic acid 4-methoxy-benzylamide; 0037 6-Benzyl-2-(3-phenyl-propionyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0038 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid prop-2-ynylamide; 0039 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (piperidin-4-ylmethyl)-amide hydrochloride; 0040 6-Benzyl-2-(1-hydroxy-3-phenyl-allyl)-8-methyl-3,2-cpyrimidine-5,7-dione; 0041 6-Benzyl-2-(1-hydroxy-3-phenyl-prop-2-ynyl)-8-methyl-3,2-cpyrimidine-5,7-dione; 0042 6-Benzyl-2-(hydroxy-phenyl-methyl)-thiazolo3,2-cpyrimidine-5,7-dione; and 0043 6-Benzyl-2-(1-hydroxy-3-phenyl-propyl)-thiazolo3,2-cpyrimidine-5,7-dione, or a pharmaceutically acceptable salt thereof. 0044 4. The combination according to Embodiment 2, wherein the compound of Formula III is selected from: 0045 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid prop-2-ynylamide; 0046 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (piperidin-4-ylmethyl)-amide hydrochloride; 0047 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0048 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0049 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0050 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0051 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0052 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0053 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0054 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0055 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0056 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0057 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0058 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0059 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0060 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0061 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-amino-pyridin-4-ylmethyl)-amide; 0062 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0063 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0064 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0065 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0066 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0067 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0068 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0069 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0070 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0071 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0072 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0073 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0074 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0075 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0076 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-ethoxy-pyridin-4-ylmethyl)-amide; 0077 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0078 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0079 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0080 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0081 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0082 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0083 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0084 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0085 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0086 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0087 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0088 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0089 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0090 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0091 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-hydroxy-pyridin-3-ylmethyl)-amide; 0092 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0093 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0094 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0095 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0096 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0097 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0098 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0099 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0100 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0101 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0102 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0103 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0104 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0105 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0106 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0107 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0108 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0109 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0110 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6;7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0111 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0112 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0113 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0114 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0115 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0116 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0117 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0118 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0119 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0120 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0121 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methyl-pyridin-4-ylmethyl)-amide; 0122 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0123 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0124 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0125 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0126 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0127 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0128 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0129 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0130 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0131 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0132 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0133 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0134 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0135 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0136 6-(4-Chloro-3-bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methylamino-pyridin-4-ylmethyl)-amide; 0137 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0138 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0139 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0140 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0141 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0142 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0143 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0144 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0145 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0146 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0147 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0148 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0149 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0150 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0151 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (pyridin-3-ylmethyl)-amide; 0152 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0153 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0154 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0155 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0156 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0157 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0158 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0159 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0160 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0161 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0162 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0163 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0164 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0165 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0166 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-amino-pyridin-3-ylmethyl)-amide; 0167 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0168 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0169 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0170 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0171 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0172 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0173 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0174 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0175 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0176 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0177 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0178 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0179 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0180 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0181 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-ethoxy-pyridin-3-ylmethyl)-amide; 0182 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0183 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0184 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0185 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0186 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0187 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0188 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0189 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0190 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0191 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0192 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0193 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0194 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0195 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0196 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methoxy-pyridin-3-ylmethyl)-amide; 0197 6-(4-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0198 6-(4-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0199 6-(4-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0200 6-(3-Bromo-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0201 6-(3-Bromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0202 6-(3,4-Dichloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0203 6-(4-Bromo-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0204 6-(3-Chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0205 6-(3-Fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0206 6-(3,4-Dibromo-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0207 6-(4-Bromo-3-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0208 6-(3,4-Difluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0209 6-(3-Bromo-4-chloro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0210 6-(3-Chloro-4-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0211 6-(4-Chloro-3-fluoro-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (6-methyl-pyridin-3-ylmethyl)-amide; 0212 6-(4-Cyano-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; and 0213 6-(4-Isopropylsulfamoyl-benzyl)-8-methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide, or a pharmaceutically acceptable salt thereof. 0214 5. The combination according to Embodiment 1, wherein the compound of Formula I is a compound of Formula IV 4

0215 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined above for Embodiment 1. 0216 6. The combination according to Embodiment 5, wherein the compound of Formula IV is selected from: 0217 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-oxazolo3,2-cpyrimidine-2-carboxylic acid benzyl ester; 0218 6-Benzyl-5,7-dioxo-6,7-dihydro-5H-oxazolo3,2-cpyrimidine-2-carboxylic acid benzyl ester; 0219 6-Benzyl-5,7-dioxo-6,7-dihydro-5H-oxazolo3,2-cpyrimidine-2-carboxylic acid benzylamide; 0220 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-oxazolo3,2-cpyrimidine-2-carboxylic acid 4-methoxy-benzylamide; 0221 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-oxazolo3,2-cpyrimidine-2-carboxylic acid (pyridin-4-ylmethyl)-amide; and 0222 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-oxazolo3,2-cpyrimidine-2-carboxylic acid (benzo1,3dioxol-5-ylmethyl)-amide, or a pharmaceutically acceptable salt thereof. 0223 7. The combination according to Embodiment 1, wherein the compound of Formula I is a compound of Formula V 5

0224 or a pharmaceutically acceptable salt thereof, wherein R1 is hydrogen, (O)n C1-C6 alkyl, or (O)n substituted C1-C6 alkyl, R2 is CO2(CH2)m aryl, CO2(CH2)m substituted aryl, 0225 R4 is (CH2)m CO2R5, (CH2)m CONR5R6, (CH2)m CNR5R6, 6

0226 CHOH(CH2)m aryl, CHOH(CH2)m substituted aryl, CHOH(CH2)m heteroaryl, CHOH(CH2)m substituted aryl. 0227 8. The combination according to Embodiment 1, wherein the compound of Formula I is a compound of Formula VI: 7

0228 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R4, Y, and X are as defined above for Embodiment 1. 0229 9. The combination according to Embodiment 8, wherein the compound of Formula VI is selected from: 0230 6-Benzyl-8-methyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo1,2-cpyrimidine-2-carboxylic acid (benzo1,3dioxol-5-ylmethyl)-amide; 0231 6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo1,2-cpyrimidine-2-carboxylic acid (benzo1,3dioxol-5-ylmethyl)-amide; 0232 6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo1,2-cpyrimidine-2-carboxylic acid benzylamide; 0233 6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo1,2-cpyrimidine-2-carboxylic acid 4-methoxy-benzylamide; 0234 6-Benzyl-1-methyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo1,2-cpyrimidine-2-carboxylic acid 4-methoxy-benzylamide; 0235 6-(4-Methoxy-benzyl)-1-methyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo1,2-cpyrimidine-2-carboxylic acid 4-methoxy-benzylamide; 0236 6-(4-Methoxy-benzyl)-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-1,2-cpyrimidine-2-carboxylic acid (pyridin-4-ylmethyl)-amide; 0237 6-Benzyl-5,7-dioxo-2,3,6,7-tetrahydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid benzyl ester 2,3-Dihydroxypropionic acid benzyl ester; 0238 6-Benzyl-5,7-dioxo-2,3,6,7-tetrahydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid pyridin-4-ylmethyl ester hydrochloride; 0239 6-Benzyl-1,5,7-trioxo-1,2,3,5,6,7-hexahydro-114-thiazolo3,2-cpyrimidine-3-carboxylic acid benzyl ester; 0240 6-Benzyl-1,8-dimethyl-5,7-dioxo-1,5,6,7-tetrahydro-imidazo-1,2-cpyrimidine-2-carboxylic acid 4-methoxy-benzyl ester; and 0241 6-benzyl-3-ethoxy-2,3-dihydro-oxazolo3,2-cpyrimidine-5,7-dione, or a pharmaceutically acceptable salt thereof. 0242 10. The combination according to Embodiment 1, wherein the compound of Formula I is a compound of Formula VII 8

0243 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and R4 are as defined above for Embodiment 1. 0244 11. The combination according to Embodiment 1, wherein the compound of Formula I is a compound of Formula VIII 9

0245 or a pharmaceutically acceptable salt thereof, wherein: 0246 R1 is H, CH3, CH2OH, or CHO; 0247 R2 is (CO2)(CH2)m aryl, (CO2)(CH2)m substituted aryl, (CO2)(CH2)m heteroaryl, (CO2)(CH2)m substituted heteroaryl, C(O)N(R5)(CH2)m-aryl, C(O)N(R5)(CH2)m substituted aryl, C(O)N(R5)(CH2)m heteroaryl, C(O)N(R5)(CH2)m substituted heteroaryl, CC(CH2)maryl, CC(CH2)m substituted aryl, CC(CH2)m heteroaryl, or CC(CH2)m substituted heteroaryl, wherein R5 is hydrogen or methyl; 0248 R3 is hydrogen or fluoro; 0249 R4 is C2-C6 alkenyl, substituted C2-C6 alkenyl, C1-C6 alkyl, substituted C1-C6 alkyl, C2-C10alkenyl, substituted C2-C10alkynyl, (CH2)mCOR5, (CH2)mS(O)0-2(CH2)naryl, C(O)N(R5)CH2)maryl, (CH2)mO-aryl, (CH2)mS(O)0-2(CH2)n substituted aryl, C(O)N(R5)CH2)m substituted aryl, (CH2)mO-substituted aryl, (CO2)n(CH2)m aryl, (CO2)n(CH2)m substituted aryl, (CO2)n(CH2)m heteroaryl, (CO2)n(CH2)m substituted heteroaryl, (CO2)n(CH2)m carbocycle, or (CO2)n(CH2)m substituted carbocycle, wherein 0250 n is 0 or 1; 0251 m is an integer of from 0 to 6; and 0252 R5 is as defined above for Embodiment 1. 0253 12. The combination according to Embodiment 11, wherein the compound of Formula VIII is a compound selected from: 0254 4-8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0255 4-2-3-(4-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0256 4-2-3-(4-Fluoro-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0257 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0258 4-2-3-(3,4-Difluoro-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0259 6-Benzyl-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0260 6-(3,4-Dichloro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-3,2-cpyrimidine-5,7-dione; 0261 6-(3,4-Dichloro-benzyl)-2-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0262 6-Benzyl-8-methyl-2-phenylethynyl-thiazolo3,2-cpyrimidine-5,7-dione; 0263 6-(4-Bromo-benzyl)-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-3,2-cpyrimidine-5,7-dione; 0264 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzenesulfonamide; 0265 4-2-3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0266 6-(4-Fluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0267 6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0268 6-(3,4-Dichloro-benzyl)-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-3,2-cpyrimidine-5,7-dione; 0269 6-(4-Methanesulfonyl-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-3,2-cpyrimidine-5,7-dione; 0270 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzonitrile; 0271 4-8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0272 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-4-(2H-tetrazol-5-yl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0273 6-Benzyl-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0274 6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0275 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-4-(morpholine-4-carbonyl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0276 8-Methyl-6-4-(morpholine-4-sulfonyl)-benzyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0277 2-3-(4-Fluoro-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0278 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0279 4-8-Methyl-5,7-dioxo-2-(4-phenyl-but-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0280 4-8-Methyl-5,7-dioxo-2-(6-phenyl-hex-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0281 4-8-Methyl-5,7-dioxo-2-(5-phenyl-pent-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0282 4-8-Methyl-5,7-dioxo-2-(7-phenyl-hept-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0283 (4-2-3-(3,4-Difluoro-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-phenyl)-acetic acid; 0284 6-(3-Fluoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0285 6-(3,4-Difluoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-3,2-cpyrimidine-5,7-dione; 0286 6-(3-Fluoro-benzyl)-2-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0287 3-(8-Methyl-5,7-dioxo-2-phenylethynyl-7H-thiazolo3,2-cpyrimidin-6-ylmethyl)-phenyl-acetic acid; 0288 6-(4-Bromo-benzyl)-2-3-(4-fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0289 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-N,N-dimethyl-benzenesulfonamide; 0290 4-2-3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-cyclohexanecarboxylic acid; 0291 6-(3,4-Difluoro-benzyl)-2-3-(3,4-difluoro-phenyl)-prop-1-ynyl-8-methyl-3,2-cpyrimidine-5,7-dione; 0292 4-8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-cyclohexanecarboxylic acid; 0293 2-Chloro-4-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0294 2-3-(4-Fluoro-phenyl)-prop-1-ynyl-6-(4-methanesulfonyl-benzyl)-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0295 4-2-3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzonitrile; 0296 (3-2-3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-phenyl)-acetic acid; 0297 (4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-phenyl)-acetic acid; 0298 6-(3,4-Difluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0299 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-4-(thiomorpholine-4-carbonyl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0300 8-Methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-6-4-(thiomorpholine-4-sulfonyl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0301 2-3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione; and 0302 2-3-(3-Methoxy-4-methyl-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione, or a pharmaceutically acceptable salt thereof. 0303 13. The combination according to Embodiment 11, wherein the compound of Formula VIII is a compound selected from: 0304 4-8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0305 4-2-3-(4-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0306 4-2-3-(4-Fluoro-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0307 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0308 4-2-3-(3,4-Difluoro-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0309 6-Benzyl-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0310 6-(3,4-Dichloro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-3,2-cpyrimidine-5,7-dione; 0311 6-(3,4-Dichloro-benzyl)-2-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0312 6-Benzyl-8-methyl-2-phenylethynyl-thiazolo3,2-cpyrimidine-5,7-dione; 0313 6-(4-Bromo-benzyl)-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-3,2-cpyrimidine-5,7-dione; 0314 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzenesulfonamide; 0315 4-2-3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0316 6-(4-Fluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0317 6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0318 6-(3,4-Dichloro-benzyl)-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-3,2-cpyrimidine-5,7-dione; 0319 6-(4-Methanesulfonyl-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-3,2-cpyrimidine-5,7-dione; 0320 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-benzonitrile; 0321 4-8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0322 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-4-(2H-tetrazol-5-yl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0323 6-Benzyl-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0324 6-Benzyl-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0325 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-4-(morpholine-4-carbonyl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0326 8-Methyl-6-4-(morpholine-4-sulfonyl)-benzyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0327 2-3-(4-Fluoro-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0328 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0329 4-8-Methyl-5,7-dioxo-2-(4-phenyl-but-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0330 4-8-Methyl-5,7-dioxo-2-(6-phenyl-hex-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0331 4-8-Methyl-5,7-dioxo-2-(5-phenyl-pent-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0332 4-8-Methyl-5,7-dioxo-2-(7-phenyl-hept-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0333 (4-2-3-(3,4-Difluoro-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-phenyl)-acetic acid; 0334 6-(3-Fluoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0335 6-(3,4-Difluoro-benzyl)-8-methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-3,2-cpyrimidine-5,7-dione; 0336 6-(3-Fluoro-benzyl)-2-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0337 3-(8-Methyl-5,7-dioxo-2-phenylethynyl-7H-thiazolo3,2-cpyrimidin-6-ylmethyl)-phenyl-acetic acid; 0338 6-(4-Bromo-benzyl)-2-3-(4-fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0339 4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-N,N-dimethyl-benzenesulfonamide; 0340 4-2-3-(3-Fluoro-4-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-cyclohexanecarboxylic acid; 0341 6-(3,4-Difluoro-benzyl)-2-3-(3,4-difluoro-phenyl)-prop-1-ynyl-8-methyl-3,2-cpyrimidine-5,7-dione; 0342 4-8-Methyl-5,7-dioxo-2-(3-phenyl-prop-1-ynyl)-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-cyclohexanecarboxylic acid; 0343 2-Chloro-4-2-3-(3-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzoic acid; 0344 2-3-(4-Fluoro-phenyl)-prop-1-ynyl-6-(4-methanesulfonyl-benzyl)-8-methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0345 4-2-3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-benzonitrile; 0346 (3-2-3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-ylmethyl-phenyl)-acetic acid; 0347 (4-2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-5,7-dioxo-7H-3,2-cpyrimidin-6-ylmethyl-phenyl)-acetic acid; 0348 6-(3,4-Difluoro-benzyl)-8-methyl-2-(3-phenyl-prop-1-ynyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0349 2-3-(3-Methoxy-phenyl)-prop-1-ynyl-8-methyl-6-4-(thiomorpholine-4-carbonyl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0350 8-Methyl-2-(3-pyridin-4-yl-prop-1-ynyl)-6-4-(thiomorpholine-4-sulfonyl)-benzyl-thiazolo3,2-cpyrimidine-5,7-dione; 0351 2-3-(4-Fluoro-3-methoxy-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione; and 0352 2-3-(3-Methoxy-4-methyl-phenyl)-prop-1-ynyl-8-methyl-6-(2-oxo-2H-1-benzopyran-6-ylmethyl)-thiazolo3,2-cpyrimidine-5,7-dione, or a pharmaceutically acceptable salt thereof. 0353 14. The combination according to Embodiment 1, wherein the compound of Formula I is a compound selected from: 0354 6-Benzoyl-thiazolo3,2-cpyrimidine-5,7-dione; 0355 6-(4-Chlorobenzyl)-thiazolo3,2-cpyrimidine-5,7-dione; 0356 6-Pyridin-4-ylmethyl-thiazolo3,2-cpyrimidine-5,7-dione; 0357 8-Methyl-thiazolo3,2-cpyrimidine-5,7-dione; 0358 8-Methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid; 0359 6-Benzyl-8-methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid; 0360 4-(8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidin-6-yl-methyl)-benzoic acid tert-butyl ester; and 0361 8-Methyl-6-4-(Morpholine-4-sulfonyl)benzyl-thiazolo3,2-cpyrimidine-5,7-dione, or a pharmaceutically acceptable salt thereof. 0362 15. The combination according to Embodiment 1, wherein the compound of Formula I is selected from: 0363 8-Methyl-5,7-dioxo-6-(3-oxo-3-phenyl-propyl)-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid 4-fluoro-benzylamide; 0364 8-Methyl-6-(1-phenylethyl) 5,7-dioxo-6,7-dihydro-SH-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0365 8-Methyl-5,7-dioxo-6-(2-phenylmethanesulfonyl-ethyl)-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0366 6-(5-Cyano-pentyl)-8-Methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0367 6-(E)-But-2-enyl-8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0368 8-Methyl-5,7-dioxo-6-(E)-pent-2-enyl-6,7-dihydro-SH-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0369 6-sec-Butyl-8-Methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0370 8-Methyl-6-(2-methyl-allyl)-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0371 6-(1-Ethyl-propyl)-8-Methyl-5,7-dioxo-6,7-dihydro-SH-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0372 8-Methyl-5,7-dioxo-6-pent-2-ynyl-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0373 6-(2-Benzensulfonyl-ethyl)-8-Methyl-5,7-dioxo-6,7-dihydro-5H-3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0374 8-Methyl-6-(3-methyl-but-2-enyl)-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0375 6-2-(4-Fluoro-benzensulfonyl)-ethyl-8-Methyl-5,7-dioxo-6,7-dihydro-3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0376 6-3-(4-Fluoro-phenyl)-3-oxo-propyl-8-Methyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0377 8-Methyl-5,7-dioxo-6-2-(1-phenyl-methanoyl)-amino-ethyl-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; 0378 8-Methyl-5,7-dioxo-6-(2-phenoxy-ethyl)-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid 4-fluorobenzylamide; and 0379 5-2-(4-Fluoro-benzylcarbamoyl)-8-methyl-5,7-dioxo-7H-thiazolo3,2-cpyrimidine-6-ylmethyl-isoxazol-3-yl-carbamic acid methyl ester, or a pharmaceutically acceptable salt thereof. 0380 16. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IA 10

0381 wherein R1, R2, and R3 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NO2, NR4R5, CN, or CF3; 0382 E is independently O or S; 0383 A and B independently are OR4 or NR4R5; 0384 each R4 and R5 independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring, optionally containing a heteroatom selected from O, S, or NH, and optionally substituted or unsubstituted; 0385 n is an integer from 0 to 6; 0386 or a pharmaceutically acceptable salt thereof. 0387 17. The combination according to Embodiment 16, wherein the compound of Formula IA is a compound of Formula IIA 11

0388 or a pharmaceutically acceptable salt thereof, 0389 wherein R1, R2, and R3 are as defined above for Embodiment 16, and each R4 independently is as defined above for Embodiment 16. 0390 18. The combination according to Embodiment 16, wherein the compound of Formula IA is a compound of Formula IIIA 12

0391 or a pharmaceutically acceptable salt thereof, 0392 wherein R1, R2, and R3 are as defined above for Embedment 16, and each R4 and R5 independently are as defined above. 0393 19. The combination according to Embodiment 16, wherein the compound of Formula IA is a compound of Formula IVA 13

0394 or a pharmaceutically acceptable salt thereof, 0395 wherein n, R1, R2, and R3 are as defined above for Embodiment 16, and R6, R7, R8, and R9 independently are hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, nitro, or NH2. 0396 20. The combination according to Embodiment 16, wherein the compound of Formula IA is a compound of Formula VA 14

0397 or a pharmaceutically acceptable salt thereof, 0398 wherein n, R1, R2, and R3 are as defined above for Embodiment 16, and Het is an unsubstituted or substituted heteroaryl group. 0399 21. The combination according to Embodiment 16, wherein the compound of Formula IA is a compound of Formula VIA 15

0400 or a pharmaceutically acceptable salt thereof, 0401 wherein R1, R2, and R3 are as defined above for Embodiment 16, and each R4 and R5 independently are as defined above for Embodiment 16. 0402 22. The combination according to Embodiment 16, wherein the compound of Formula IA is selected from: 0403 4-Methoxy-N,N-bis-(4-methoxybenzyl)-isophthalamide; 0404 Isophthalic acid di-(2,1,3-benzothiadiazol-5-yl) methyl ester; 0405 4-Methoxy-isophthalic acid dibenzyl ester; 0406 4-Methoxy-isophthalic acid dipyridin-4-ylmethyl ester; 0407 Isophthalic acid bis-(4-fluoro-benzyl) ester; 0408 Isophthalic acid bis-(3-fluoro-benzyl) ester; 0409 Isophthalic acid bis-(4-methoxy-benzyl) ester; 0410 Isophthalic acid bis-(3-methoxy-benzyl) ester; 0411 Isophthalic acid bis-(1,3-benzodioxol-5-ylmethyl) ester; 0412 N,N-Bis-(3-fluoro-benzyl)-isophthalamide; 0413 4-Acetyl-isophthalic acid dibenzyl ester; 0414 4-Methoxycarbonylmethoxy-isophthalic acid dibenzyl ester; 0415 N,N-Bis-1,3-benzodioxol-5-ylmethyl-4-methoxy-isophthalamide; 0416 N-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-(4-methoxy-benzyl)-isophthalamide; 0417 4-Methoxy-N,N-bis-(4-methoxy-benzyl)-isophthalamide; 0418 N-1,3-Benzodioxol-5-ylmethyl-N-(4-chloro-benzyl)-4-methoxy-isophthalamide; 0419 N-Benzyl-4-methoxy-N-(4-methoxy-benzyl)-isophthalamide; 0420 N-Benzyl-4-methoxy-N-(4-methoxy-benzyl)-isophthalamide; 0421 4-Methoxy-N-(4-methoxy-benzyl)-N-pyridin-4-ylmethyl-isophthalamide; 0422 N-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-(2-phenoxy-ethyl)-isophthalamide; 0423 N-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-(2-phenoxy-ethyl)-isophthalamide; 0424 N-1,3-Benzodioxol-5-ylmethyl-N-furan-2-ylmethyl-isophthalamide; 0425 N-1,3-Benzodioxol-5-ylmethyl-N-(2-ethoxy-ethyl)-4-methoxy-isophthalamide; 0426 N,N-Bis-(3-hydroxymethyl-phenyl)-isophthalamide; 0427 N-Benzyl-4-methoxy-N-(2-phenoxy-ethyl)-isophthalamide; 0428 4-Methoxy-N,N-bis-(4-methyl-benzyl)-isophthalamide; 0429 4-Methoxy-N,N-bis-(3-methoxy-benzyl)-isophthalamide; 0430 N-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-(4-methoxy-benzyl)-isophthalamide; 0431 N-1,3-Benzodioxol-5-ylmethyl-isophthalamic acid, (4-carboxyphenyl) methyl ester; 0432 4-3-(3-Methoxy-benzylcarbamoyl)-benzoylamino-methyl-benzoic acid; 0433 4-Methoxy-isophthalic acid di-2,1,3-benzothiadiazol-5-ylmethyl ester; 0434 4-3-(3-Methoxy-benzylcarbamoyl)-benzoylamino-methyl-benzoic acid methyl ester; 0435 N-(3-Methoxy-benzyl)-N-(4-nitro-benzyl)-isophthalamide; 0436 N-(3,4-Dichloro-benzyl)-N-pyridin-4-ylmethyl-isophthalamide; 0437 N-1,3-Bis-1,3-benzodioxol-5-ylmethyl-4-ethoxy-isophthalamide; 0438 N-(4-Chloro-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0439 N-(3,4-Dichloro-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0440 N-(4-Methoxy-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0441 N,N-Bis-(4-fluoro-3-methoxy-benzyl)-isophthalamide; 0442 4-Ethoxy-N1,N3-bis-(3-methoxy-benzyl)-isophthalamide; 0443 N1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-ethoxy-isophthalamide; 0444 N-(3-Methoxy-benzyl)-N-pyridin-3-ylmethyl-isophthalamide; 0445 N-(3-Methoxy-benzyl)-N-pyridin-4-ylmethyl-isophthalamide; 0446 N1-1,3-Benzodioxol-5-ylmethyl-N-3-pyridin-3-ylmethyl-isophthalamide; 0447 N-(3-Methoxy-benzyl)-N-(3-trifluoromethoxy-benzyl)-isophthalamide; 0448 N1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-isopropoxy-isophthalamide; 0449 4-Isopropoxy-N1,N3-bis-(3-methoxy-benzyl)-isophthalamide; 0450 N1-Benzyl-4-methoxy-N-3-(4-methoxy-benzyl)-isophthalamide; 0451 N1-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-3-(4-methoxy-benzyl)-isophthalamide; 0452 N1-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N-3-(2-phenoxy-ethyl)-isophthalamide; 0453 N1-Benzyl-4-methoxy-N-3-(2-phenoxy-ethyl)-isophthalamide; 0454 N1-1,3-Benzodioxol-5-ylmethyl-N-3-(4-chloro-benzyl)-4-methoxy-isophthalamide; 0455 N3-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N 1-(4-methoxy-benzyl)-isophthalamide; 0456 N3-Benzyl-4-methoxy-N-1-(4-methoxy-benzyl)-isophthalamide; 0457 N3-1,3-Benzodioxol-5-ylmethyl-4-methoxy-N 1-(2-phenoxy-ethyl)-isophthalamide; 0458 N3-1,3-Benzodioxol-5-ylmethyl-N 1-(2-ethoxy-ethyl)-4-methoxy-isophthalamide; 0459 4-Methoxy-N1-(4-methoxy-benzyl)-N-3-pyridin-4-ylmethyl-isophthalamide; 0460 4-Amino-N1,N3-bis-1,3-benzodioxol-5-ylmethyl-isophthalamide; 0461 4-Acetylamino-N1,N3-bis-1,3-benzodioxol-5-ylmethyl-isophthalamide; 0462 N-(3-Methoxy-benzyl)-N-pyridin-3-ylmethyl-isophthalamide; 0463 N-(3-Methoxy-benzyl)-N-pyridin-4-ylmethyl-isophthalamide; 0464 N1-1,3-Benzodioxol-5-ylmethyl-N-3-pyridin-3-ylmethyl-isophthalamide; 0465 N-(4-Chloro-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0466 N-(3,4-Dichloro-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0467 N-(4-Methoxy-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0468 N-(3-Methoxy-benzyl)-N-(4-methyl-benzyl)-isophthalamide; 0469 N,N-Bis-(4-fluoro-3-methoxy-benzyl)-isophthalamide; 0470 (3-(1,3-Benzodioxol-5-ylmethyl)-carbamoyl-benzoyl-benzyl-amino)-acetic acid; 0471 N-Benzo1,3dioxol-5-ylmethyl-isophthalamic(4-hydroxymethyl-benzoic acid) ester; 0472 N-(3,4-Dichloro-benzyl)-N-pyridin-4-ylmethyl-isophthalamide; 0473 N-(3-Methoxy-benzyl)-N-(4-nitro-benzyl)-isophthalamide; 0474 4-3-(3-Methoxy-benzylcarbamoyl)-benzoylamino-methyl-benzoic acid methyl ester; 0475 N-3-Methoxybenzyl-isophthalamic(4-hydroxymethyl-benzoic acid) ester; 0476 4-3-(3-Methoxy-benzylcarbamoyl)-benzoylamino-methyl-benzoic acid; 0477 N-(3-Amino-benzyl)-N-(3-methoxy-benzyl)-isophthalamide; 0478 N-(3-Methoxy-benzyl)-N-(3-nitro-benzyl)-isophthalamide; 0479 4-Ethoxy-N1,N3-bis-(3-methoxy-benzyl)-isophthalamide; 0480 N1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-ethoxy-isophthalamide; 0481 N1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-propoxy-isophthalamide; 0482 N1,N3-Bis-1,3-benzodioxol-5-ylmethyl-4-isopropoxy-isophthalamide; 0483 N1,N3-Bis-2,1,3-benzothiadiazol-5-ylmethyl-4-methoxy-isophthalamide; and 0484 4-Methoxy-isophthalic acid di-2,1,3-benzothiadiazol-5-ylmethyl ester, or a pharmaceutically acceptable salt thereof. 0485 23. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IB 16

0486 or a pharmaceutically acceptable salt thereof; 0487 wherein: 0488 W, together with the carbon atoms to which it is attached, form a 5-membered ring diradical 17

0489 B is O or NR5; or 0490 A and B are taken together to form CC; 0491 X is O, S, SO, SO2, NR5, or CH2; 0492 each Y independently is O or S; 0493 R1, R4, and R5 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)n cycloalkyl, (CH2)n heterocyclic, C1-C6 alkanoyl, (CH2)n aryl, or (CH2)n heteroaryl; 0494 R2 and R3 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, NO2, NR4R5, (CH2)n cycloalkyl, (CH2)n aryl, or (CH2)n heteroaryl; CONR4R5, or COR6; 0495 R2 may further be halo; 0496 n is an integer of from 0 to 5; 0497 R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing O, S, or N, and substituted or unsubstituted; 0498 wherein R1 and R3 are not both selected from: hydrogen and C1-C6 alkyl. 0499 24. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formula IIB 18

0500 or a pharmaceutically acceptable salt thereof, wherein A, B, R1, R2, R3, R4, and Y are as defined above for Embodiment 23. 0501 25. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formula IIIB 19

0502 or a pharmaceutically acceptable salt thereof, wherein A, B, R1, R2, and R4 are as defined above for Embodiment 23, and R3 is (CH2)n aryl, (CH2)n cycloalkyl, or (CH2)n heteroaryl. 0503 26. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formula IVB 20

0504 or a pharmaceutically acceptable salt thereof, wherein A, B, R1, R2, R3, and R4 are as defined above for Embodiment 23. 0505 27. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formula VB 21

0506 or a pharmaceutically acceptable salt thereof, wherein A, B, R1, R2, R3, R4, and R5 are as defined above for Embodiment 23. 0507 28. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formulas VIIB, VIIB, VIIIB, or IXB: 22

0508 or a pharmaceutically acceptable salt thereof, wherein A, B, X, R1, R2, R3, and R4 are as defined above for Embodiment 23. 0509 29. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formula XB 23

0510 or a pharmaceutically acceptable salt thereof, wherein R1R4, A, B, and X are as defined above for Embodiment 23. 0511 30. The combination according to Embodiment 23, wherein the compound of Formula IB is a compound of Formula XIB 24

0512 or a pharmaceutically acceptable salt thereof, 0513 wherein: 0514 W, together with the carbon atoms to which it is attached, form a 5-membered ring diradical 25

0515 each Y independently is O or S; 0516 X is S, O, or NR5; 0517 R1, R4, and R5 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)n cycloalkyl, (CH2)n heterocyclic, C1-C6 alkanoyl, (CH2)n aryl, or (CH2)n heteroaryl; 0518 R2 is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, CN, NO2, NR4R5, (CH2)n cycloalkyl, (CH2)n aryl, or (CH2)n heteroaryl; R3 is hydrogen, halo, C1-C6 alkyl, C2-C6 alkenyl, CN, NO2, NR4R5, (CH2)q cycloalkyl, (CH2)q aryl, or (CH2)q heteroaryl; 0519 n is 0, 1, or 2; 0520 q is 2, 3, or 4; and 0521 R4 and R5 when taken together with the nitrogen to which they are attached complete a 3- to 8-membered ring containing carbon atoms and optionally containing O, S, or N, and substituted or unsubstituted; 0522 wherein R1 and R3 are not both selected from: hydrogen and C1-C6 alkyl. 0523 31. The combination according to Embodiment 23, wherein the compound of Formula 1B is selected from: 0524 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0525 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0526 3-(4-Pyridyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0527 3-(4-Pyridyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-d-pyrimidine-6-carboxylic acid benzyl ester; 0528 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (4-pyridyl) ester; 0529 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (4-pyridyl) ester; 0530 3-(4-Pyridyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (4-pyridyl) ester; 0531 3-(4-Pyridyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-d-pyrimidine-6-carboxylic acid (4-pyridyl) ester; 0532 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid piperoyl ester; 0533 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid piperoyl ester; 0534 3-Piperoyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid piperoyl ester; 0535 3-Piperoyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-d-pyrimidine-6-carboxylic acid piperoyl ester; 0536 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0537 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo2,3-d-pyrimidine-6-carboxylic acid benzyl ester; 0538 3-Benzyl-1,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo2,3-d-pyrimidine-6-carboxylic acid benzyl ester; 0539 3-Benzyl-1,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo2,3-d-pyrimidine-6-carboxylic acid benzofuran-6-ylmethyl ester; 0540 3-Benzyl-1-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo2,3-d-pyrimidine-6-carboxylic acid benzofuran-6-ylmethyl ester; 0541 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo2,3-dpyrimidine-6-carboxylic acid benzofuran-6-ylmethyl ester; 0542 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzofuran-6-ylmethyl ester; 0543 3-Benzyl-1,7-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo2,3-d-pyrimidine-6-carboxylic acid benzothiophene-6-ylmethyl ester; 0544 3-Benzyl-1-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-1H-pyrrolo2,3-d-pyrimidine-6-carboxylic acid benzothiophene-6-ylmethyl ester; 0545 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo2,3-dpyrimidine-6-carboxylic acid benzothiophene-6-ylmethyl ester; 0546 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzothiophene-6-ylmethyl ester; 0547 3-(3-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0548 3-(4-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0549 3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0550 3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0551 3-(3-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0552 1-Methyl-3-(2-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0553 1-Methyl-3-(4-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0554 3-(4-Carboxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0555 1-Methyl-2,4-dioxo-3-(3-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0556 3-Biphenyl-4-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0557 1-Methyl-2,4-dioxo-3-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0558 3-(3-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0559 3-(2-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0560 1-Methyl-2,4-dioxo-3-(4-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0561 3-2-Hydroxy-3-(naphthalen-1-yloxy)-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0562 3-(3-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0563 1-Methyl-3-naphthalen-1-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0564 3-(6-Chloro-benzo1,3dioxol-5-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0565 1-Methyl-2,4-dioxo-3-(4-oxo-4-thiophen-2-yl-butyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0566 1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0567 1-Methyl-2,4-dioxo-3-(4-m-tolyloxy-butyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0568 3-(3,5-Dimethyl-isoxazol-4-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0569 3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0570 3-Dihydro-benzo1,4dioxin-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0571 1-Methyl-2,4-dioxo-3-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0572 3-2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0573 3-Benzyloxymethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0574 1-Methyl-2,4-dioxo-3-(4-m-tolyloxy-butyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0575 1-Methyl-2,4-dioxo-3-(2-phenylmethanesulfonyl-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0576 3-(4-Amino-6-phenylamino-1,3,5triazin-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0577 3-4-(4-Fluoro-phenyl)-4-oxo-butyl-11-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0578 3-4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyl-11-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0579 1-Methyl-2,4-dioxo-3-(4-phenoxy-butyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0580 1-Methyl-2,4-dioxo-3-(4-oxo-4-phenyl-butyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0581 1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0582 3-3-4-(3-Chloro-phenyl)-piperazin-1-yl-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0583 3-1-Bromo-2-(1H-indol-3-yl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0584 3-(2-Benzenesulfinyl-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0585 3-3-(3-Fluoro-phenylcarbamoyl)-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0586 1-Methyl-2,4-dioxo-3-2-(2-trifluoromethyl-phenylcarbamoyl)-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0587 3-2-(4-Methoxy-phenyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0588 3-2-(4-Chloro-2-nitro-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0589 1-Methyl-3-(5-nitro-furan-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0590 3-(1-Benzyl-1H-imidazol-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0591 3-3-(Benzyl-methyl-amino)-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0592 3-(Bis-trifluoromethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0593 3-3-(2-Bromo-4-methyl-phenoxy)-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0594 3-Benzenesulfonylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0595 3-2-(4-Chloro-benzenesulfonyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0596 3-Benzo1,3dioxol-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0597 3-(3-Iodo-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0598 1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0599 3-(4-Acetoxy-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0600 3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0601 1-Methyl-2,4-dioxo-3-(4-1,2,3thiadiazol-4-yl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0602 3-(5-Methoxycarbonyl-furan-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0603 3-(2-Carboxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0604 1-Methyl-2,4-dioxo-3-(3-pyrrol-1-yl-propyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0605 3-(3-Carboxy-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0606 3-(2-Cyano-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0607 3-(3-Ethoxycarbonyl-furan-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0608 3-(3-Amino-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0609 3-(3-Cyano-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0610 3-(2-Hydroxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0611 3-(2-Carboxy-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0612 1-Methyl-2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0613 1-Methyl-2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxyl carboxylic acid benzyl ester; 0614 Iodomethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0615 3-(2-Fluoro-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0616 Methyl-2,4-dioxo-3-(tetrahydro-furan-2-ylmethyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0617 3-1-(4-Carboxy-phenyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0618 3-(Hex-5-enyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0619 3-(2-Ethyl-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0620 1-Methyl-2,4-dioxo-3-(2,2,2-trifluoro-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxyl pyrimidine acid benzyl ester; 0621 3-(Diethoxy-phosphorylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0622 3-But-2-ynyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0623 Bromo-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid; 0624 1-Methyl-2,4-dioxo-3-2-(tetrahydro-pyran-2-yloxy)-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0625 1-Methyl-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0626 3-(2-Acetoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid; 0627 3-Butyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0628 3-Isobutyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0629 3-Ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0630 3-(3-Bromo-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0631 3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0632 3-(2-Ethylamino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0633 3-Cyclobutylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0634 3-((R)-3-Hydroxy-2-methyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0635 3-(4-Hydroxy-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0636 3-(2-Ethoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0637 3-Isobutyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0638 3-(2-Chloro-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0639 1-Methyl-3-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0640 3-Allyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0641 3-(2,2-Dimethoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0642 1-Methyl-3-oxiranylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0643 1-Methyl-2,4-dioxo-3-propyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0644 3-Benzo1,2,5oxadiazol-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0645 3-(3-Hydroxy-2,2-dimethyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0646 3-(2-Carboxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0647 3-Propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic benzyl ester; 0648 1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0649 1-Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0650 3-(4-Dimethylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0651 3-(4-Methanesulfonylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0652 3-4-(Methanesulfonyl-methyl-amino)-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0653 3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0654 3-4-(Acetyl-methyl-amino)-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0655 3-(4-Dimethylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0656 1-Methyl-3-(4-methylamino-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0657 3-(4-Carbamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0658 3-(4-Dimethylcarbamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0659 3-(4-Carboxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0660 3-(4-Methoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0661 3-4-Bis-(2-hydroxy-ethyl)-amino-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0662 3-(3,5-Dimethoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0663 3-(4-tert-Butyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0664 1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0665 3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0666 2,4-Dioxo-3-1,3,4thiadiazol-2-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0667 3-Isoxazol-3-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0668 3-Oxazol-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0669 2,4-Dioxo-3-thiazol-2-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0670 3-(1H-imidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0671 3-(1-Methyl-1H-imidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0672 3-(1-Methyl-1H-pyrrol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0673 2,4-Dioxo-3-(1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0674 2,4-Dioxo-3-(1H-pyrrol-2-ylmethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0675 2,4-Dioxo-3-thiophen-2-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0676 2,4-Dioxo-3-1,2,3,4tetrazin-5-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0677 2,4-Dioxo-3-1,2,4,5tetrazin-3-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0678 3-(1-Methyl-piperidin-4-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0679 2,4-Dioxo-3-pyrimidin-2-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0680 2,4-Dioxo-3-(2H-pyran-2-ylmethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0681 3-(1H-Imidazo4,5-bpyridin-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0682 3-(1H-Benzoimidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0683 3-Benzobthiophen-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0684 2,4-Dioxo-3-quinolin-2-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0685 3-(2H-Chromen-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0686 3-(1H-Benzoimidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0687 3-(1-Methyl-1H-benzoimidazol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0688 3-(1H-Indol-2-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0689 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid furan-3-ylmethyl ester; 0690 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-ethyl-propyl ester; 0691 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,1-dioxo-tetrahydro-116-thiophen-3-yl ester; 0692 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-hydroxy-benzyl ester; 0693 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-oxy-pyridin-4-ylmethyl ester; 0694 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid but-3-enyl ester; 0695 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-diethylamino-propyl ester; 0696 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-cyano-1-phenyl-methyl ester; 0697 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-amino-benzyl ester; 0698 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzyl ester; 0699 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-oxy-pyridin-3-ylmethyl ester; 0700 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-ethoxy-ethyl ester; 0701 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid thiophen-2-ylmethyl ester; 0702 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,6-dichloro-benzyl ester; 0703 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid dimethylamino-methyl-ethyl ester; 0704 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,2-diphenyl-ethyl ester; 0705 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-pyridin-2-yl-ethyl ester; 0706 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-ethanesulfonyl-ethyl ester; 0707 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid diethylamino-methyl-ethyl ester; 0708 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid dimethylamino-methyl-propyl ester; 0709 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-chloro-phenoxy)-ethyl ester; 0710 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; 0711 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-hydroxy-benzyl ester; 0712 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-morpholin-4-yl-ethyl ester; 0713 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl ester; 0714 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,3-dihydro-benzo1,4dioxin-2-ylmethyl ester; 0715 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-methyl-piperidin-4-yl ester; 0716 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(4-hydroxy-phenyl)-ethyl ester; 0717 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-cyano-ethyl ester; 0718 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid hexyl ester; 0719 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-fluoro-benzyl ester; 0720 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-hydroxy-6-methyl-pyridin-2-ylmethyl ester; 0721 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-benzyloxy-ethyl ester; 0722 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-methoxy-benzyl ester; 0723 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzyl ester; 0724 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,2,2-trifluoro-ethyl ester; 0725 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,2,2-trichloro-ethyl ester; 0726 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pyridin-3-ylmethyl ester; 0727 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester; 0728 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-pyridin-3-yl-propyl ester; 0729 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid; 0730 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-phenoxy-ethyl ester; 0731 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,3-dimethyl-butyl ester; 0732 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 2-methyl-benzyl ester; 0733 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-phenyl-ethyl ester; 0734 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-benzyl-piperidin-4-yl ester; 0735 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid propyl ester; 0736 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid methyl ester; 0737 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-trifluoromethyl-benzyl ester; 0738 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-p-tolyl-ethyl ester; 0739 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-trifluoromethyl-benzyl ester; 0740 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid tetrahydro-furan-2-ylmethyl ester; 0741 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid octahydro-inden-5-yl ester; 0742 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-amino-benzyl ester; 0743 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-aziridin-1-yl-ethyl ester; 0744 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methyl-but-2-enyl ester; 0745 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0746 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid trifluoro-trifluoromethyl-ethyl ester; 0747 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid phenethyl ester; 0748 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-methoxy-ethyl ester; 0749 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid biphenyl-4-ylmethyl ester; 0750 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 2-chloro-6-fluoro-benzyl ester; 0751 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid tetrahydro-pyran-4-yl ester; 0752 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-ethyl-oxetan-3-ylmethyl ester; 0753 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid butyl ester; 0754 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-hydroxy-phenyl)-ethyl ester; 0755 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(4-fluoro-phenyl)-ethyl ester; 0756 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclopropylmethyl ester; 0757 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-ethyl-benzyl ester; 0758 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (S)-1-phenyl-ethyl ester; 0759 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,6-difluoro-benzyl ester; 0760 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclobutyl methyl ester; 0761 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-pyridin-4-yl-ethyl ester; 0762 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-hydroxy-cyclopentyl ester; 0763 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-pentafluorophenyl-ethyl ester; 0764 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-benzyloxycarbonylamino-ethyl ester; and 0765 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid ethyl ester; or a pharmaceutically acceptable salt thereof. 0766 32. The combination according to Embodiment 23, wherein the compound of Formula 1B is selected from: 0767 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-pyridin-4-yl-ethyl)-amide; 0768 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid (2-morpholin-4-yl-ethyl)-amide; 0769 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methyl-benzylamide; 0770 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid sec-butylamide; 0771 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclopentylamide; 0772 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclopropylamide; 0773 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyanomethyl-amide; 0774 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclohexylamide; 0775 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methyl-benzylamide; 0776 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (3-ethoxy-propyl)-amide; 0777 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-chloro-benzylamide; 0778 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-methyl-benzylamide; 0779 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2,2-diphenyl-ethyl)-amide; 0780 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (pyridin-3-ylmethyl)-amide; 0781 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclopropylmethyl-amide; 0782 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (1-ethyl-pyrrolidin-2-ylmethyl)-amide; 0783 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (pyridin-2-ylmethyl)-amide; 0784 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(3,4-dimethoxy-phenyl)-ethyl-amide; 0785 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (furan-2-ylmethyl)-amide; 0786 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-fluoro-benzylamide; 0787 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-bromo-ethyl)-amide; 0788 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-sulfamoyl-benzylamide; 0789 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0790 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0791 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid phenethyl-amide; 0792 (S)-2-1-(3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidin-6-yl)-methanoyl-amino-propionic acid; 0793 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (1-phenyl-ethyl)-amide; 0794 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-methoxy-benzylamide; 0795 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzylamide; 0796 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-d pyrimidine-6-carboxylic acid 3-bromo-benzylamide; 0797 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(4-sulfamoyl-phenyl)-ethyl-amide; 0798 2-1-(3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidin-6-yl)-methanoyl-amino-3-phenyl-propionic acid methyl ester; 0799 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (3-imidazol-1-yl-propyl)-amide; 0800 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-methoxy-phenyl)-ethyl-amide; 0801 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-trifluoromethyl-benzylamide; 0802 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-amino-benzylamide; 0803 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(4-fluoro-phenyl)-ethyl-amide; and 0804 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid ((R)-2-hydroxy-1-methyl-ethyl)-amide; or a pharmaceutically acceptable salt thereof. 0805 33. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 0806 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzofuran-5-ylmethyl ester; 0807 (3-11-(3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidin-6-yl)-methanoyl-amino-propyl)-carbamic acid tert-butyl ester; 0808 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzofuran-2-ylmethyl ester; 0809 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid thiophen-3-ylmethyl ester; 0810 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3H-1,2,3oxathiazol-5-ylmethyl ester; 0811 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3H-1,2,3oxathiazol-5-ylmethyl ester; 0812 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,4,2dioxazol-3-ylmethyl ester; 0813 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,4,2dioxazol-3-ylmethyl ester; 0814 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid furazan-3-ylmethyl ester; 0815 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid furazan-3-ylmethyl ester; 0816 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,2,4oxadiazol-5-ylmethyl ester; 0817 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,2,4oxadiazol-5-ylmethyl ester; 0818 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3H-1,2,3triazol-4-ylmethyl ester; 0819 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3H-1,2,3triazol-4-ylmethyl ester; 0820 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-1,2,4triazol-3-ylmethyl ester; 0821 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-1,2,4triazol-3-ylmethyl ester; 0822 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid isoxazol-5-ylmethyl ester; 0823 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid isoxazol-5-ylmethyl ester; 0824 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid oxazol-2-ylmethyl ester; 0825 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid oxazol-2-ylmethyl ester; 0826 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid isothiazol-5-ylmethyl ester; 0827 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid isothiazol-5-ylmethyl ester; 0828 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid thiazol-2-ylmethyl ester; 0829 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid thiazol-2-ylmethyl ester; 0830 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-imidazol-2-ylmethyl ester; 0831 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-imidazol-2-ylmethyl ester; 0832 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-pyrazol-3-ylmethyl ester; 0833 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-pyrazol-3-ylmethyl ester; 0834 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-pyrrol-2-ylmethyl ester; 0835 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-pyrrol-2-ylmethyl ester; 0836 3-Furazan-3-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0837 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-chromen-2-ylmethyl ester; 0838 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-thiochromen-2-ylmethyl ester; 0839 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2H-thiochromen-2-ylmethyl ester; 0840 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,3,4thiadiazol-2-ylmethyl ester; 0841 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,3,4thiadiazol-2-ylmethyl ester; 0842 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-benzoimidazol-5-ylmethyl ester; 0843 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-benzoimidazol-5-ylmethyl ester; 0844 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-benzoimidazol-2-ylmethyl ester; 0845 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-benzoimidazol-2-ylmethyl ester; 0846 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-indol-2-ylmethyl ester; 0847 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-indol-2-ylmethyl ester; 0848 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-indol-5-ylmethyl ester; 0849 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1H-indol-5-ylmethyl ester; 0850 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,3-dihydro-benzofuran-5-ylmethyl ester; and 0851 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,3-dihydro-benzofuran-5-ylmethyl ester; or a pharmaceutically acceptable salt thereof. 0852 34. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 0853 4-6-3-(4-Methoxy-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0854 3-(4-Methanesulfonyl-benzyl)-6-3-(4-methoxy-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0855 4-6-3-(3-Methoxy-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0856 3-(4-Methanesulfonyl-benzyl)-6-3-(3-methoxy-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0857 4-1-Methyl-2,4-dioxo-6-(3-pyridine-4-yl-prop-1-ynyl)-1,4-dihydro-2H-2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0858 3-(4-Methanesulfonyl-benzyl)-16-(3-pyridin-4-yl-prop-1-ynyl)-1H-2,3-dpyrimidine-2,4-dione; 0859 4-1-Methyl-2,4-dioxo-6-(3-pyridine-3-yl-prop-1-ynyl)-1,4-dihydro-2H-2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0860 3-(4-Methanesulfonyl-benzyl)-6-(3-pyrimidin-3-yl-prop-1-ynyl)-1H-2,3-dpyrimidine-2,4-dione; 0861 4-6-3-(4-Fluoro-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid 6-3-(4-Fluoro-phenyl)-prop-1-ynyl-3-(4-methanesulfonyl-benzyl)-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0862 4-6-3-(3-Fluoro-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0863 6-3-(3-Fluoro-phenyl)-prop-1-ynyl-3-(4-methanesulfonyl-benzyl)-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0864 4-6-3-(4-Chloro-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0865 6-3-(4-Chloro-phenyl)-prop-1-ynyl-3-(4-methanesulfonyl-benzyl)-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0866 4-6-3-(3-Chloro-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrmidine-3-ylmehtyl-benzoic acid; 0867 6-3-(3-Chloro-phenyl)-prop-1-ynyl-3-(4-methanesulfonyl-benzyl)-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0868 4-6-3-(4-Bromo-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0869 6-3-(4-Bromo-phenyl)-prop-1-ynyl-3-(4-methanesulfonyl-benzyl)-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0870 4-6-3-(3-Bromo-phenyl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0871 6-3-(3-Bromo-phenyl)-prop-1-ynyl-3-(4-methanesulfonyl-benzyl)-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0872 4-1-Methyl-6-3-(4-nitro-phenyl)-prop-1-ynyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0873 3-(4-Methanesulfonyl-benzyl)-1-methyl-6-3-(4-nitro-phenyl)-prop-1-ynyl)-1H-thieno2,3-dpyrimidine-2,4-dione; 0874 4-6-3-(2-Methoxy-pyridin-4-yl)-prop-1-ynyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0875 3-(4-Methanesulfonyl-benzyl)-6-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0876 4-1-Methyl-6-3-(4-methylsulfanyl-phenyl)-prop-1-ynyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0877 3-(4-Methanesulfonyl-benzyl)-1-methyl-6-3-(4-methylsulfanyl-phenyl)-prop-1-ynyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0878 4-1-Methyl-6-3-(3-methylsulfanyl-phenyl)-prop-1-ynyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidine-3-ylmehtyl-benzoic acid; 0879 3-(4-Methanesulfonyl-benzyl)-1-methyl-6-3-(3-methylsulfanyl-phenyl)-prop-1-ynyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0880 4-1-Methyl-2,4-dioxo-6-(3-p-tolyl-prop-1-ynyl)-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethylbenzoic acid; 0881 3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(3-p-tolyl-prop-1-ynyl)-1H-2,3-dpyrimidine-2,4-dione; 0882 4-1-Methyl-2,4-dioxo-6-(3-m-tolyl-prop-1-ynyl)-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethylbenzoic acid; 0883 3-(4-Methanesulfonyl-benzyl)-1-methyl-6-(3-m-tolyl-prop-1-ynyl)-1H-2,3-dpyrimidine-2,4-dione; 0884 3-Benzyl-6-3-(4-methoxy-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0885 3-Benzyl-6-3-(3-methoxy-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0886 3-Benzyl-1-methyl-6-(3-pyridin-4-yl-prop-1-ynyl)-1H-thieno2,3-dpyrimidine-2,4-dione; 0887 3-Benzyl-1-methyl-6-(3-pyridin-3-yl-prop-1-ynyl)-1H-thieno2,3-dpyrimidine-2,4-dione; 0888 3-Benzyl-6-3-(4-fluoro-phenyl)-prop-1-ynyl-11-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0889 3-Benzyl-6-3-(3-fluoro-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0890 3-Benzyl-6-3-(4-chloro-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0891 3-Benzyl-6-3-(3-chloro-phenyl)-prop-1-ynyl-1-methyl-1H-thieno 2,3-dpyrimidine-2,4-dione; 0892 3-Benzyl-6-3-(4-bromo-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0893 3-Benzyl-6-3-(3-bromo-phenyl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0894 3-Benzyl-6-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0895 3-Benzyl-1-methyl-6-3-(4-methylsulfanyl-phenyl)-prop-1-ynyl-1H-2,3-dpyrimidine-2,4-dione; 0896 3-Benzyl-1-methyl-6-3-(3-methylsulfanyl-phenyl)-prop-1-ynyl-1H-2,3-dpyrimidine-2,4-dione; 0897 3-Benzyl-1-methyl-6-(3-p-tolyl-prop-1-ynyl)-1H-thieno 2,3-dpyrimidine-2,4-dione; 0898 3-Benzyl-1-methyl-6-(3-m-tolyl-prop-1-ynyl)-1H-thieno2,3-dpyrimidine-2,4-dione; 0899 3-(3-Fluoro-benzyl)-6-3-(4-methoxy-phenyl)-prop-1-ynyl-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0900 3-(3-Fluoro-benzyl)-6-3-(3-methoxy-phenyl)-prop-1-ynyl-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0901 3-(3-Fluoro-benzyl)-1-methyl-6-(3-pyridine-4-yl-prop-1-ynyl)-1H-2,3-dpyrimidine-2,4-dione; 0902 3-(3-Fluoro-benzyl)-1-methyl-6-(3-pyridine-3-yl-prop-1-ynyl)-1H-2,3-dpyrimidine-2,4-dione; 0903 3-(3-Fluoro-benzyl)-6-3-(4-fluoro-phenyl)-prop-1-ynyl-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0904 3-(3-Fluoro-benzyl)-6-3-(3-fluoro-phenyl)-prop-1-ynyl-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0905 6-3-(4-Chloro-phenyl)-prop-1-ynyl-3-(3-fluoro-benzyl)-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0906 6-3-(3-Chloro-phenyl)-prop-1-ynyl-3-(3-fluoro-benzyl)-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0907 6-3-(4-Bromo-phenyl)-prop-1-ynyl-3-(3-fluoro-benzyl)-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0908 6-3-(3-Bromo-phenyl)-prop-1-ynyl-3-(3-fluoro-benzyl)-1-methyl-1H-2,3-dpyrimidine-2,4-dione; 0909 3-(3-Fluoro-benzyl)-6-3-(2-methoxy-pyridin-4-yl)-prop-1-ynyl-1-methyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0910 3-(3-Fluoro-benzyl)-1-methyl-6-3-(4-methylsulfanyl-phenyl)-prop-1-ynyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0911 3-(3-Fluoro-benzyl)-1-methyl-6-3-(3-methylsulfanyl-phenyl)-prop-1-ynyl-1H-thieno2,3-dpyrimidine-2,4-dione; 0912 3-(3-Fluoro-benzyl)-1-methyl-6-(3-p-tolyl-prop-1-ynyl)-1H-thieno2,3-dpyrimidine-2,4-dione; and 0913 3-(3-Fluoro-benzyl)-1-methyl-6-(3-m-tolyl-prop-1-ynyl)-1H-thieno2,3-dpyrimidine-2,4-dione; or a pharmaceutically acceptable salt thereof. 0914 35. The combination according to Embodiment 23, wherein the compound of Formula 1B is selected from: 0915 3-(3-Methoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0916 3-(3-Methoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0917 3-Benzofuran-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0918 1-Methyl-3-(4-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0919 3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0920 1-Methyl-2,4-dioxo-3-(4-vinyl-benzyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0921 1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0922 3-(4-Bromo-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester; 0923 1-Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0924 1-Methyl-2,4-dioxo-3-4-(2H-tetrazol-5-yl)-benzyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0925 3-(4-Fluoro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester; 0926 3-(4-tert-Butyoxycarbonyl-benzyl)-1-methyl2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0927 3-(4-tert-Butyoxycarbonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid; 0928 4-6-(4-Fluoro-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0929 4-6-(4-Dimethylamino-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid, compound with trifluoro-acetic acid; 0930 4-6-(2-Ethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-3-ylmethyl-benzoic acid; 0931 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid; 0932 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0933 1-Methyl-2,4-dioxo-3-4-(1H-tetrazol-5-yl)-benzyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0934 1-Methyl-3-4-(morpholine-4-sulfonyl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0935 1-Methyl-3-4-(morpholine-4-carbonyl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0936 3-But-2-ynyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0937 1-Methyl-2,4-dioxo-3-3-(1H-tetrazol-5-yl)-benzyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0938 3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0939 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-phenyl-acetic acid; 0940 3-2-(2,4-Dichloro-benzenesulfonyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0941 3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0942 1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno2,3-d-pyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0943 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 0944 1-Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0945 3-(4-Isopropylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0946 1-Methyl-2,4-dioxo-3-4-(pyrrolidine-1-sulfonyl)-benzyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; and 0947 1-Methyl-3-4-(4-methyl-piperidine-1-sulfonyl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; or a pharmaceutically acceptable salt thereof. 0948 36. The combination according to Embodiment 23, wherein the compound of Formula 1B is selected from: 0949 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzofuran-2-ylmethyl ester; 0950 3-(4-Bromo-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester; 0951 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzyl ester; 0952 4-1-Methyl-2,4-dioxo-6-(pyridin-4-ylmethyl)-carbamoyl-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid, compound with trifluoro-acetic acid; 0953 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0954 4-6-(3,4-Dimethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid tert-butyl ester; 0955 4-6-(3,4-Dimethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0956 4-6-(4-Bromo-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0957 4-6-(4-Bromo-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid tert-butyl ester; 0958 4-6-(3,5-Bis-trifluoromethyl-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0959 4-6-(4-Chloro-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0960 4-1-Methyl-2,4-dioxo-6-(4-sulfamoyl-benzylcarbamoyl)-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0961 3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0962 3-(4-Iodo-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0963 3-(4-Dimethylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0964 3-(3-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0965 3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0966 3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0967 5-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-furan-2-carboxylic acid ethyl ester; 0968 3-(4-Cyano-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzyl ester; 0969 1-Methyl-2,4-dioxo-3-4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-benzyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0970 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid 2-dimethylamino-ethyl ester; 0971 3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0972 3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 0973 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid furan-3-ylmethyl ester; 0974 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pentafluorophenylmethyl ester; 0975 3-Benzyl-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0976 3-Benzyl-1-cyclopropylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0977 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (pyridin-4-ylmethyl)-amide; 0978 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-bromo-benzyl ester; 0979 4-6-(3-Difluoromethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0980 4-6-(3-Difluoromethoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid tert-butyl ester; 0981 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0982 4-6-(4-Methanesulfonyl-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid tert-butyl ester; 0983 4-6-(4-Methanesulfonyl-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0984 4-1-Methyl-2,4-dioxo-6-(2-pyridin-4-yl-ethylcarbamoyl)-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 0985 1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0986 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid methyl ester; 0987 3-(2,3-Dihydro-benzofuran-6-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0988 1-Methyl-3-(2-methyl-thiazol-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 0989 1-Methyl-2,4-dioxo-3-4-(1H-tetrazol-5-yl)-benzyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-fluoro-benzylamide; 0990 3-Benzyl-2-methoxy-4-oxo-3,4-dihydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 0991 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid 2,2-dimethyl-propionyloxymethyl ester; 0992 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-cyclohexanecarboxylic acid; 0993 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-cyclohexanecarboxylic acid methyl ester; 0994 1-4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-phenyl-cyclopropanecarboxylic acid methyl ester; 0995 1-4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-phenyl-cyclopropanecarboxylic acid tert-butyl ester; 0996 1-4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-phenyl-cyclopropanecarboxylic acid; 0997 2-4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-phenoxy-2-methyl-propionic acid tert-butyl ester; 0998 2-4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-phenoxy-2-methyl-propionic acid; 0999 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-furo2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1000 3-(3-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1001 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1002 3-Biphenyl-4-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1003 3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1004 3-(4-Methanesulfonyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1005 1-Methyl-3-(4-methyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1006 1-Methyl-2,4-dioxo-3-phenethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1007 3-(4-Amino-6-phenylamino-1,3,5-triazin-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1008 1-Methyl-2,4-dioxo-3-(4-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1009 3-(6-Cyano-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1010 3-2-(2,5-Dimethoxy-phenyl)-2-oxo-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1011 3-(3-Iodo-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1012 1-Methyl-2,4-dioxo-3-(3-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1013 3-(2,4-Bis-trifluoromethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1014 3-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1015 3-2-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1016 3-(2-Carboxy-allyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1017 3-(2-Carboxy-allyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1018 3-(3-Amino-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1019 3-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1020 3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1021 1-Methyl-3-oxiranylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1022 1-Methyl-3-((S)-2-methyl-butyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1023 1-Methyl-2,4-dioxo-3-(4-phenoxy-butyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1024 3-(2-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1025 1-Methyl-2,4-dioxo-3-(3-phenoxy-propyl)-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1026 3-Hex-5-enyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1027 1-Methyl-2,4-dioxo-3-pyridin-3-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1028 3-2-Hydroxy-3-(naphthalen-1-yloxy)-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1029 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1030 3-Cyclobutylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1031 3-Allyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1032 1-Methyl-2,4-dioxo-3-prop-2-ynyl-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1033 3-But-2-ynyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1034 1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1035 1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1036 3-((R)-3-Hydroxy-2-methyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1037 3-Isobutyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1038 3-(6-Chloro-pyridin-3-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1039 3-(2-Benzenesulfonylmethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1040 1-Methyl-3-naphthalen-1-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1041 1-Methyl-2,4-dioxo-3-(2-trifluoromethyl-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1042 3-(3-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1043 3-(4-Methoxycarbonyl-butyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1044 3-Ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1045 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-fluoro-benzyl ester; 1046 3-2-(4-Chloro-benzenesulfonyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1047 3-(2-Acetoxy-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1048 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-phenoxy-ethyl ester; 1049 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1050 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzylamide; 1051 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,6-dichloro-benzyl ester; 1052 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid butyl ester; 1053 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,3-dihydro-1,4-benzodioxin-2-ylmethyl ester; 1054 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-diethylamino-1-methyl-ethyl ester; 1055 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-fluoro-benzyl ester; 1056 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-isopropyl-benzyl ester; 1057 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-p-tolyl-ethyl ester; 1058 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-trifluoromethyl-benzyl ester; 1059 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclobutylmethyl ester; 1060 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 2,6-difluoro-benzyl ester; 1061 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-hydroxy-phenyl)-ethyl ester; 1062 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-hydroxy-phenyl)-ethyl ester; 1063 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-methyl-piperidin-4-yl ester; 1064 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-methyl-piperidin-4-yl ester; 1065 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pyridin-3-ylmethyl ester; 1066 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-pyridin-3-yl-propyl ester; 1067 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 2-dimethylamino-1-methyl-ethyl ester; 1068 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzyl ester; 1069 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid tetrahydro-pyran-4-yl ester; 1070 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,2,2-trifluoro-1-trifluoromethyl-ethyl ester; 1071 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-trifluoromethyl-benzyl ester; 1072 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-benzyloxy-ethyl ester; 1073 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,2,2-trichloro-ethyl ester; 1074 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid phenethyl ester; 1075 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-ethyl-oxetan-3-ylmethyl ester; 1076 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-morpholin-4-yl-ethyl ester; 1077 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester; 1078 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-pyrrolidin-1-yl-ethyl ester; 1079 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 2-(2-ethoxy-ethoxy)-ethyl ester; 1080 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid tetrahydro-pyran-2-ylmethyl ester; 1081 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 4-nitro-benzyl ester; 1082 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid pentyl ester; 1083 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-phenyl-propyl ester; 1084 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-phenoxy-benzyl ester; 1085 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,5-dimethoxy-benzyl ester; 1086 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methyl-butyl ester; 1087 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-chloro-benzyl ester; 1088 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-ethyl-piperidin-3-yl ester; 1089 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-benzyloxy-benzyl ester; 1090 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid isobutyl ester; 1091 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-(4-methoxy-phenyl)-propyl ester; 1092 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 2-chloro-6-fluoro-benzyl ester; 1093 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (S)-(tetrahydro-furan-3-yl) ester; 1094 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzyl ester; 1095 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzyl ester; 1096 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-pyridin-2-yl-propyl ester; 1097 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-piperidin-2-yl-ethyl ester; 1098 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 5-bromo-2-methoxy-benzyl ester; 1099 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cycloheptylmethyl ester; 1100 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,2,3,4-tetrahydro-naphthalen-1-yl ester; 1101 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (S)-1-pyrrolidin-2-ylmethyl ester; 1102 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-chloro-benzyl ester; 1103 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester; 1104 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methylsulfanyl-benzyl ester; 1105 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methylsulfanyl-benzyl ester; 1106 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,4-dichloro-benzyl ester; 1107 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,3-diphenyl-propyl ester; 1108 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-pyridin-2-yl-ethyl ester; 1109 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid furan-3-ylmethyl ester; 1110 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid but-3-enyl ester; 1111 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-cyano-ethyl ester; 1112 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-ethoxy-ethyl ester; 1113 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyano-phenyl-methyl ester; 1114 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-trifluoromethyl-benzylamide; 1115 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methyl-benzylamide; 1116 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid phenethyl-amide; 1117 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid cyclopropylamide; 1118 1-Methyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1119 1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1120 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1121 1-Methyl-2,4-dioxo-3-(3-oxo-3-phenyl-propyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1122 3-4-(N-Hydroxycarbamimidoyl)-benzyl-11-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1123 1-Methyl-2,4-dioxo-3-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-benzyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1124 1-Methyl-2,4-dioxo-3-4-(5-thioxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-benzyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1125 4-(5-Isopropyl-2H-pyrazol-3-yl)-pyridine; 1126 3-Cyanomethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1127 (E)-4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-yl-but-2-enoic acid methyl ester; 1128 (E)-4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-yl-but-2-enoic acid; 1129 3-(2-Benzenesulfonyl-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1130 2-Methoxy-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid methyl ester; 1131 3-(2-Methoxymethyl-1,1,3-trioxo-2,3-dihydro-1H-116-1,2-benzisothiazol-6-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1132 1-Methyl-3-oct-2-ynyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1133 3-2-(4-Chloro-benzenesulfonylamino)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1134 3-2-(4-Bromo-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1135 3-2-(4-Bromo-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1136 3-2-(4-Fluoro-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1137 3-2-(4-Chloro-benzenesulfonyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1138 3-2-(4-Fluoro-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1139 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 1140 3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1141 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-2-methyl-benzoic acid methyl ester; 1142 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid methyl ester; 1143 2-Methoxy-4-6-(3-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl-benzoic acid methyl ester; 1144 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-2-methyl-benzoic acid methyl ester; 1145 1-Methyl-2,4-dioxo-3-(3-oxo-3-phenyl-propyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1146 3-2-(4-Chloro-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1147 1-Methyl-2,4-dioxo-3-2-(3-trifluoromethyl-benzenesulfonyl)-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1148 1-Methyl-2,4-dioxo-3-2-(3-trifluoromethyl-benzenesulfonyl)-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1149 3-2-(4-Chloro-benzenesulfonyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; and 1150 3-(2-Amino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; or a pharmaceutically acceptable salt thereof. 1151 37. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 1152 38. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 1153 1-Methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid; 1154 4-(6-Carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl)-2-methyl-benzoic acid; 1155 4-(6-Carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl)-2-methyl-benzoic acid methyl ester; 1156 4-6-(3-Hydroxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-2-methyl-benzoic acid; 1157 4-(6-Carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-ylmethyl)-2-hydroxy-benzoic acid; 1158 3-(2-Amino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; and 1159 4-(2,5-Di-pyridin-4-yl-thiophen-3-yl)-benzaldehyde. 1160 39. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 1161 1-Methyl-2,4-dioxo-3-(1-phenyl-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1162 1-Methyl-2,4-dioxo-3-(3-oxo-3-phenyl-propyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1163 3-((S)-3,7-Dimethyl-oct-6-enyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1164 3-(2-Ethyl-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1165 3-(5-Cyano-pentyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1166 3-(E)-But-2-enyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1167 1-Methyl-3-(2-naphthalen-1-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1168 1-Methyl-2,4-dioxo-3-(E)-pent-2-enyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1169 1-Methyl-2,4-dioxo-3-(2-phenylsulfanyl-ethyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1170 3-sec-Butyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1171 1-Methyl-3-(2-methyl-allyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1172 3-(1-Ethyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1173 1-Methyl-2,4-dioxo-3-pent-2-ynyl-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1174 3-(2-Benzenesulfonyl-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1175 1-Methyl-3-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1176 3-2-(4-Fluoro-benzenesulfonyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1177 1-Methyl-2,4-dioxo-3-2-(toluene-4-sulfonyl)-ethyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1178 3-3-(4-Fluoro-phenyl)-3-oxo-propyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1179 3-3-(4-Chloro-phenyl)-3-oxo-propyl-11-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1180 3-(2-Benzoylamino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1181 3-2-(4-Bromo-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1182 3-Benzofurazan-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1183 1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1184 5-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-isoxazol-3-yl-carbamic acid methyl ester; 1185 3-Benzyloxycarbonylamino-5-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-yl-4-oxo-pentanoic acid tert-butyl ester; 1186 3-2-(4-Chloro-phenylsulfanyl)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1187 1-Methyl-2,4-dioxo-3-(1-phenyl-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1188 1-Methyl-2,4-dioxo-3-(E)-pent-2-enyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1189 3-(2-Ethyl-hexyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1190 1-Methyl-2,4-dioxo-3-(2-phenylmethanesulfonyl-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1191 3-(5-Cyano-pentyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1192 3-(E)-But-2-enyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1193 1-Methyl-3-(2-naphthalen-1-yl-ethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1194 1-Methyl-2,4-dioxo-3-(E)-pent-2-enyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1195 1-Methyl-2,4-dioxo-3-(2-phenylsulfanyl-ethyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1196 3-sec-Butyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1197 1-Methyl-3-(2-methyl-allyl)-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1198 3-(1-Ethyl-propyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1199 1-Methyl-2,4-dioxo-3-pent-2-ynyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1200 1-Methyl-3-(3-methyl-but-2-enyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1201 1-Methyl-2,4-dioxo-3-2-(toluene-4-sulfonyl)-ethyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1202 3-(2-Benzoylamino-ethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1203 3-2-(4-Bromo-phenoxy)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1204 3-Benzofurazan-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1205 1-Methyl-2,4-dioxo-3-(2-phenoxy-ethyl)-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1206 5-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-isoxazol-3-yl-carbamic acid methyl ester; and 1207 3-Benzyloxycarbonylamino-5-6-(3-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-thieno2,3-dpyrimidin-3-yl-4-oxo-pentanoic acid tert-butyl ester. 1208 40. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 1209 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid methyl ester; 1210 3-(4-Bromo-benzyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1211 3-(4-Fluoro-benzyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1212 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno 2,3-dpyrimidine-6-carboxylic acid pyridin-4-ylmethyl ester; 1213 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzobthiophen-2-ylmethyl ester; 1214 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 1-methyl-1H-indol-5-ylmethyl ester; 1215 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid thiophen-3-ylmethyl ester; 1216 3-1,3-Benzodioxol-5-ylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1217 1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1218 3-(4-tert-Butyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1219 3-(3,4-Dichloro-benzyl)-5-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1220 1-Methyl-2,4-dioxo-3-(4-trifluoromethoxy-benzyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1221 1-Methyl-3-naphthalen-2-ylmethyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1222 3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1223 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzofuran-5-ylmethyl ester; 1224 3-(3,5-Dimethoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1225 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1226 3-(3,5-Dinitro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid benzyl ester; 1227 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid; and 1228 3-(4-Carboxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-ethoxy-benzyl ester. 1229 41. The combination according to Embodiment 23, wherein the compound of Formula IB is selected from: 1230 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(3,4-dimethoxy-phenyl)-ethyl-amide; 1231 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-amino-benzylamide; 1232 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(4-chloro-phenyl)-ethyl-amide; 1233 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (biphenyl-2-ylmethyl)-amide; 1234 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,4-dimethoxy-benzylamide; 1235 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-pyridin-4-yl-ethyl)-amide; 1236 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-difluoromethoxy-benzylamide; 1237 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(3-ethoxy-phenyl)-ethyl-amide; 1238 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-chloro-4-fluoro-benzylamide; 1239 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,4-dichloro-benzylamide; 1240 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-phenyl-propyl)-amide; 1241 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,4,5-trimethoxy-benzylamide; 1242 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-chloro-benzylamide; 1243 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,5-dimethoxy-benzylamide; 1244 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,3-dimethoxy-benzylamide; 1245 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-trifluoromethyl-benzylamide; 1246 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-methoxy-benzylamide; 1247 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-methyl-benzylamide; 1248 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (4-phenyl-butyl)-amide; 1249 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (pyridin-3-ylmethyl)-amide; 1250 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1251 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid ((S)-2,2-dimethyl-4-phenyl-1,3-dioxinan-5-yl)-amide; 1252 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(3-methoxy-phenyl)-ethyl-amide; 1253 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1254 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (thiophen-2-ylmethyl)-amide; 1255 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-chloro-benzylamide; 1256 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (5-methyl-furan-2-ylmethyl)-amide; 1257 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2,2-diphenyl-ethyl)-amide; 1258 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2-methoxy-phenyl)-ethyl-amide; 1259 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(3-trifluoromethyl-phenyl)-ethyl-amide; 1260 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-bromo-benzylamide; 1261 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(1H-indol-3-yl)-ethyl-amide; 1262 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,5-dichloro-benzylamide; 1263 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid indan-1-ylamide; 1264 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (furan-2-ylmethyl)-amide; 1265 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(4-methoxy-phenyl)-ethyl-amide; 1266 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2,4-dimethoxy-benzylamide; 1267 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-chloro-benzylamide; 1268 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (1-phenyl-ethyl)-amide; 1269 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3,4-dichloro-benzylamide; 1270 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-fluoro-3-trifluoromethyl-benzylamide; 1271 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-pyridin-2-yl-ethyl)-amide; 1272 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2,4-dimethyl-phenyl)-ethyl-amide; 1273 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 2-(2,4-dichloro-phenyl)-ethyl-amide; 1274 1,3-Dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1275 3-Cyanomethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1276 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1277 3-(4-Cyclopropylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1278 1-Methyl-3-(6-nitro-pyridin-3-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1279 1-Methyl-3-(6-nitro-pyridin-3-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1280 1-Methyl-3-(6-nitro-pyridin-3-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 1281 3-Cyclohexylmethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 1282 3-2-(1H-Benzimidazole-5-carbonyl)-aniino-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1283 1-Methyl-2,4-dioxo-3-2-(3-piperidin-1-yl-propionylamino)-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1284 1-Methyl-2,4-dioxo-3-2-(6-pyrazol-1-yl-pyridine-3-carbonyl)-amino-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1285 3-2-(4-Diethylamino-benzoylamino)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1286 3-2-(6-Chloro-pyridine-3-carbonyl)-amino-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1287 1-Methyl-2,4-dioxo-3-2-(1H-pyrrole-2-carbonyl)-amino-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1288 3-2-(2-Dimethylamino-acetylamino)-ethyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1289 1-Methyl-2,4-dioxo-3-2-(pyrazine-2-carbonyl)-amino-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1290 1-Methyl-3-2-(2-methyl-2-methylamino-propionylamino)-ethyl-2,4-dioxo-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1291 1-Methyl-2,4-dioxo-3-2-(pyrrolidine-2-carbonyl)-amino-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1292 1-Methyl-2,4-dioxo-3-2-3-(5-phenyl-1H-pyrrol-2-yl)-propionylamino-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1293 1-Methyl-2,4-dioxo-3-2-2-(pyridin-4-ylsulfanyl)-acetylamino-ethyl-1,2,3,4-tetrahydro-thieno2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1294 3-(6-Amino-pyridin-3-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; 1295 1-Methyl-2,4-dioxo-3-(3-phenyl-prop-2-ynyl)-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1296 3-(6-Amino-pyridin-3-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1297 3-(6-Amino-pyridin-3-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid (pyridin-4-ylmethyl)-amide; 1298 1-Methyl-2,4-dioxo-3-2-(pyridin-2-ylamino)-ethyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1299 1-Methyl-2,4-dioxo-3-2-(pyrimidin-2-ylamino)-ethyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; and 1300 1-Methyl-2,4-dioxo-3-2-(pyrimidin-2-ylamino)-ethyl-1,2,3,4-tetrahydro-2,3-dpyrimidine-6-carboxylic acid 3-methoxy-benzylamide; or a pharmaceutically acceptable salt thereof. 1301 42. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IC 26

1302 or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, 1303 in which: 1304 R1 represents a group selected from: 1305 hydrogen, amino, 1306 (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, mono(C1-C6)alkylamino(C1-C6)alkyl, di(C1-C6)alkylamino(C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, heterocycle, and 3- to 6-membered cycloalkyl(C1-C6)alkyl, these groups being unsubstituted or substituted with one or more groups, which may be identical or different, selected from amino, (C1-C6)alkyl, cyano, halo(C1-C6)alkyl, C(O)OR4, OR4 and SR4, in which R4 represents hydrogen or (C1-C6)alkyl, 1307 W represents an oxygen atom, a sulphur atom, or a group NR, in which R represents (C1-C6)alkyl, hydroxyl, or cyano, 1308 X1, X2 and X3 represent, independently of each other, a nitrogen atom or a group CR6 in which R6 represents a group selected from hydrogen, (C1-C6)alkyl, amino, mono(C1-C6)alkylamino, di(C1-C6)alkylamino, hydroxyl, (C1-C6)alkoxy, and halogen, 1309 with the proviso that not more than two of the groups X1, X2 and X3 simultaneously represent a nitrogen atom, 1310 Y represents a group selected from oxygen atom, sulphur atom, NH, and N(C1-C6)alkyl, 1311 Z represents: 1312 an oxygen atom, a sulphur atom, 1313 or a group NR7 in which R7 represents a group selected from hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, cycloalkyl, aryl, and heteroaryl, and 1314 when Y is an oxygen atom, a sulphur atom, or a group N(C1-C6)alkyl, Z optionally represents a carbon atom which is unsubstituted or substituted with a (C1-C6)alkyl, an aryl, an aryl(C1-C6)alkyl, an aromatic or non-aromatic heterocycle or a cycloalkyl, 1315 n is an integer from 1 to 8 inclusive, 1316 Z1 represents CR8R9 wherein R8 and R9, independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, halogen, amino, OR4, SR4 or C(O)OR4 in which R4 represents a hydrogen or (C1-C6)alkyl, and 1317 when n is greater than or equal to 2, the hydrocarbon chain Z1 optionally contains one or more multiple bonds, 1318 and/or one of the carbon atoms in the hydrocarbon chain Z1 may be replaced with an oxygen atom, a sulphur atom which is unsubstituted or substituted with one or two oxygen atoms, or a nitrogen atom which is unsubstituted or substituted with a (C1-C6)alkyl, 1319 and when one of the carbon atoms in the hydrocarbon chain Z1 is replaced with a sulphur atom which is unsubstituted or substituted with one or two oxygen atoms, then the group C(Y)-Z- optionally may be absent in the general formula (I), 1320 A represents a group selected from: 1321 aromatic or non-aromatic, 5- or 6-membered monocycle comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and 1322 bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered rings, which may be identical or different, comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1323 m is an integer from 0 to 7 inclusive, 1324 the group(s) R2, which may be identical or different, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, SCF3, CF3, OCF3, NR10R11, OR10, SR10, SOR10, SO2R10, (CH2)kSO2NR10R11, X5(CH2)kC(O)OR10, (CH2)kC(O)OR10, X5(CH2)kC(O)NR10R11, (CH2)kC(O)NR10R11, and X4R12 in which: 1325 X5 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (C1-C6)alkyl, 1326 k is an integer from 0 to 3 inclusive, 1327 R10 and R11, which may be identical or different, are selected from hydrogen and (C1-C6)alkyl, 1328 X4 represents a group selected from single bond, CH2, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group, 1329 R12 represents an aromatic or non-aromatic, heterocyclic or non-heterocyclic, 5- or 6-membered ring which is unsubstituted or substituted with one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxyl and amino, and when the ring is heterocyclic, it comprises from 1 to 4 beteroatoms selected from nitrogen, oxygen and sulphur; 1330 R3 represents a group selected from: 1331 hydrogen, 1332 (C1-C6)alkyl, (C3-C6)alkenyl, (C3-C6)alkynyl, these groups being unsubstituted or substituted with one or more groups, which may be identical or different, selected from amino, cyano, halo(C1-C6)alkyl, cycloalkyl, C(O)NR10R11, C(O)OR10, OR10, and SR10, in which R10 and R11, which may be identical or different, represent hydrogen or (C1-C6)alkyl, 1333 and the group of formula: 27

1334 in which p is an integer from 0 to 8 inclusive, 1335 Z2 represents CR13R14 wherein R13 and R14, independently of each other, represent a group selected from hydrogen, (C1-C6)alkyl, phenyl, halo(C1-C6)alkyl, halogen, amino, OR4, SR4 and C(O)OR4 in which R4 represents hydrogen or (C1-C6)alkyl, and 1336 when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or more multiple bonds, 1337 and/or one of the carbon atoms in the hydrocarbon chain Z2 may be replaced with an oxygen atom, a sulphur atom which is unsubstituted or substituted with one or two oxygen atoms, a nitrogen atom which is unsubstituted or substituted with a (C1-C6)alkyl, or a carbonyl group, 1338 B represents a group selected from: 1339 an aromatic or non-aromatic 5- or 6-membered monocycle comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and 1340 a bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered rings, which may be identical or different, comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1341 q is an integer from 0 to 7 inclusive, 1342 the group(s) R5, which may be identical or different, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, CF3, OCF3, (CH2)kNR15R16, N(R15)C(O)R16, N(R15)C(O)OR16, N(R15)SO2R16, N(SO2R15)2, OR15, S(O)k1R15, SO2N(R15)(CH2)k2NR16R17, (CH2)kSO2NR15R16, X7(CH2)kC(O)OR15, (CH2)kC(O)OR15, C(O)O(CH2)k2NR15R16, C(O)O(CH2)k2C(O)OR18, X7(CH2)kC(O)NR15R16, (CH2)kC(O)NR15R16, R19C(O)OR15, X6R20, and C(O)R21NR15R16 in which: 1343 X7 represents a group selected from oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by a hydrogen atom or a (C1-C6)alkyl group, 1344 k is an integer from 0 to 3 inclusive, 1345 k1 is an integer from 0 to 2 inclusive, 1346 k2 is an integer from 1 to 4 inclusive, 1347 R15, R16 and R17, which may be identical or different, are selected from hydrogen and (C1-C6)alkyl, 1348 R18 represents a group selected from (C1-C6)alkyl, R21NR15R16, R2, NR15C(O)R21NR16R17, and C(O)OR21NR15R16 in which R21 represents a linear or branched (C1-C6)alkylene group, and R15, R16 and R17 are as defined hereinbefore, 1349 R19 represents a (C3-C6)cycloalkyl group, 1350 X6 represents a group selected from single bond, CH2, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group, 1351 R20 represents an aromatic or non-aromatic, heterocyclic or non-heterocyclic, 5- or 6-membered ring, which is unsubstituted or substituted with one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxyl, oxo, cyano, tetrazole, amino, and C(O)OR4 wherein R4 represents hydrogen or (C1-C6)alkyl, and, when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1352 with the proviso that when X1 represents a nitrogen atom, X2 cannot represent a carbon atom substituted with a methyl group or with NHCH3. 1353 43. The combination according to Embodiment 42, wherein the compound of Formula IC is selected from: 1354 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-3,4-dpyrimidin-3-ylmethyl-benzoic acid; 1355 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido3,4-dpyrimidine-6-carboxylic acid (1,3-benzodioxol-5-ylmethyl)-amide; 1356 4-6-(4-Fluoro-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1357 1-Methyl-2,4-dioxo-3-4-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-benzyl-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1358 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid hemi calcium salt; 1359 Methyl 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-pyrido3,4-dpyrimidin-3-ylmethyl-benzoate; 1360 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1361 1-Methyl-2,4-dioxo-3-4-(2H-tetrazol-5-yl)-benzyl-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1362 Methyl 2-hydroxy-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1363 3-(4-Chloro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxy-benzylamide; 1364 4-6-(1,3-Benzodioxol-5-ylmethyl)-carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1365 2-Hydroxy-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1366 Methyl 4-6-(3-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1367 3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 3-methoxy-benzylamide; 1368 4-Pyridylmethyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate; 1369 Methyl 4-6-(1,3-benzodioxol-5-ylmethyl)-carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1370 1-Methyl-3-4-(5-methyl-1,2,4-oxadiazol-3-yl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1371 1-Methyl-3-4-(3-methyl-1,2,4-oxadiazol-5-yl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1372 3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 1373 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1374 1-4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-phenyl-cyclopropanecarboxylic acid; 1375 4-Pyridylmethyl 3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate; 1376 3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 3-methoxy-benzylamide; 1377 3-(3,4-Difluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1378 3-(4-Dimethylcarbamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1379 1-Methyl-3-4-(2-methyl-2H-tetrazol-5-yl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1380 3-(4-Bromo-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 1381 3-(3,4-Difluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid (pyridin-3-ylmethyl)-amide; 1382 Benzo1,3dioxol-5-ylmethyl-3-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate; 1383 3-Benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo1,3dioxol-5-ylmethyl)amide; 1384 1-Methyl-3-(4-methylcarbamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1385 3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1386 4-6-(4-Hydroxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1387 Methyl 4-6-(4-fluoro-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1388 3-(4-Chlorobenzyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo1,3dioxol-5-ylmethyl)amide; 1389 1-Methyl-3-4-(1-methyl-1H-tetrazol-5-yl)-benzyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1390 3-(4-Methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide; 1391 4-Pyridylmethyl 3-(benzo1,3dioxol-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate; 1392 Methyl 4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1393 1-Methyl-2,4-dioxo-3-pyridin-4-ylmethyl-1,2,3,4-tetrahydro-quinazoline-carboxylic acid 4-methoxy-benzylamide; 1394 3-(4-Amino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1395 1-Methyl-3-(4-nitro-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1396 2-Methoxy-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1397 1-Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1398 1-Methyl-2,4-dioxo-3-(4-sulfamoyl-benzyl)-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1399 3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1400 3-(4-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid (pyridin-4-ylmethyl)-amide; 1401 3-(4-Methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid (pyridin-4-ylmethyl)-amide; 1402 2-Methyl-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1403 3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1404 4-1-Methyl-2,4-dioxo-6-(pyridin-4-ylmethyl)-carbamoyl-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1405 3-(3-fluoro-4-methoxy-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy benzylamine; 1406 4-1-Ethyl-6-(4-methoxy-benzylcarbamoyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1407 3-(Benzo1,3dioxol-5-ylmethyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo1,3dioxol-5-ylmethyl)amide; 1408 3-(2-Cyano-biphenyl-4-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1409 4-1-Methyl-6-(4-methylsulfanyl-benzylcarbamoyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1410 4-6-(Benzofurazan-5-ylmethyl)-carbamoyl-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1411 Methyl 2-methyl-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1412 3-(4-Acetylamino-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1413 3-(Benzo1,3dioxol-5-ylmethyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo1,3dioxol-5-ylmethyl)amide; 1414 3-(4-Dimethylcarbamoylmethyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1415 Benzo1,3dioxol-5-ylmethyl 3-benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylate; 1416 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-phenyl-acetic acid; 1417 (4-1-Methyl-2,4-dioxo-6-(pyridin-4-ylmethyl)-carbamoyl-1,4-dihydro-2H-quinazolin-3-ylmethyl-phenyl)-acetic acid; 1418 3-Benzyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid 4-methoxybenzylamide; 1419 Methyl 4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-phenyl-acetate; 1420 3-(3-Fluoro-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid (pyridin-4-ylmethyl)-amide; 1421 2,4-Dioxo-3-(thien-2-ylmethyl)-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo1,3dioxol-5-ylmethyl)amide; 1422 1-Methyl-3-(4-methylsulfamoyl-benzyl)-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1423 Methyl 4-1-methyl-2,4-dioxo-6-(pyridin-4-ylmethyl)-carbamoyl-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1424 2-Fluoro-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid; 1425 3-(4-Cyano-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrido3,4-dpyrimidine-6-carboxylic acid 4-methoxy-benzylamide; 1426 4-6-(3-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-3,4-dpyrimidin-3-ylmethyl-benzoic acid; 1427 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoic acid hemi magnesium salt; 1428 4-6-(4-Methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-2,3-dpyrimidin-3-ylmethyl-benzoic acid; 1429 3-4-(N-methylsulfonylamino)-benzyl-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; 1430 Ethyl 2-Fluoro-4-6-(4-methoxy-benzylcarbamoyl)-1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl-benzoate; 1431 3-(4-Dimethylsulfamoyl-benzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazoline-6-carboxylic acid 4-methoxy-benzylamide; and 1432 3-(4-Methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-6-carboxylic acid (benzo1,3dioxol-5-ylmethyl)amide; or a pharmaceutically acceptable salt thereof. 1433 44. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula ID 28

1434 or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, 1435 in which: 1436 W represents N or CR1; in which R1 is selected from: 1437 hydrogen atom, 1438 OR5, SR5 in which R5 is selected from hydrogen, (C1-C6)alkyl and aryl(C1-C6)alkyl, 1439 (C1-C6)alkyl, cycloalkyl of 3 to 8 carbon atoms optionally interrupted with one hetero atom selected from oxygen, sulfur and nitrogen, aryl, heteroaryl and aryl(C1-C6)alkyl, these groups being optionally substituted by (CH2)pOH or (CH2)pNH2, in which p is an integer from 0 to 4 inclusive, 1440 X represents N or CR2 in which R2 is selected from: 1441 hydrogen atom, 1442 NR6R7, OR6, SR6 in which R6 and R7, identical or different, are selected from hydrogen, (C1-C6)alkyl and aryl(C1-C6)alkyl, 1443 (C1-C6)alkyl, cycloalkyl of 3 to 8 carbon atoms optionally interrupted with one hetero atom selected from oxygen, sulfur and nitrogen, aryl, heteroaryl and aryl(C1-C6)alkyl, these groups being optionally substituted by (CH2)pOH or (CH2)pNH2, in which p is an integer from 0 to 4 inclusive, 1444 Y represents a group selected from oxygen, sulfur, NH, and N(C1-C6)alkyl, 1445 Z represents a group selected from: 1446 oxygen, sulphur, 1447 and NR8 in which R8 represents a group selected from hydrogen, (C1-C6)alkyl, aryl(C1-C6)alkyl, cycloalkyl, aryl, and heteroaryl, and 1448 when Y is oxygen, sulphur, or N(C1-C6)alkyl, Z optionally represents a carbon atom which is optionally substituted by a group selected from (C1-C6)alkyl, aryl, aryl(C1-C6)alkyl, aromatic heterocycle, non-aromatic heterocycle, and cycloalkyl, 1449 n is an integer from 0 to 8 inclusive, 1450 Z1 represents a group CR9R10 wherein R9 and R10, identical or different, represent a group selected from hydrogen, (C1-C6)alkyl, halo(C1-C6)alkyl, halogen, NR5R11, OR5, SR5 and C(O)OR5 in which R5 and R11, identical or different, represents hydrogen atom or (C1-C6)alkyl, and 1451 when n is greater than or equal to 2, the hydrocarbon chain Z1 optionally contains one or more multiple bonds, 1452 and/or one of the carbon atoms in the hydrocarbon chain Z1 may be replaced with an oxygen atom, a sulphur atom which is optionally substituted by one or two oxygen atoms, or a nitrogen atom which is optionally substituted by (C1-C6)alkyl, 1453 A represents a group selected from: 1454 aromatic or non-aromatic, 5- or 6-membered monocycle comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and 1455 bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered rings, which may be identical or different, comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1456 m is an integer from 0 to 7 inclusive, 1457 the group(s) R4, which may be identical or different, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, SCF3, CF3, OCF3, NR5R11, OR5, SR5, SOR5, SO2R5, (CH2)kSO2NR5R11X1(CH2)kC(O)OR5, (CH2)kC(O)OR5, X1(CH2)kC(O)NR5R11, (CH2)kC(O)NR5R11, and X2R12 in which: 1458 X1 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by hydrogen or (C1-C6)alkyl, 1459 k is an integer from 0 to 3 inclusive, 1460 R5 and R11, which may be identical or different, are selected from hydrogen and (C1-C6)alkyl, 1461 X2 represents a group selected from single bond, CH2, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group, 1462 R12 represents an aromatic or non-aromatic, heterocyclic or non-heterocyclic, 5- or 6-membered ring which is optionally substituted by one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxyl, and amino, and when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1463 R3 represents a group selected from: 1464 hydrogen, 1465 (C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, these groups being optionally substituted by one or more groups, which may be identical or different, selected from amino, cyano, halo(C1-C6)alkyl, cycloalkyl, C(O)NR5R11, C(O)OR5, OR5, and SR5, in which R5 and R11, which may be identical or different, are as defined hereinbefore, 1466 and the group of formula: 29

1467 in which p is an integer from 0 to 8 inclusive, 1468 Z2 represents CR14R15 wherein R14 and R15, identical or different, represent a group selected from hydrogen, (C1-C6)alkyl, phenyl, halo(C1-C6)alkyl, halogen, amino, OR5, NR5R11, SR5 and C(O)OR5 in which R5 and R11, identical or different, are as defined hereinbefore, and 1469 when p is greater than or equal to 2, the hydrocarbon chain Z2 optionally contains one or more multiple bonds, 1470 and/or one of the carbon atoms in the hydrocarbon chain Z2 may be replaced with an oxygen atom, a sulphur atom which is optionally substituted by one or two oxygen atoms, or a nitrogen atom which is optionally substituted by (C1-C6)alkyl, 1471 B represents a group selected from: 1472 aromatic or non-aromatic 5- or 6-membered monocycle comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, and 1473 bicycle, composed of two aromatic or non-aromatic, 5- or 6-membered rings, which may be identical or different, comprising from 0 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1474 q is an integer from 0 to 7 inclusive, 1475 the group(s) R13, which may be identical or different, is (are) selected from (C1-C6)alkyl, halogen, CN, NO2, CF3, OCF3, (C1-C6)acyl, (CH2)kNR16R17, X3(CH2)kNR16R17N(R16)C(O)R17, N(R16)C(O)OR17, N(R16)SO2R17, N(SO2R16)2, OR16, S(O)k1R16, (CH2)kSO2NR16R17, X3(CH2)kC(O)OR16, (CH2)kC(O)OR16, X3(CH2)kC(O)NR16R17, (CH2)kC(O)NR16R17, C(O)OR19NR16NR17 and X4R18, in which: 1476 X3 represents a group selected from oxygen, sulphur optionally substituted by one or two oxygen atoms, and nitrogen substituted by a hydrogen atom or a (C1-C6)alkyl group, 1477 k is an integer from 0 to 3 inclusive, 1478 k1 is an integer from 0 to 2 inclusive, R16 and R17, which may be identical or different, are selected from hydrogen and (C1-C6)alkyl, 1479 X4 represents a group selected from single bond, CH2, oxygen atom, sulphur atom optionally substituted by one or two oxygen atoms, and nitrogen atom substituted by hydrogen atom or (C1-C6)alkyl group, 1480 R18 represents an aromatic or non-aromatic, heterocyclic or non-heterocyclic, 5- or 6-membered ring, which is optionally substituted by one or more groups, which may be identical or different, selected from (C1-C6)alkyl, halogen, hydroxyl, (C1-C6)alkoxy, oxo, cyano, tetrazole, NR5R11, and C(O)OR5 wherein R5 and R11 are as defined hereinbefore, and, when the ring is heterocyclic, it comprises from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur, 1481 R19 represents a (C1-C6)alkylene group. 1482 45. The combination according to Embodiment 44, wherein the compound of Formula ID is selected from: 1483 benzyl 4-benzyl-5-oxo-4H-1,2,4triazolo4,3-aquinazol-7-ylcarboxylate; 1484 4-pyridylmethyl 4-benzyl-5-oxo-4H-1,2,4triazolo4,3-aquinazol-7-ylcarboxylate; 1485 N-(3,4-methylenedioxybenzyl)-4-benzyl-5-oxo-4H-1,2,4triazolo4,3-aquinazol-7-ylcarboxamide; 1486 N-(4-pyridylmethyl)-4-benzyl-5-oxo-4H-1,2,4triazolo 4,3-aquinazol-7-ylcarboxamide; 1487 N-(3,4-methylenedioxybenzyl)-4-benzyl-5-oxo-4H-imidazo1,2-aquinazol-7-ylcarboxamide; 1488 N-(4-pyridylmethyl)-4-benzyl-5-oxo-4H-imidazo1,2-aquinazol-7-ylcarboxamide; 1489 N-(4-methoxybenzyl)-4-benzyl-5-oxo-4,5-dihydro1,2,4triazolo4,3-aquinazoline-7-carboxamide; 1490 N-3-(4-pyridylsulphanyl)propyl-4-benzyl-5-oxo-4,5-dihydro1,2,4triazolo-4,3-aquinazoline-7-carboxamide; 1491 N-(3,4-Methylenedioxybenzyl)-4-(4-cyanobenzyl)-5-oxo-4H-1,2,4triazolo4,3-aquinazol-7-ylcarboxamide; 1492 Methyl 4-7-(1,3-benzodioxol-5-ylmethyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoate; 1493 Methyl 4-7-(4-methoxybenzyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoate; 1494 Methyl 4-7-(pyridin-4-ylmethyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoate; 1495 (2-Dimethylamino-ethyl) 4-7-(4-fluoro-benzylcarbamoyl)-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoate; 1496 4-(4-Dimethylcarbamoyl-benzyl)-5-oxo-4,5-dihydro-1,2,4triazolo4,3-ajquinazoline-7-carboxylic acid 4-methoxy-benzylamide; 1497 N-(pyridin-4-ylmethyl)-4-(4-cyanobenzyl)-5-oxo-4H-1,2,4triazolo4,3-aquinazol-7-ylcarboxamide; 1498 Methyl (4-7-(1,3-benzodioxol-5-ylmethyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazolin-4-ylmethyl-phenyl)-acetate; 1499 Methyl (4-7-(4-methoxy)-benzylcarbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazolin-4-ylmethyl-phenyl)-acetate; 1500 Methyl (4-7-(pyridin-4-yl)-methylcarbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazolin-4-ylmethyl-phenyl)-acetate; 1501 N-(pyridin-4-ylmethyl) 4-3-(pyridin-4-yl)-2-propen-1-yl-5-oxo-4H-1,2,4triazolo4,3-aquinazol-7-ylcarboxamide; 1502 4-2-(4-Chloro-phenoxy)-ethyl-5-oxo-4,5-dihydro-1,2,4triazolo4,3-aquinazoline-7-carboxylic acid 4-methoxy-benzylamide; 1503 4-7-(4-methoxybenzyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoic acid; 1504 4-7-(1,3-benzodioxol-5-ylmethyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoic acid; 1505 4-7-(pyridin-4-ylmethyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoic acid; 1506 4-7-(4-fluoro)-benzylcarbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazol-4-ylmethylbenzoic acid; 1507 (4-7-(4-methoxy)-benzylcarbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazolin-4-ylmethyl-phenyl)-acetic acid; 1508 (4-7-(1,3-benzodioxol-5-ylmethyl)-carbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazolin-4-ylmethyl-phenyl)-acetic acid; and 1509 (4-7-(pyridin-4-yl)-methylcarbamoyl-5-oxo-5H-1,2,4triazolo4,3-aquinazolin-4-ylmethyl-phenyl)-acetic acid. 1510 46. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IE 30

1511 or a pharmaceutically acceptable salt thereof, wherein: 1512 n is 0, 1, or 2; 1513 X is O or NH; 1514 R2 is H, C1-C6 alkyl, or C1-C6 substituted alkyl; 1515 R1 and R3 independently are H, acyl, substituted acyl, C1-C6 alkyl, C1-C6 substituted alkyl, C2-C6 alkenyl, C2-C6 substituted alkenyl, C2-C6 alkynyl, C1-C6 substituted alkynyl, (CH2)m aryl, (CH2)m substituted aryl, (CH2)m heteroaryl, (CH2)m substituted heteroaryl, (CH2)m cycloalkyl, or (CH2)m substituted cycloalkyl; and 1516 each m independently is an integer of from 0 to 6, 1517 with the proviso that R3 is not (CH2)m biphenyl or (CH2)m substituted biphenyl. 1518 47. The combination according to Embodiment 46, wherein the compound of Formula IE is a compound of Formula IIE 31

1519 or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, and X are as defined above for Embodiment 46. 1520 48. The combination according to Embodiment 46, wherein the compound of Formula IE is selected from: 1521 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzyl ester; 1522 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzylamide; 1523 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1524 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (1H-indol-5-ylmethyl)-amide; 1525 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1526 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-(2-tert-butylsulfamoyl-ethyl)-benzylamide; 1527 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (1H-indol-2-ylmethyl)-amide; 1528 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-(2-sulfamoyl-ethyl)-benzylamide; 1529 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzylamide; 1530 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1531 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1532 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-benzoic acid tert-butyl ester; 1533 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-benzoic acid; 1534 2-(4-Carbamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1535 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1536 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-fluoro-benzylamide; 1537 4-Methyl-2-(4-nitro-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1538 4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1539 4-Methyl-2-4-(morpholine-4-sulfonyl)-benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1540 4-7-(4-Fluoro-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-benzoic acid methyl ester; 1541 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (2-methoxy-pyridin-4-ylmethyl)-amide; 1542 4-Methyl-2-naphthalen-2-ylmethyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1543 2-Biphenyl-4-ylmethyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1544 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (2,1,3-benzothiadiazol-5-ylmethyl)-amide; 1545 4-7-(4-Fluoro-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-benzoic acid; 1546 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-benzoic acid 2-dimethylamino-ethyl ester hydrochloride; 1547 4-Methyl-1,1,3-trioxo-2-4-(piperidine-1-carbonyl)-benzyl-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1548 2-(4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-benzoylamino-3-methyl-butyric acid; 1549 2-(4-Cyano-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1550 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-16-benzo1,2,4thiadiazin-2-ylmethyl-phenyl-acetic acid; 1551 4-7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-16-benzo1,2,4thiadiazin-2-ylmethyl-benzoic acid; 1552 4-Methyl-1,1,3-trioxo-2-4-(2H-tetrazol-5-yl)-benzyl-1,2,3,4-tetrahydro-16-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1553 2-(4-Amino-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-16-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1554 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-16-1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1555 4-Methyl-1,1,3-trioxo-2-pent-2-ynyl-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1556 4-Methyl-1,1,3-trioxo-2-(1-phenyl-ethyl)-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1557 2-(5-Cyano-pentyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1558 2-(E)-But-2-enyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1559 4-Methyl-1,1,3-trioxo-2-(E)-pent-2-enyl-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1560 4-Methyl-2-(2-methyl-allyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1561 4-Methyl-2-(3-methyl-but-2-enyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1562 4-Methyl-1,1,3-trioxo-2-2-(toluene-4-sulfonyl)-ethyl-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1563 2-3-(4-Fluoro-phenyl)-3-oxo-propyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1564 4-Methyl-1,1,3-trioxo-2-2-(1-phenyl-methanoyl)-amino-ethyl-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1565 2-Benzo1,2,5oxadiazol-5-ylmethyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1566 5-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl-isoxazol-3-yl-carbamic acid methyl ester; and 1567 4-Methyl-1,1,3-trioxo-2-thiazol-4-ylmethyl-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; or a pharmaceutically acceptable salt thereof. 1568 49. The combination according to Embodiment 46, wherein the compound of Formula IE is selected from: 1569 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1570 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1571 2-Benzyl-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1572 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1573 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1574 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1575 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1576 4-7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1577 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1578 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1579 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1580 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1581 4-7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1582 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1583 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1584 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1585 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1586 4-7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1587 4-(7-Benzylcarbamoyl-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1588 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1589 4-(4-Methyl-1,1,3-trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1590 4-7-(4-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1591 4-7-(3-Methoxy-benzylcarbamoyl)-4-methyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1592 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzylamide; 1593 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1594 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1595 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1596 2-(4-Methanesulfonyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1597 4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzylamide; 1598 4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1599 4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1600 4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1601 4-Methyl-2-(4-methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1602 2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzylamide; 1603 2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1604 2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1605 2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1606 2-(4-Dimethylsulfamoyl-benzyl)-4-methyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1607 2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid benzylamide; 1608 2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1609 2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1610 2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1611 2-Benzyl-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-benzo1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1612 4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1613 4-(1,1,3-Trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1614 4-(1,1,3-Trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1615 4-7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1616 4-7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid tert-butyl ester; 1617 4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1618 4-(1,1,3-Trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1619 4-(1,1,3-Trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1620 4-7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1621 4-7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-benzoic acid; 1622 4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1623 4-(1,1,3-Trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1624 4-(1,1,3-Trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1625 4-7-(4-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1626 4-7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid tert-butyl ester; 1627 4-(7-Benzylcarbamoyl-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1628 4-(1,1,3-Trioxo-7-(pyridin-4-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1629 4-(1,1,3-Trioxo-7-(pyridin-3-ylmethyl)-carbamoyl-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1630 4-7-(4-Methoxy-benzylcarbamoyl)1,1,3-trioxo-3,4-dihydro-1H-1l6-benzo1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1631 4-7-(3-Methoxy-benzylcarbamoyl)-1,1,3-trioxo-3,4-dihydro-1H-1l6-1,2,4thiadiazin-2-ylmethyl)-phenyl-acetic acid; 1632 2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid benzylamide; 1633 2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1634 2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1635 2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1636 2-(4-Methanesulfonyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1637 2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid benzylamide; 1638 2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1639 2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1640 2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; 1641 2-(4-Methylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; 1642 2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid benzylamide; 1643 2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-4-ylmethyl)-amide; 1644 2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid (pyridin-3-ylmethyl)-amide; 1645 2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 4-methoxy-benzylamide; and 1646 2-(4-Dimethylsulfamoyl-benzyl)-1,1,3-trioxo-1,2,3,4-tetrahydro-1l6-1,2,4thiadiazine-7-carboxylic acid 3-methoxy-benzylamide; or a pharmaceutically acceptable salt thereof. 1647 50. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IF 32

1648 or a pharmaceutically acceptable salt thereof, 1649 wherein: 1650 R2 is hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NO2, NR4R5, CN, or CF3; 1651 E is independently O or S; 1652 A and B independently are OR4 or NR5R6; 1653 R4 and R5 independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and R5 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, or NH, and optionally substituted or unsubstituted; and 1654 n is an integer from 0 to 6. 1655 51. The combination according to Embodiment 50, wherein the compound of Formula IF is a compound of Formula IIF 33

1656 or a pharmaceutically acceptable salt thereof, wherein R2 is as defined above, and each R4 independently is as defined above for Embodiment 50. 1657 52. The combination according to Embodiment 50, wherein the compound of Formula IF is a compound of Formula IIIF 34

1658 or a pharmaceutically acceptable salt thereof, wherein R2 is as defined above, and each R4 and R5 independently are as defined above for Embodiment 50. 1659 53. The combination according to Embodiment 50, wherein the compound of Formula IF is a compound of Formula IVF 35

1660 or a pharmaceutically acceptable salt thereof, wherein n and R2 are as defined above for Embodiment 50, and R6, R7, R8, and R9 independently are hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, nitro, or NH2. 1661 54. The combination according to Embodiment 50, wherein the compound of Formula IF is a compound of Formula VF 36

1662 or a pharmaceutically acceptable salt thereof, wherein n and R2 are as defined above for Embodiment 50, and each Ar independently is aryl or Het, wherein aryl is phenyl or substituted phenyl, and Het is an unsubstituted or substituted heteroaryl group. 1663 55. The combination according to Embodiment 50, wherein the compound of Formula IF is selected from: 1664 Pyrimidine-4,6-dicarboxylic acid, (4-chloro-benzylamide), (1,3-benzodioxol-5-ylmethyl)-amide; 1665 Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (1,3-benzodioxol-5-ylmethyl)-amide; 1666 Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (4-methoxy-benzylamide); 1667 Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-methoxy-benzylamide); 1668 Pyrimidine-4,6-dicarboxylic acid, (4-carbomethoxy-benzylamide), (3-methoxy-benzylamide); 1669 Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-pyridylmethylamide); 1670 Pyrimidine-4,6-dicarboxylic acid, (4-carboxy-benzylamide), (3-thiophenemethylamide); 1671 Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (1,3-benzodioxol-5-ylmethyl)-amide; 1672 Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl) amide, (1,3-benzodioxol-5-ylmethyl)-amide; 1673 Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide); 1674 Pyrimidine-4,6-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (3-methoxy-benzylamide); 1675 Pyrimidine-4,6-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester; 1676 Pyrimidine-4,6-dicarboxylic acid, bis-(4-chloro-benzylamide); 1677 Pyrimidine-4,6-dicarboxylic acid, bis-(1,3-benzodioxol-5-ylmethyl)-amide; 1678 Pyrimidine-4,6-dicarboxylic acid, bis-(4-methoxy-benzylamide); 1679 Pyrimidine-4,6-dicarboxylic acid, bis-(3-methoxy-benzylamide); 1680 Pyrimidine-4,6-dicarboxylic acid, bis-(4-carboxy-benzylamide); and 1681 Pyrimidine-4,6-dicarboxylic acid, bis-(4-carbomethoxy-benzylamide); or a pharmaceutically acceptable salt thereof. 1682 56. A combination, comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13 of Formula IG 37

1683 or a pharmaceutically acceptable salt thereof, 1684 wherein: 1685 R1 and R2 independently are hydrogen, halo, hydroxy, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, NO2, NR4R5, CN, or CF3; 1686 E is independently O or S; 1687 A and B independently are OR4 or NR4R5; 1688 R4 and R5 independently are H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, (CH2)n aryl, (CH2)n cycloalkyl, (CH2)n heteroaryl, or R4 and R5 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, or NH, and optionally substituted or unsubstituted; 1689 n is an integer from 0 to 6. 1690 57. The combination according to Embodiment 56, wherein the compound of Formula IG is a compound of Formula IIG 38

1691 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined above, and each R4 independently is as defined above for Embodiment 56. 1692 58. The combination according to Embodiment 56, wherein the compound of Formula IG is a compound of Formula IIIG 39

1693 or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are as defined above, and each R4 and R5 independently are as defined above for Embodiment 56. 1694 59. The combination according to Embodiment 56, wherein the compound of Formula IG is a compound of Formula IVG 40

1695 or a pharmaceutically acceptable salt thereof, wherein n, R1, and R2 are as defined above, and R6, R7, R8, and R9 independently are hydrogen, halo, C1-C6 alkyl, C1-C6 alkoxy, nitro, or NH2. 1696 60. The combination according to Embodiment 56, wherein the compound of Formula IG is a compound of Formula VG 41

1697 or a pharmaceutically acceptable salt thereof, wherein n, R1, and R2 are as defined above for Embodiment 56, and each Ar independently is aryl or Het, wherein aryl is phenyl or substituted phenyl, and Het is an unsubstituted or substituted heteroaryl group. 1698 61. The combination according to Embodiment 56, wherein the compound of Formula IG is selected from: 1699 Pyridine-3,5-dicarboxylic acid, (4-chloro-benzylamide), (1,3-benzodioxol-5-ylmethyl)-amide; 1700 Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (1,3-benzodioxol-5-ylmethyl)-amide; 1701 Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (4-methoxy-benzylamide); 1702 Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (3-methoxy-benzylamide); 1703 Pyridine-3,5-dicarboxylic acid, (4-carbomethoxy-benzylamide), (3-methoxy-benzylamide); 1704 Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (3-pyridylmethylamide); 1705 Pyridine-3,5-dicarboxylic acid, (4-carboxy-benzylamide), (3-thiophenemethylamide); 1706 Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (1,3-benzodioxol-5-ylmethyl)-amide; 1707 Pyridine-3,5-dicarboxylic acid, (2,1,3-benzooxadiazol-5-ylmethyl) amide, (1,3-benzodioxol-5-ylmethyl)-amide; 1708 Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (4-methoxy-benzylamide); 1709 Pyridine-3,5-dicarboxylic acid, (2,1,3-benzothiadiazol-5-ylmethyl) amide, (3-methoxy-benzylamide); 1710 Pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl) ester; 1711 2-Methoxy-pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)-amide; 1712 2-Ethoxy-pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)-amide; 1713 2-Amino-pyridine-3,5-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)-amide; 1714 2-Oxo-1,2-dihydro-pyridine-3,5-dicarboxylic acid bis-benzylamide; 1715 2-Methoxy-pyridine-3,5-dicarboxylic acid bis-benzylamide; 1716 (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid tert-butyl ester; 1717 (3,5-Bis-benzylcarbamoyl-pyridin-2-yloxy)-acetic acid; 1718 Pyridine-2,4-dicarboxylic acid bis-(3-methoxy-benzylamide); 1719 Pyridine-2,4-dicarboxylic acid bis-(1,3-benzodioxol-5-ylmethyl)-amide; 1720 Pyridine-2,4-dicarboxylic acid bis-(2,4-dimethoxy-benzylamide); 1721 Pyridine-2,4-dicarboxylic acid bis-(4-chloro-benzylamide); 1722 Pyridine-2,4-dicarboxylic acid bis-benzylamide; 1723 Pyridine-2,4-dicarboxylic acid bis-(naphthalen-1-ylmethyl)-amide; 1724 Pyridine-2,4-dicarboxylic acid bis-(2-p-tolyl-ethyl)-amide; 1725 Pyridine-2,4-dicarboxylic acid bis-(4-methoxy-benzylamide); 1726 Pyridine-2,4-dicarboxylic acid bis-(3-fluoro-benzylamide); 1727 Pyridine-2,4-dicarboxylic acid bis-(benzyl-ethyl-amide); 1728 Pyridine-2,4-dicarboxylic acid bis-2-(3,4-dimethoxy-phenyl)-ethyl-amide; 1729 Pyridine-2,4-dicarboxylic acid bis-2-(2-phenoxy-phenyl)-ethyl-amide; 1730 Pyridine-2,4-dicarboxylic acid bis-(4-phenyl-butyl)-amide; 1731 Pyridine-2,4-dicarboxylic acid bis-2-(4-methoxy-phenyl)-ethyl-amide; 1732 Pyridine-2,4-dicarboxylic acid bis-2-(2-fluoro-phenyl)-ethyl-amide; 1733 Pyridine-2,4-dicarboxylic acid bis-2-(3-chloro-phenyl)-ethyl-amide; 1734 Pyridine-2,4-dicarboxylic acid bis-2-(2,4-dimethyl-phenyl)-ethyl-amide; 1735 Pyridine-2,4-dicarboxylic acid bis-(2-o-tolyl-ethyl)-amide; 1736 Pyridine-2,4-dicarboxylic acid bis-2-(4-ethyl-phenyl)-ethyl-amide; 1737 Pyridine-2,4-dicarboxylic acid bis-(2-phenyl-propyl)-amide; 1738 Pyridine-2,4-dicarboxylic acid bis-(1,2-diphenyl-ethyl)-amide; 1739 Pyridine-2,4-dicarboxylic acid bis-(2,4-dichloro-benzylamide); 1740 Pyridine-2,4-dicarboxylic acid bis-(biphenyl-2-ylmethyl)-amide; 1741 Pyridine-2,4-dicarboxylic acid bis-(3,4,5-trimethoxy-benzylamide); 1742 Pyridine-2,4-dicarboxylic acid bis-(3-chloro-benzylamide); 1743 Pyridine-2,4-dicarboxylic acid bis-(3,5-dimethoxy-benzylamide); 1744 Pyridine-2,4-dicarboxylic acid bis-(3,4-dimethoxy-benzylamide); 1745 Pyridine-2,4-dicarboxylic acid bis-(ethyl-pyridin-4-ylmethyl-amide); 1746 Pyridine-2,4-dicarboxylic acid bis-(2-pyridin-4-yl-ethyl)-amide; 1747 Pyridine-2,4-dicarboxylic acid bis-(2-pyridin-3-yl-ethyl)-amide; 1748 Pyridine-2,4-dicarboxylic acid bis-2-(4-chloro-phenyl)-ethyl-amide; 1749 Pyridine-2,4-dicarboxylic acid bis-(pyridin-4-ylmethyl)-amide; 1750 Pyridine-2,4-dicarboxylic acid bis-(3,5-bis-trifluoromethyl-benzylamide); 1751 Pyridine-2,4-dicarboxylic acid bis-(2,3-dimethoxy-benzylamide); 1752 Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethyl-benzylamide); 1753 Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethoxy-benzylamide); 1754 Pyridine-2,4-dicarboxylic acid bis-(3-difluoromethoxy-benzylamide); 1755 Pyridine-2,4-dicarboxylic acid bis-(2-difluoromethoxy-benzylamide); 1756 Pyridine-2,4-dicarboxylic acid bis-(4-fluoro-3-trifluoromethyl-benzylamide); 1757 Pyridine-2,4-dicarboxylic acid bis-(2-methoxy-benzylamide); 1758 Pyridine-2,4-dicarboxylic acid bis-2-(3-ethoxy-phenyl)-ethyl-amide; 1759 Pyridine-2,4-dicarboxylic acid bis-(3-chloro-4-fluoro-benzylamide); 1760 Pyridine-2,4-dicarboxylic acid bis-(2,4-difluoro-benzylamide); 1761 Pyridine-2,4-dicarboxylic acid bis-(4-amino-benzylamide); 1762 Pyridine-2,4-dicarboxylic acid bis-(2-methyl-benzylamide); 1763 Pyridine-2,4-dicarboxylic acid bis-bis-(4-methoxy-phenyl)-methyl-amide; 1764 Pyridine-2,4-dicarboxylic acid bis-(3,3-diphenyl-propyl)-amide; 1765 Pyridine-2,4-dicarboxylic acid bis-(1-methyl-3-phenyl-propyl)-amide; 1766 Pyridine-2,4-dicarboxylic acid bis-(3,4-dimethoxy-phenyl)-amide; 1767 Pyridine-2,4-dicarboxylic acid bis-(2-fluoro-benzylamide); 1768 Pyridine-2,4-dicarboxylic acid bis-(3-imidazol-1-yl-propyl)-amide; 1769 Pyridine-2,4-dicarboxylic acid bis-(2-chloro-benzylamide); 1770 Pyridine-2,4-dicarboxylic acid bis-(2-trifluoromethyl-benzylamide); 1771 Pyridine-2,4-dicarboxylic acid bis-(4-methyl-benzylamide); 1772 Pyridine-2,4-dicarboxylic acid bis-2-(3-methoxy-phenyl)-ethyl-amide; 1773 Pyridine-2,4-dicarboxylic acid bis-(1-phenyl-ethyl)-amide; 1774 Pyridine-2,4-dicarboxylic acid bis-(pyridin-3-ylmethyl)-amide; 1775 Pyridine-2,4-dicarboxylic acid bis-(4-ethoxy-phenyl)-amide; 1776 Pyridine-2,4-dicarboxylic acid bis-(phenethyl-amide); 1777 Pyridine-2,4-dicarboxylic acid bis-(thiophen-2-ylmethyl)-amide; 1778 Pyridine-2,4-dicarboxylic acid bis-(4-trifluoromethyl-benzylamide); 1779 Pyridine-2,4-dicarboxylic acid bis-(5-methyl-furan-2-ylmethyl)-amide; 1780 Pyridine-2,4-dicarboxylic acid bis-1-(4-fluoro-phenyl)-ethyl-amide; 1781 Pyridine-2,4-dicarboxylic acid bis-(2-amino-benzylamide); 1782 Pyridine-2,4-dicarboxylic acid bis-(1-naphthalen-1-yl-ethyl)-amide; 1783 Pyridine-2,4-dicarboxylic acid bis-2-(4-hydroxy-phenyl)-ethyl-amide; 1784 Pyridine-2,4-dicarboxylic acid bis-(3-trifluoromethoxy-benzylamide); 1785 Pyridine-2,4-dicarboxylic acid bis-1-(3-methoxy-phenyl)-ethyl-amide; 1786 Pyridine-2,4-dicarboxylic acid bis-(1-phenyl-propyl)-amide; 1787 Pyridine-2,4-dicarboxylic acid bis-2-(2-methoxy-phenyl)-ethyl-amide; 1788 Pyridine-2,4-dicarboxylic acid bis-2-(3-trifluoromethyl-phenyl)-ethyl-amide; 1789 Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide; 1790 Pyridine-2,4-dicarboxylic acid bis-indan-1-ylamide; 1791 Pyridine-2,4-dicarboxylic acid bis-(3,4-dichloro-benzylamide); 1792 Pyridine-2,4-dicarboxylic acid bis-(2-ethoxy-ethyl)-amide; 1793 Pyridine-2,4-dicarboxylic acid bis-2-(4-bromo-phenyl)-ethyl-amide; 1794 Pyridine-2,4-dicarboxylic acid bis-(2-pyridin-2-yl-ethyl)-amide; 1795 Pyridine-2,4-dicarboxylic acid bis-(2-thiophen-2-yl-ethyl)-amide; 1796 Pyridine-2,4-dicarboxylic acid bis-2-(5-methoxy-1H-indol-3-yl)-ethyl-amide); 1797 Pyridine-2,4-dicarboxylic acid bis-2-(1H-indol-3-yl)-ethyl-amide; and 1798 Pyridine-2,4-dicarboxylic acid bis-(3,5-dichloro-benzylamide); or a pharmaceutically acceptable salt thereof. 1799 62. A pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1800 63. The pharmaceutical composition according to Embodiment 62, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1801 64. The pharmaceutical composition according to Embodiment 62 or 63, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1802 65. The pharmaceutical composition according to Embodiment 64, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1803 66. The pharmaceutical composition according to Embodiment 65, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1804 67. The pharmaceutical composition according to Embodiment 66, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1805 68. The pharmaceutical composition according to Embodiment 67, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1806 69. A method of treating cartilage damage in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 1807 70. The method according to Embodiment 69, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1808 71. A method of treating cartilage damage in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1809 72. The method according to Embodiment 71, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1810 73. The method according to Embodiment 71 or 72, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1811 74. The method according to Embodiment 73, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1812 75. The method according to Embodiment 74, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1813 76. The method according to Embodiment 75, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1814 77. The method according to Embodiment 76, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1815 78. A method of treating inflammation in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 1816 79. The method according to Embodiment 78, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1817 80. A method of treating inflammation in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1818 81. The method according to Embodiment 80, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1819 82. The method according to Embodiment 80 or 81, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1820 83. The method according to Embodiment 82, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1821 84. The method according to Embodiment 83, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1822 85. The method according to Embodiment 84, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1823 86. The method according to Embodiment 85, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1824 87. A method of treating osteoarthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 1825 88. The method according to Embodiment 87, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1826 89. A method of treating osteoarthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1827 90. The method according to Embodiment 89, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1828 91. The method according to Embodiment 89 or 90, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1829 92. The method according to Embodiment 91, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1830 93. The method according to Embodiment 92, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1831 94. The method according to Embodiment 93, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1832 95. The method according to Embodiment 94, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1833 96. A method of treating rheumatoid arthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 1834 97. The method according to Embodiment 96, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1835 98. A method of treating rheumatoid arthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1836 99. The method according to Embodiment 98, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1837 100. The method according to Embodiment 98 or 99, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1838 101. The method according to Embodiment 100, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1839 102. The method according to Embodiment 101, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1840 103. The method according to Embodiment 102, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1841 104. The method according to Embodiment 103, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1842 105. A method of treating psoriatic arthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 1843 106. The method according to Embodiment 105, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1844 107. A method of treating psoriatic arthritis in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1845 108. The method according to Embodiment 107, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1846 109. The method according to Embodiment 107 or 108, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1847 110. The method according to Embodiment 109, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1848 111. The method according to Embodiment 110, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1849 112. The method according to Embodiment 111, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1850 113. The method according to Embodiment 112, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1851 114. A method of treating pain in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. 1852 115. The method according to Embodiment 114, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1853 116. A method of treating pain in a mammal in need thereof, comprising administering to the mammal a therapeutically effective amount of a pharmaceutical composition, comprising a combination of valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1854 117. The method according to Embodiment 116, wherein the combination is the combination according to any one of Embodiments 1 to 61. 1855 118. The method according to Embodiment 116 or 117, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 600 milligrams. 1856 119. The method according to Embodiment 118, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 50 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 10 milligrams to 300 milligrams. 1857 120. The method according to Embodiment 119, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 300 milligrams. 1858 121. The method according to Embodiment 120, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 5 milligrams to 25 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 200 milligrams. 1859 122. The method according to Embodiment 121, wherein valdecoxib, or the pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 1 milligram to 5 milligrams, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is in unit dosage form in an amount of from 25 milligrams to 100 milligrams. 1860 Another invention embodiment is a combination according to any one of Embodiments 1 to 61, except where valdecoxib, or the pharmaceutically acceptable salt thereof, is replaced by celecoxib, or a pharmaceutically acceptable salt thereof. 1861 Another invention embodiment is use of any one of the above combination Embodiments to treat a mammalian disease in a mammal in need of treatment, wherein the disease is selected from arthritis, rheumatoid arthritis, osteoarthritis, osteoporosis, periodontal diseases, inflammatory bowel disease, psoriasis, multiple sclerosis, cardiac insufficiency, atherosclerosis, asthma, chronic obstructive pulmonary disease, age-related macular degeneration, and cancers. 1862 Another invention embodiment is any of the above embodiments of a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. 1863 Another invention embodiment is any of the above embodiments of pharmaceutical compositions, comprising a combination containing an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient. 1864 Another invention embodiment is any of the above embodiments of a methods of treating a disease in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. 1865 Another invention embodiment is a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. 1866 Another invention embodiment is a pharmaceutical composition, comprising a combination containing an allosteric carboxylic inhibitor of P-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier, diluent, or excipient. 1867 Another invention embodiment is a method of treating a disease that is responsive to inhibition of MMP-13 and to selective inhibition of COX-2 in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of the combination according to any one of Embodiments 1 to 104. 1868 Another invention embodiment is a method of treating a disease that is responsive to inhibition of MMP-13 and to selective inhibition of COX-2 in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of MMP-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. 1869 Another invention embodiment is a method of treating a first disease that is responsive to inhibition of MMP-13 and a second disease that is responsive to selective inhibition of COX-2 in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of the combination according to any one of Embodiments 1 to 104. 1870 Another invention embodiment is a method of treating a first disease that is responsive to inhibition of MMP-13 and a second disease that is responsive to selective inhibition of COX-2 in a mammal suffering therefrom, comprising administering to the mammal a therapeutically effective amount of a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13 is any single compound named below in the Examples of allosteric carboxylic inhibitors of M-13, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. 1871 Another invention embodiment is a method of treating an arthritic condition in a mammal, comprising administering to the mammal an amount of any one of the above described invention combinations, or any one of the above-described invention pharmaceutical compositions, sufficient to effectively treat the arthritic condition. 1872 Use of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating cartilage damage in a mammal in need thereof. 1873 Use of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating inflammation in a mammal in need thereof. 1874 Use of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating osteoarthritis in a mammal in need thereof. 1875 Use of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating rheumatoid arthritis in a mammal in need thereof. 1876 Use of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating psoriatic arthritis in a mammal in need thereof. 1877 Use of a combination comprising valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for treating pain in a mammal in need thereof.

DETAILED DESCRIPTION OF THE INVENTION 1878 As noted above, the invention provides a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. This invention also provides a method of treating a disease that is responsive to inhibition of MMP-13 and cyclooxygenase-2, comprising administering to a patient suffering from such a disease the invention combination comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof. This invention also provides a pharmaceutical composition, comprising the invention combination comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 1879 The invention combinations may also be further combined with other pharmaceutical agents depending on the disease being treated. 1880 The terms are as defined below or as they otherwise occur in the specification. 1881 Definitions of Terms Used to Define Compounds of Formula I: 1882 In Formula I, R1 to R4 include C1-C6 alkyl groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano. 1883 Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like. 1884 Halo includes fluoro, chloro, bromo, and iodo. It should be appreciated that invention compounds do not include compounds containing an N-halo group. 1885 Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. 1886 Alkynyl means straight and branched hydrocarbon radicals having from 2 to 10 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, 1-hexyn-1-yl, 7,7-dimethyl-1-octyn-1-yl, and the like. 1887 Cycloalkyl means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Examples of substituted cycloalkyl include 4-carboxycyclohexyl, 4-oxo-cyclohexyl, 4-(carboxymethyl)-cyclobutyl, 3-methyl-cyclopentyl, and 3-(carboxymethyl)cyclopentyl. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed heterocycle or heterocyclyl, which mean a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, 4-methylpiperazinyl, piperidyl, tetrahydropyranyl, and morpholinyl. The group R2 here is as defined above for Formula I, except where R2 contains the functional group NR5R6, the groups R5 and R6 are not taken together with the nitrogen atom to which they are attached to complete a 3- to 7-membered ring. 1888 Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as O(CH2)2OCH3, and the like. 1889 Alkanoyl groups are alkyl linked through a carbonyl, i.e., C1-C5C(O). Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl. 1890 Acyl means an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., RC(O). For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like. 1891 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, heteroaryl, substituted heteroaryl, heterocycle, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. Substituted nitrogen means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced. 1892 Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, benzyl(Bn), 3-morpholinopropyl, piperazinylmethyl, pyridyl-4-methyl(Py-4-me), 3-(pyridyl-4-thio)propyl, and 2-(4-methylpiperazinyl)ethyl. 1893 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. 1894 Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. 1895 Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 3-(3-methoxyphenyl)-propyn-1-yl, 3-(3,4-difluorophenyl)-propyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. 1896 The terms Ar and aryl refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl groups include phenyl and naphthyl. Typical substituted aryl groups include 3,4-difluorophenyl, 4-carboxyphenyl, 3,4-methylenedioxyphenyl, 4-carboxymethylphenyl, 3-methoxyphenyl, and 7-fluoro-1-naphthyl. Typical heteroaryl groups include pyridyl, thienyl, benzothienyl, indolyl, furanyl, thiazolyl, isothiazolyl, indazolyl, 2-oxo-2H-1-benzopyranyl, and imidazolyl. Typical substituted heteroaryl groups include 3-methoxy-isothiazolyl, 3-methoxypyridin-4-yl, 4-ethylbenzothienyl, 4-thiopyridyl, 2-methoxy-pyridin-4-yl, 1-methylpyrazol-4-yl, and 2-methyl-pyridin-3-yl. 1897 Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from alkyl, alkoxy, alkoxycarbonyl, thio, thioalkyl, (C1-C6 alkyl)sulfanyl, (C1-C6 alkyl)sulfonyl, halo, hydroxy, (CH2)0-6CO2R7, trifluoromethyl, trifluoromethoxy, nitro, amino of the formula NR4R5, C(O)NR5R6, N(R4)C(O)OR5, and T(CH2)mQR4 or T(CH2)mCO2R4, wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y, wherein R4R6 are as described above, and R7 is hydrogen, alkyl, or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Examples of substituted phenyl are 3-methoxyphenyl, 2,6-dichlorophenyl, 3-nitrophenyl, 4-dimethylaminophenyl, and biphenyl. 1898 Preferred heteroaryl groups include thienyl, furanyl, pyrrolyl, isoxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, 1,2,4-oxadiazolyl, 1,2,4,-thiadiazolyl, 1,2,4-triazolyl, tetrazolyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzotriazolyl, benzoxazolyl, benzthiazolyl, pyridinyl, pyrimidinyl, quinolinyl, isoquinolinyl, and 2-oxo-2H-1-benzopyranyl. 1899 Preferred heteroaryl groups may be substituted on a carbon atom as described above for substituted phenyl, and may further be substituted on a ring nitrogen atom (i.e., by replacing a hydrogen from a ring nitrogen atom, which is an NH group) with (C1-C6 alkyl) C(O), C1-C6 alkyl, C2-C6 alkenyl, C2-C10alkynyl, or benzyl. 1900 Definitions of Terms Used to Define Compounds of Formula IA: 1901 In Formula IA, R1 to R9 include C1-C6 alkyl groups. Alkyl groups are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano. 1902 Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring containing from 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like. 1903 Halo includes fluoro, chloro, bromo, and iodo. 1904 Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. 1905 Alkynyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like. 1906 Cycloalkyl means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed heterocyclyl, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine. 1907 Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as O(CH2)2OOH3, and the like. 1908 Acyl means an R group that is a C1-C6 alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., RC(O), where R is alkyl or aryl. For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, isonicotinoyl, and the like. 1909 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. Substituted nitrogen means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced. 1910 Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and 2-(4-methylpiperazinyl)ethyl. 1911 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. 1912 Typical substituted alkoxy groups include aminomethoxy, acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. 1913 Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. 1914 The terms Ar and aryl refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. A bicyclic aryl group is naphthyl for example. Bicyclic heteroaryl groups include indolyl and benzothienyl, to name a few. Preferred substituent groups include alkyl, alkoxy, halo, amino, alkylamino, dialkylamino, CN, CF3, thioalkyl, acyl and hydroxy. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole, benzo-2,1,3-oxadiazole, and the like. 1915 Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, halo, hydroxy, COOR7, trifluoromethyl, nitro, amino of the formula NR4R5, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y wherein R4 and R5 are as described above, and R7 is H, alkyl or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl, 3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl, 2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and 3,5-dinitrophenyl. 1916 The term substituted, unless otherwise defined, includes from 1 to 3 substituents selected from: 1917 C1-C6 alkyl; C2-C6 alkenyl; C2-C6 alkynyl; C1-C6 alkoxy; phenyl; 1918 (C1-C6 alkoxy)carbonyl; (C1-C6 alkyl)sulfanyl; (C1-C6 alkyl)carbonyl; 1919 OH; NH2; N(H)R4, wherein R4 is as defined above for Formula IA; 1920 NR4R5, wherein R4 and R5 are as defined above for Formula IA, or R4 and R5 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered saturated ring containing carbon atoms and optionally from 1 or 2 heteroatoms selected from O, S, S(O), S(O)2, N(H), and N(C1-C6 alkyl), wherein the ring may be optionally substituted on a carbon atom with 1 oxo (i.e., O) group; 1921 C(O)NR4R5, wherein R4 and R5 are as defined immediately above, or R4 and R5 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered saturated ring containing carbon atoms and optionally 1 or 2 heteroatoms selected from O, S, S(O), S(O)2, N(H), and N(C1-C6 alkyl), wherein the ring may be optionally substituted on a carbon atom with 1 oxo (i.e., O) group; 1922 CN; NO2; CF3; CO2H; CHO; SH; (C1-C6alkyl) S(O); 1923 (C1-C6 alkyl)sulfonyl; halo; S(O)2NR4R5, wherein R4 and R5 are as defined above for Formula IA, or R4 and R5 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered saturated ring containing carbon atoms and optionally 1 or 2 heteroatoms selected from O, S, S(O), S(O)2, N(H), and N(C1-C6 alkyl), wherein the ring may be optionally substituted on a carbon atom with 1 oxo (i.e., O) group; 1924 OCF3; and (CH2)mCO2H, wherein m is as defined above for Formula IA. 1925 Definitions of Terms Used to Define Compounds of Formula IB: 1926 In Formula IB, R1R4 include C1-C6 alkyl groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance, with groups such as aryl-O, wherein aryl is as defined below, heteroaryl-O, wherein heteroaryl is as defined below, hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano. Typical substituted alkyl groups thus are aminomethyl, 2-nitroethyl, 4-cyanobutyl, 2,3-dichloropentyl, and 3-hydroxy-5-carboxyhexyl. 1927 Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like. 1928 Halo includes fluoro, chloro, bromo, and iodo. 1929 Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. 1930 Alkynyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like. 1931 Carbocycle or Cycloalkyl mean a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed heterocycle or heterocyclic or heterocyclyl, which mean a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine. 1932 Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as O(CH2)2OOH3, and the like. 1933 Alkanoyl groups are alkyl linked through a carbonyl, ie, C1-C5-C(O). Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl. 1934 Acyl means an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., RC(O). For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like. 1935 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, aryl-O, wherein aryl is as defined below, heteroaryl-O, wherein heteroaryl is as defined below, C1-C6 alkoxycarbonyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. Substituted nitrogen means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced. Oxo (O) substitution of a CH2 carbon group to provide a carbonyl (CO) is also embraced. 1936 Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, and 2-(4-methylpiperazinyl)ethyl. 1937 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. 1938 Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. 1939 Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. 1940 The terms Ar and aryl refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 10 ring atoms which are carbon atoms, and from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, and the like. 1941 Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, 1H-tetrazol-5-yl, halo, hydroxy, COOR6, trifluoromethyl, nitro, amino of the formula NR4R5, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R5Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR4R5Y wherein R4 and R5 are as described above, and R6 is hydrogen, alkyl, or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl, 3-methoxyphenyl, 4-trifluoromethylphenyl, 4-styrylphenyl, 3-amino-4-nitrophenyl, 3,5-dihydroxyphenyl, and the like. 1942 Most preferred aryl is phenyl, 4- or 3-methoxy-phenyl, 4-fluorophenyl, and 3-fluorophenyl, and each of 3,4-disubstituted phenyls wherein the substituents are methoxy and fluoro. 1943 Most preferred heteroaryl is pyridin-4-yl or 2-methoxypyridin-4-yl. 1944 Definitions of Terms Used to Define Compounds of Formula IC: 1945 In Formula IC,: 1946 The term halogen means F, Cl, Br, or I; preferably F, Br and Cl. 1947 The term (C1-C6)alkyl means linear or branched alkyl containing from 1 to 6, and preferably from 1 to 3 carbon atoms. 1948 The term (C1-C6)alkoxy means linear or branched alkyl containing from 1 to 6, and preferably from 1 to 3, carbon atoms bonded through an oxygen atom. 1949 The term (C3-C6)alkenyl means an alkenyl containing from 3 to 6, and preferably 3 or 4 carbon atoms, more particularly allyl. 1950 The term (C3-C6)alkynyl means alkynyl containing from 3 to 6, and preferably 3 or 4, carbon atoms, more particularly propargyl. 1951 The term aryl means an aromatic ring containing from 5 to 10, and preferably 5 or 6, carbon atoms. 1952 The term heteroaryl means a heteroaromatic aryl group interrupted with one or several hetero atom selected from nitrogen, oxygen and sulphur. The term interrupted means that the hetero atom can replace a carbon atom of the ring. Examples of such groups containing a heteroatom are, inter alia, thienyl, pyridyl, benzofurazanyl. 1953 The term heterocycle means an aromatic or non-aromatic, 5-or 6-membered monocycle comprising carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur. 1954 The term aryl(C1-C6)alkyl means an aryl, as defined above, bonded through an alkyl, wherein the alkyl contains from 1 to 6, and preferably from 1 to 4, carbon atoms. 1955 The term cycloalkyl means a cycloalkyl containing from 3 to 8, and preferably from 3 to 6, carbon atoms. 1956 The term cycloalkyl(C1-C6)alkyl means a cycloalkyl group bonded through an alkyl group, wherein the alkyl contains from 1 to 6, and preferably from 1 to 3, carbon atoms and the cycloalkyl contains from 3 to 6 carbon atoms. 1957 The phrase multiple bond represents a double bond or a triple bond. 1958 Definitions of Terms Used to Define Compounds of Formula ID: 1959 The term halogen means F, Cl, Br, or I; preferably F, Br and Cl. 1960 The term (C1-C6)alkyl means linear or branched alkyl containing from 1 to 6, and preferably from 1 to 3 carbon atoms. 1961 The term halo(C1-C6)alkyl means (C1-C6)alkyl as defined above substituted with one or more halogen atoms, and preferably trihalogenomethyl. 1962 The term (C1-C6)alkoxy means linear or branched alkyl containing from 1 to 6, and preferably from 1 to 3, carbon atoms bonded through an oxygen atom. 1963 The term (C3-C6)alkenyl means an alkenyl containing from 3 to 6, and preferably 3 or 4 carbon atoms, more particularly allyl. 1964 The term (C3-C6)alkynyl means alkynyl containing from 3 to 6, and preferably 3 or 4, carbon atoms, more particularly propargyl. 1965 The term aryl means an aromatic ring containing from 5 to 10, and preferably 5 or 6, carbon atoms. 1966 The term heteroaryl means a heteroaromatic aryl group interrupted with one or several hetero atom selected from nitrogen, oxygen and sulphur. The term interrupted means that the hetero atom can replace a carbon atom of the ring. Examples of such groups containing a heteroatom are, inter alia, thienyl, pyridyl, benzofurazanyl. 1967 The term heterocycle means an aromatic or non-aromatic, 5-or 6-membered monocycle comprising carbon atoms and from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulphur. 1968 The term aryl(C1-C6)alkyl means an aryl, as defined above, bonded through an alkyl, wherein the alkyl contains from 1 to 6, and preferably from 1 to 4, carbon atoms. 1969 The term cycloalkyl means a cycloalkyl containing from 3 to 8, and preferably from 3 to 6, carbon atoms. 1970 The term cycloalkyl(C1-C6)alkyl means a cycloalkyl group bonded through an alkyl group, wherein the alkyl contains from 1 to 6, and preferably from 1 to 3, carbon atoms and the cycloalkyl contains from 3 to 6 carbon atoms. 1971 The phrase multiple bond represents a double bond or a triple bond. 1972 Definitions of Terms Used to Define Compounds of Formula IE: 1973 In Formula IE, R1 to R3 include C1-C6 alkyl groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, alkoxy, amino, alkyl and dialkylamino, alkanoyl, acyl, halo, trifluoromethyl, carboxy, nitro, and cyano. 1974 Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. 1975 Alkynyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like. 1976 Cycloalkyl means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed heterocycle or heterocyclyl, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine. 1977 Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as O(CH2)2OCH3, and the like. Thioalkoxy is an alkoxy group wherein the 0 is replaced by an S. 1978 Alkanoyl groups are alkyl linked through a carbonyl, ie, C1-C5-C(O). Such groups include formyl, acetyl, propionyl, butyryl, and isobutyryl. 1979 Acyl means an R group that is a C1-C6 alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., RC(O), wherein C1-C6 alkyl and aryl are as defined above and below, respectively. The phrase substituted acyl means an R group that is a substituted C1-C6 alkyl or a substituted aryl (substituted Ar) group bonded through a carbonyl group. For example, substituted acyl includes substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, and the like. Typical substituted acyl groups include trifluoroacetyl, 4-carboxybenzoyl, and the like. 1980 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, (CH2)mC(O) phenyl, (CH2)m C(O) substituted phenyl, (CH2)mS(O)0-2 phenyl, (CH2)m S(O)0-2 substituted phenyl, (CH2)mC(O) heteroaryl, (CH2)m C(O) substituted heteroaryl, (CH2)mS(O)0-2 heteroaryl, (CH2)mS(O)0-2 substituted heteroaryl, (CH2)m cycloalkyl, heterocycle, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, acyl, carboxy, alkanoyl, C1-C6 alkoxycarbonyl, halo, nitro, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. Substituted nitrogen means nitrogen bearing C1-C6 alkyl or (CH2)yPh where y is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced. 1981 R4 and R5 independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, acyl, (CH2)m aryl, (CH2)m heteroaryl, (CH2)m cycloalkyl, wherein these groups may be unsubstituted or substituted as described herein, or R4 and R5 are taken together with the nitrogen atom to which they are attached to form a 3- to 7-membered ring containing carbon atoms, the nitrogen atom bearing R4 and R5, and optionally 1 or 2 heteroatoms selected from O, S, NH, and NR2, wherein R2 is as defined above, the ring optionally may be substituted with oxo (O) on a carbon atom. 1982 Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like. 1983 Halo includes fluoro, chloro, bromo, and iodo. 1984 Examples of substituted alkyl groups include 2-aminoethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, benzyl(Bn), 3-morpholinopropyl, piperazinylmethyl, pyridyl-4-methyl(Py-4-me), 3-(pyridyl-4-thio)propyl, and 2-(4-methylpiperazinyl)ethyl. 1985 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. 1986 Typical substituted alkoxy groups include aminomethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. 1987 Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. 1988 The terms Ar and aryl refer to unsubstituted and substituted aromatic groups. Heteroaryl groups have from 4 to 10 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 3,4-methylenedioxyphenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, 4-thiopyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, and the like. 1989 Preferred Ar groups are phenyl or naphthyl, and phenyl or naphthyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, thioalkoxy, (CH2)mN(R4)S(O)2(C1-C6 alkyl), (CH2)mS(O)2NR4R5, wherein R4, R5, and m are as defined above, S(O)2NR4R5, C(O)NR4R5, N(H)C(O)NR4R5, OC(O)NR4R5, halo, hydroxy, COOR6, trifluoromethyl, nitro, amino of the formula NR4R5, C(O)NR4R5, S(O)C1-C6 alkyl, S(O)2C1-C6 alkyl, 5-membered heteroaryl, N(R5)C(O)O(C1-C6 alkyl), and T(CH2)pQR4 or T(CH2)pCO2R4, wherein p is 1 to 6, T is O, S, SO, SO2, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, SO, SO2, NR5, N(O)R5, or NR5R6Y, wherein R4 and R5 are as described above, Y is a counter ion such as halo, R6 is H, C1-C6 alkyl, or substituted C1-C6 alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Examples of substituted phenyl are 3-methoxyphenyl, 2,6-dichlorophenyl, 3-nitrophenyl, 4-dimethylaminophenyl, and biphenyl. Examples of quaternary ammonium groups defined by NR4R6Y are trimethylammonium chloride and triethylammonium bromide. 1990 Heteroaryl groups may be substituted with up to 3 groups independently selected from the 1, 2, or 3 groups described above for substituted phenyl. 1991 Definitions of Terms Used to Define Compounds of Formula IF: 1992 In Formula IF, R1 to R9 include C1-C6 alkyl groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, amino, alkyl, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano. 1993 Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. 1994 Alkynyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like. 1995 Cycloalkyl means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed heterocyclyl, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyranyl, and morpholinyl. 1996 Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as O(CH2)2OOH3, and the like. 1997 Acyl means an R group that is an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., RC(O), where R is alkyl or aryl. For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, isonicotinoyl, and the like. 1998 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. Substituted nitrogen means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced. 1999 Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and 2-(4-methylpiperazinyl)ethyl. 2000 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. 2001 Typical substituted alkoxy groups include aminomethoxy, acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. 2002 Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. 2003 The terms Ar and aryl refer to unsubstituted and substituted aromatic groups. Heteroaryl (Het) groups have from 4 to 9 ring atoms, from 1 to 4 ring atoms of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Preferred substituent groups include alkyl, alkoxy, halo, amino, alkylamino, dialkylamino, CN, CF3, thioalkyl, acyl and hydroxy. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole, benzo-2,1,3-oxadiazole, and the like. 2004 Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, halo, hydroxy, COOR7, trifluoromethyl, nitro, amino of the formula NR4R5, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y wherein R4 and R5 are as described above, and R7 is hydrogen, alkyl, or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl, 3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl, 2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and 3,5-dinitrophenyl. 2005 Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like. 2006 Halo includes fluoro, chloro, bromo, and iodo. 2007 Definitions of Terms Used to Define Compounds of Formula IG: 2008 In Formula IG, R1 to R9 include C1-C6 alkyl groups. These are straight and branched carbon chains having from 1 to 6 carbon atoms. Examples of such alkyl groups include methyl, ethyl, isopropyl, tert-butyl, neopentyl, and n-hexyl. The alkyl groups can be substituted if desired, for instance with groups such as hydroxy, amino, alkyl, aryl, and dialkylamino, halo, trifluoromethyl, carboxy, nitro, and cyano. 2009 Alkenyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one double bond and includes ethenyl, 3-buten-1-yl, 2-ethenylbutyl, 3-hexen-1-yl, and the like. 2010 Alkynyl means straight and branched hydrocarbon radicals having from 2 to 6 carbon atoms and one triple bond and includes ethynyl, 3-butyn-1-yl, propynyl, 2-butyn-1-yl, 3-pentyn-1-yl, and the like. 2011 Cycloalkyl means a monocyclic or polycyclic hydrocarbyl group such as cyclopropyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclobutyl, adamantyl, norpinanyl, decalinyl, norbornyl, cyclohexyl, and cyclopentyl. Such groups can be substituted with groups such as hydroxy, keto, and the like. Cycloalkyl groups can also be fused by two points of attachment to other groups such as aryl and heteroaryl groups. Also included are rings in which 1 to 3 heteroatoms replace carbons. Such groups are termed heterocyclyl, which means a cycloalkyl group also bearing at least one heteroatom selected from O, S, or NR2, examples being oxiranyl, pyrrolidinyl, piperidyl, tetrahydropyran, and morpholine. 2012 Alkoxy refers to the alkyl groups mentioned above bound through oxygen, examples of which include methoxy, ethoxy, isopropoxy, tert-butoxy, and the like. In addition, alkoxy refers to polyethers such as O(CH2)2OOH3, and the like. 2013 Acyl means an R group that is an alkyl or aryl (Ar) group bonded through a carbonyl group, i.e., RC(O), where R is alkyl or aryl. For example, acyl includes a C1-C6 alkanoyl, including substituted alkanoyl, wherein the alkyl portion can be substituted by NR4R5 or a carboxylic or heterocyclic group. Typical acyl groups include acetyl, benzoyl, isonicotinoyl, and the like. 2014 The alkyl, alkenyl, alkoxy, and alkynyl groups described above are optionally substituted, preferably by 1 to 3 groups selected from NR4R5, phenyl, substituted phenyl, naphthyl, thio C1-C6 alkyl, C1-C6 alkoxy, hydroxy, carboxy, C1-C6 alkoxycarbonyl, acyl, halo, nitrile, cycloalkyl, and a 5- or 6-membered carbocyclic ring or heterocyclic ring having 1 or 2 heteroatoms selected from nitrogen, substituted nitrogen, oxygen, and sulfur. Substituted nitrogen means nitrogen bearing C1-C6 alkyl or (CH2)nPh where n is 1, 2, or 3. Perhalo and polyhalo substitution is also embraced. 2015 Examples of substituted alkyl groups include 2-aminoethyl, acetylmethyl, pentachloroethyl, trifluoromethyl, 2-diethylaminoethyl, 2-dimethylaminopropyl, ethoxycarbonylmethyl, 3-phenylbutyl, methanylsulfanylmethyl, methoxymethyl, 3-hydroxypentyl, 2-carboxybutyl, 4-chlorobutyl, 3-cyclopropylpropyl, pentafluoroethyl, 3-morpholinopropyl, piperazinylmethyl, 4-benzoylbutyl, and 2-(4-methylpiperazinyl)ethyl. 2016 Examples of substituted alkynyl groups include 2-methoxyethynyl, 2-benzoylethylyl, 2-ethylsulfanyethynyl, 4-(1-piperazinyl)-3-(butynyl), 3-phenyl-5-hexynyl, 3-diethylamino-3-butynyl, 4-chloro-3-butynyl, 4-cyclobutyl-4-hexenyl, and the like. 2017 Typical substituted alkoxy groups include aminomethoxy, acetoxymethoxy, trifluoromethoxy, 2-diethylaminoethoxy, 2-ethoxycarbonylethoxy, 3-hydroxypropoxy, 6-carboxhexyloxy, and the like. 2018 Further, examples of substituted alkyl, alkenyl, and alkynyl groups include dimethylaminomethyl, carboxymethyl, 4-dimethylamino-3-buten-1-yl, 5-ethylmethylamino-3-pentyn-1-yl, 4-morpholinobutyl, 4-tetrahydropyrinidylbutyl, 3-imidazolidin-1-ylpropyl, 4-tetrahydrothiazol-3-yl-butyl, phenylmethyl, 3-chlorophenylmethyl, and the like. 2019 The terms Ar and aryl refer to unsubstituted and substituted aromatic groups. Heteroaryl (Het) groups have from 4 to 9 ring atoms, from 1 to 4 of which are independently selected from the group consisting of O, S, and N. Preferred heteroaryl groups have 1 or 2 heteroatoms in a 5- or 6-membered aromatic ring. Mono- and bicyclic aromatic ring systems are included in the definition of aryl and heteroaryl. Preferred substituent groups include alkyl, alkoxy, aryloxy, halo, amino, alkylamino, dialkylamino, CN, CF3, thioalkyl, acyl and hydroxy. Typical aryl and heteroaryl groups include phenyl, 3-chlorophenyl, 2,6-dibromophenyl, pyridyl, 3-methylpyridyl, benzothienyl, 2,4,6-tribromophenyl, 4-ethylbenzothienyl, furanyl, 3,4-diethylfuranyl, naphthyl, 4,7-dichloronaphthyl, morpholinyl, indolyl, benzotriazolyl, indazolyl, pyrrole, pyrazole, imidazole, thiazole, methylenedioxyphenyl, benzo-2,1,3-thiadiazole, benzo-2,1,3-oxadiazole, and the like. 2020 Preferred Ar groups are phenyl and phenyl substituted by 1, 2, or 3 groups independently selected from the group consisting of alkyl, alkoxy, thio, thioalkyl, halo, hydroxy, COOR7, trifluoromethyl, nitro, amino of the formula NR4R5, and T(CH2)mQR4 or T(CH2)mCO2R4 wherein m is 1 to 6, T is O, S, NR4, N(O)R4, NR4R6Y, or CR4R5, Q is O, S, NR5, N(O)R5, or NR5R6Y wherein R4 and R5 are as described above, and R7 is hydrogen, alkyl, or substituted alkyl, for example, methyl, trichloroethyl, diphenylmethyl, and the like. The alkyl and alkoxy groups can be substituted as defined above. For example, typical groups are carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, hydroxyalkoxy, and alkoxyalkyl. Typical substituted aryl groups include 2,6-dichlorophenyl, 3-hydroxyphenyl, 1,3-benzodioxolyl, 4-dimethylaminophenyl, 2,4,6-triethoxyphenyl, 3-cyanophenyl, 4-methylthiophenyl, and 3,5-dinitrophenyl. 2021 Examples of NR4R5 groups include amino, methylamino, di-isopropylamino, acetyl amino, propionyl amino, 3-aminopropyl amino, 3-ethylaminobutyl amino, 3-di-n-propylamino-propyl amino, 4-diethylaminobutyl amino, and 3-carboxypropionyl amino. R4 and R5 can be taken together with the nitrogen to which they are attached to form a ring having 3 to 7 carbon atoms and 1, 2, or 3 heteroatoms selected from the group consisting of nitrogen, substituted nitrogen, oxygen, and sulfur. Examples of such cyclic NR4R5 groups include pyrrolidinyl, piperazinyl, 4-methylpiperazinyl, 4-benzylpiperazinyl, pyridinyl, piperidinyl, pyrazinyl, morpholinyl, and the like. 2022 Halo includes fluoro, chloro, bromo, and iodo. 2023 Unless moieties of a compound of the invention are defined as being unsubstituted, the moieties of the compound of the invention may be substituted. In the event where the substituents of the moieties which may be substituted are not defined above, the moieties of the compound of the invention may be optionally substituted from 1 to 3 times at any of from 1 to 3 carbon atoms, respectively, wherein each carbon atom is capable of substitution by replacement of a hydrogen atom with a group independently selected from: 2024 C1-C4 alkyl; 2025 C2-C4 alkenyl; 2026 C2-C4 alkynyl; 2027 CF3; 2028 halo; 2029 OH; 2030 O(C1-C4 alkyl); 2031 OCH2F; 2032 OCHF2; 2033 OCF3; 2034 OC(O)(C1-C4 alkyl); 2035 OC(O)O(C1-C4 alkyl); 2036 OC(O)NH(C1-C4 alkyl); 2037 OC(O)N(C1-C4 alkyl)2; 2038 OC(S)NH(C1-C4 alkyl); 2039 OC(S)N(C1-C4 alkyl)2; 2040 SH; 2041 S(C1-C4 alkyl); 2042 S(O)(C1-C4 alkyl); 2043 S(O)2(C1-C4 alkyl); 2044 SC(O)(C1-C4 alkyl); 2045 SC(O)O(C1-C4 alkyl); 2046 NH2; 2047 N(H)(C1-C4 alkyl); 2048 N(C1-C4 alkyl)2; 2049 N(H)C(O)(C1-C4 alkyl); 2050 N(CH3)C(O)(C1-C4 alkyl); 2051 N(H)C(O)CF3; 2052 N(CH3)C(O)CF3; 2053 N(H)C(S)(C1-C4 alkyl); 2054 N(CH3)C(S)(C1-C4 alkyl); 2055 N(H)S(O)2(C1-C4 alkyl); 2056 N(H)C(O)NH2; 2057 N(H)C(O)NH(C1-C4 alkyl); 2058 N(CH3)C(O)NH(C1-C4 alkyl); 2059 N(H)C(O)N(C1-C4 alkyl)2; 2060 N(CH3)C(O)N(C1-C4 alkyl)2; 2061 N(H)S(O)2NH2; 2062 N(H)S(O)2NH(C1-C4 alkyl); 2063 N(CH3)S(O)2NH(C1-C4 alkyl); 2064 N(H)S(O)2N(C1-C4 alkyl)2; 2065 N(CH3)S(O)2N(C1-C4 alkyl)2; 2066 N(H)C(O)O(C1-C4 alkyl); 2067 N(CH3)C(O)O(C1-C4 alkyl); 2068 N(H)S(O)2O(C1-C4 alkyl); 2069 N(CH3)S(O)2O(C1-C4 alkyl); 2070 N(CH3)C(S)NH(C1-C4 alkyl); 2071 N(CH3)C(S)N(C1-C4 alkyl)2; 2072 N(CH3)C(S)O(C1-C4 alkyl); 2073 N(H)C(S)NH2; 2074 NO2; 2075 CO2H; 2076 CO2(C1-C4 alkyl); 2077 C(O)N(H)OH; 2078 C(O)N(CH3)OH; 2079 C(O)N(CH3)OH; 2080 C(O)N(CH3)O(C1-C4 alkyl); 2081 C(O)N(H)(C1-C4 alkyl); 2082 C(O)N(C1-C4 alkyl)2; 2083 C(S)N(H)(C1-C4 alkyl); 2084 C(S)N(C1-C4 alkyl)2; 2085 C(NH)N(H)(C1-C4 alkyl); 2086 C(NH)N(C1-C4 alkyl)2; 2087 C(NCH3)N(H)(C1-C4 alkyl); 2088 C(NCH3)N(C1-C4 alkyl)2; 2089 C(O)(C1-C4 alkyl); 2090 C(NH)(C1-C4 alkyl); 2091 C(NCH3)(C1-C4 alkyl); 2092 C(NOH)(C1-C4 alkyl); 2093 C(NOCH3)(C1-C4 alkyl); 2094 CN; 2095 CHO; 2096 CH2OH; 2097 CH2O(C1-C4 alkyl); 2098 CH2NH2; 2099 CH2N(H)(C1-C4 alkyl); and 2100 CH2N(C1-C4 alkyl)2; wherein 2101 C1-C4 alkyl means a straight or branched, unsubstituted alkyl chain of from 1 to 4 carbon atoms; 2102 C2-C4 alkenyl means a straight or branched, unsubstituted alkenyl chain of from 2 to 4 carbon atoms; and 2103 C2-C4 alkynyl means a straight or branched, unsubstituted alkynyl chain of from 2 to 4 carbon atoms. 2104 It should be appreciated that the S1 site of MMP-13 was previously thought to be a grossly linear channel which contained an opening at the top that allowed an amino acid side chain from a substrate molecule to enter during binding, and was closed at the bottom. Applicant has discovered that the S1 site is actually composed of an S1 channel angularly connected to a newly discovered pocket which applicant calls the S1 site. The S1 site is open to solvent at the bottom, which can expose a functional group of Applicant's allosteric carboxylic inhibitors to solvent. For illustrative purposes, the S1 site of the MMP-13 enzyme can now be thought of as being like a sock with a hole in the toes, wherein the S1 channel is the region from approximately the opening to the ankle, and the S1 site is the foot region below the ankle, which foot region is angularly connected to the ankle region. 2105 More particularly, the S1 channel is a specific part of the S1 site and is formed largely by Leu218, Val219, His222 and by residues from Leu239 to Tyr244. The S1 binding site which has been newly discovered is defined by residues from Tyr246 to Pro255. The S1 site contains at least two hydrogen bond donors and aromatic groups which interact with a compound which is an allosteric carboxylic inhibitor of MMP-13. 2106 Without wishing to be bound by any particular theory, the inventor believes that the S1 site could be a recognition site for triple helix collagen, the natural substrate for MMP-13. It is possible that the conformation of the S1 site is modified only when an appropriate compound binds to MMP-13, thereby interfering with the collagen recognition process. This newly discovered pattern of binding offers the possibility of greater selectivity than what is achievable with the binding pattern of known selective inhibitors of MMP-13, wherein the known binding pattern requires ligation of the catalytic zinc atom at the active site and occupation the S1 channel, but not the S1 site. 2107 The instant allosteric carboxylic inhibitors of MMP-13 are described in co-pending PCT international applications and their corresponding United States nonprovisional application Ser. Nos. 10/071,032; 10/075,918; 10/075,073; 10/075,069; 10/075,954; 10/075,654; 10/074,646; 10/075,909; and 10/071,073, and the related U.S. provisional application Nos. 60/268,780; 60/268,736; 60/268,756; 60/268,821; 60/268,861; 60/268,757; 60/268,782; 60/268,779; and 60/268,781, respectively, all provisional applications filed on Feb. 14, 2001, and from which benefit of priority is claimed. All of the these PCT International applications, United States provisional applications, and United States nonprovisional applications are incorporated herein by reference. For convenience, the allosteric inhibitors of MMP-13 patent application filing information is listed below in Table A. 1TABLE AAllosteric inhibitors of MMP-13 patentapplication filing informationCorrespondingU.S.CorrespondingU.S. ProvisionalU.S. ProvisionalNonprovisionalPCT InternationalApplicationApplicationApplicationApplicationNumberFiling DateNumberNumber60/268,780Feb. 14, 200110/071,032PCT/IB02/0031360/268,736Feb. 14, 200110/075,918PCT/IB02/0034460/268,756Feb. 14, 200110/075,073PCT/IB02/0020460/268,821Feb. 14, 200110/075,069PCT/IB02/0044760/268,661Feb. 14, 200110/075,954PCT/EP02/0197960/268,757Feb. 14, 200110/075,654PCT/FR02/0050460/268,782Feb. 14, 200110/074,646PCT/IB02/0008360/268,779Feb. 14, 200110/075,909PCT/IB02/0019060/268,781Feb. 14, 200110/071,073PCT/IB02/00345

2108 It should be appreciated that invention combinations may comprise celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, wherein the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, may embrace any one of the compound embodiments described in co-pending PCT international applications and their corresponding United States nonprovisional application Ser. Nos. 10/071,032; 10/075,918; 10/075,073; 10/075,069; 10/075,954; 10/075,654; 10/074,646; 10/075,909; and 10/071,073, and the related U.S. provisional application Nos. 60/268,780; 60/268,736; 60/268,756; 60/268,821; 60/268,861; 60/268,757; 60/268,782; 60/268,779; and 60/268,781, respectively, including variants thereof described in the respective specifications and claims. It should be further appreciated that the above-described pharmaceutical compositions may comprise these invention combinations. It should be further appreciated that the above described methods of prevention, treatment, or inhibition may comprise administration of these invention combinations. 2109 A compound that is an allosteric carboxylic inhibitor of MMP-13 may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying an carboxylic test compound for inhibition of MMP-13 as described below in Biological Methods 1 or 2, and for allosteric inhibition of MMP-13 by assaying the carboxylic test compound for inhibition of MMP-13 in the presence of an inhibitor to the catalytic zinc of MMP-13 as described below in Biological Methods 3 or 4. 2110 Further, an allosteric carboxylic inhibitor of MMP-13 having an anti-inflammatory, an analgesic, anti-arthritic, or a cartilage damage inhibiting effect, or any combination of these effects, may be readily identified by one of ordinary skill in the pharmaceutical or medical arts by assaying the allosteric carboxylic inhibitor of MMP-13 in any number of well known assays for measuring determining the allosteric carboxylic inhibitor of MMP-13's effects on cartilage damage, arthritis, inflammation, or pain. These assays include in vitro assays that utilize cartilage samples and in vivo assays in whole animals that measure cartilage degradation, inhibition of inflammation, or pain alleviation. 2111 For example with regard to assaying cartilage damage in vitro, an amount of an allosteric carboxylic inhibitor of MMP-13 or control vehicle may be administered with a cartilage damaging agent to cartilage, and the cartilage damage inhibiting effects in both tests studied by gross examination or histopathologic examination of the cartilage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content. Further, in vivo assays to assay cartilage damage may be performed as follows: an amount of an allosteric carboxylic inhibitor of MMP-13 or control vehicle may be administered with a cartilage damaging agent to an animal, and the effects of the allosteric carboxylic inhibitor of MMP-13 being assayed on cartilage in the animal may be evaluated by gross examination or histopathologic examination of the cartilage, by observation of the effects in an acute model on functional limitations of the affected joint that result from cartilage damage, or by measurement of biological markers of cartilage damage such as, for example, proteoglycan content or hydroxyproline content. Several methods of identifying an allosteric carboxylic inhibitor of MMP-13 with cartilage damage inhibiting properties are described below. The amount to be administered in an assay to identify an allosteric carboxylic inhibitor of MMP-13 is dependent upon the particular assay employed, but in any event is not higher than the well known maximum amount of a compound that the particular assay can effectively accommodate. 2112 Similarly, allosteric carboxylic inhibitors of MMP-13 having pain-alleviating properties may be identified using any one of a number of in vivo animal models of pain. 2113 Still similarly, allosteric carboxylic inhibitors of MMP-13 having anti-inflammatory properties may be identified using any one of a number of in vivo animal models of inflammation. For example, for an example of inflammation models, see U.S. Pat. No. 6, 329,429, which is incorporated herein by reference. 2114 Still similarly, allosteric carboxylic inhibitors of MMP-13 having anti-arthritic properties may be identified using any one of a number of in vivo animal models of arthritis. For example, for an example of arthritis models, see also U.S. Pat. No. 6, 329,429. 2115 Any allosteric carboxylic inhibitor of MMP-13 is readily available, either commercially, or by synthetic methodology, well known to those skilled in the art of organic chemistry. For specific syntheses, see the examples below and the preparations of allosteric carboxylic inhibitors of MMP-13 described in the above-referenced patent applications. 2116 The term celecoxib means the compound named 4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)-benzenesulfonamide. Celecoxib is currently approved by the FDA for the treatment of osteoarthritis, rheumatoid arthritis, and Polyposis-familial adenomatus. Celecoxib is marketed under the tradename Celebrex. Celecoxib is currently in clinical trials for the treatment of bladder cancer, chemopreventative-lung cancer, and post-operative pain, and is registered for the treatment of dysmenorrhea. Celecoxib has the structure drawn below: 42

2117 It should be appreciated that the invention combination may include celecoxib, or a pharmaceutically acceptable salt thereof. Preferred invention combinations include celecoxib. 2118 The term valdecoxib means the compound named 4-(5-methyl-3-phenyl-4-isoxazolyl)-benzenesulfonamide. Valdecoxib has been approved by the FDA for treating osteoarthritis, rheumatoid arthritis, dysmenorrhea, and general pain, and is marketed under the tradename Bextra. Valdecoxib is in clinical trials for the treatment of migraine. Valdecoxib has the structure drawn below: 43

2119 It should be appreciated that the invention combination may include valdecoxib, or a pharmaceutically acceptable salt thereof. Preferred invention combinations include valdecoxib. 2120 It should be further appreciated that celecoxib and valdecoxib are each selective inhibitors of COX-2, which is also known as prostaglandin synthase-2 and prostaglandin PGH2 synthase. 2121 A selective inhibitor of COX-2 means compounds that inhibit COX-2 selectively versus COX-1 such that a ratio of IC50 for a compound with COX-1 divided by a ratio of IC50 for the compound with COX-2 is greater than, or equal to, 5, where the ratios are determined in one or more of the in vitro, in vivo, or ex vivo assays described below. All that is required to determine whether a compound is a selective COX-2 inhibitor is to assay a compound in one of the pairs of assays described in Biological Methods 5 to 8 below. Preferred selective COX-2 inhibitors have a selectivity greater than 5 fold versus COX-1 in the assay described in Biological Method 5 below. 2122 The term NSAID is an acronym for the phrase nonsteroidal anti-inflammatory drug, which means any compound which inhibits cyclooxygenase-1 (COX-1) and cyclooxygenase-2. Most NSAIDs fall within one of the following five structural classes: (1) propionic acid derivatives, such as ibuprofen, naproxen, naprosyn, diclofenac, and ketoprofen; (2) acetic acid derivatives, such as tolmetin and sulindac; (3) fenamic acid derivatives, such as mefenamic acid and meclofenamic acid; (4) biphenylcarboxylic acid derivatives, such as diflunisal and flufenisal; and (5) oxicams, such as piroxim, peroxicam, sudoxicam, and isoxicam. Other useful NSAIDs include aspirin, acetaminophen, indomethacin, and phenylbutazone. Selective inhibitors of cyclooxygenase-2 as described above may be considered to be NSAIDs also. 2123 For the purposes of this invention, the term arthritis, which is synonymous with the phrase arthritic condition, includes osteoarthritis, rheumatoid arthritis, degenerative joint disease, spondyloarthropathies, gouty arthritis, systemic lupus erythematosus, juvenile arthritis, and psoriatic arthritis. An allosteric carboxylic inhibitor of MMP-13 having an anti-arthritic effect is a compound as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the arthritic diseases and disorders listed above. 2124 Other mammalian diseases and disorders which are treatable by administration of an invention combination alone, or contained in a pharmaceutical composition as defined below, include: fever (including rheumatic fever and fever associated with influenza and other viral infections), common cold, dysmenorrhea, menstrual cramps, inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, bronchitis, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity, cancer (such as solid tumor cancer including colon cancer, breast cancer, lung cancer and prostrate cancer; hematopoietic malignancies including leukemias and lymphomas; Hodgkin's disease; aplastic anemia, skin cancer and familiar adenomatous polyposis), tissue ulceration, peptic ulcers, gastritis, regional enteritis, ulcerative colitis, diverticulitis, recurrent gastrointestinal lesion, gastrointestinal bleeding, coagulation, anemia, synovitis, gout, ankylosing spondylitis, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), periarteritis nodosa, congestive heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury, neuralgia, neuro-degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease, Parkinson's disease, migraine, depression, peripheral neuropathy, pain (including low back and neck pain, headache and toothache), gingivitis, cerebral amyloid angiopathy, nootropic or cognition enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, conjunctivitis, abnormal wound healing, muscle or joint sprains or strains, tendonitis, skin disorders (such as psoriasis, eczema, scleroderma and dermatitis), myasthenia gravis, polymyositis, myositis, bursitis, bums, diabetes (including types I and II diabetes, diabetic retinopathy, neuropathy and nephropathy), tumor invasion, tumor growth, tumor metastasis, corneal scaring, scleritis, immunodeficiency diseases (such as AIDS in humans and FLV, FIV in cats), sepsis, premature labor, hypoprothrombinemia, hemophilia, thyroiditis, sarcoidosis, Behcet's syndrome, hypersensitivity, kidney disease, Rickettsial infections (such as Lyme disease, Erlichiosis), Protozoan diseases (such as malaria, giardia, coccidia), reproductive disorders (preferably in livestock), epilepsy, convulsions, and septic shock. 2125 The term Thr245 means threonine 245 of an MMP-13 enzyme. 2126 The term Thr247 means threonine 247 of an MMP-13 enzyme. 2127 The term Met253 means methionine 253 of an MMP-13 enzyme. 2128 The term His251 means histidine 251 of an MMP-13 enzyme. 2129 It should be appreciated that the matrix metalloproteinases include, but are not limited to, the following enzymes: 2130 MMP-1, also known as interstitial collagenase, collagenase-1, or fibroblast-type collagenase; 2131 MMP-2, also known as gelatinase A or 72 kDa Type IV collagenase; 2132 MMP-3, also known as stromelysin or stromelysin-1; 2133 MMP-7, also known as matrilysin or PUMP-1; 2134 MMP-8, also known as collagenase-2, neutrophil collagenase or polymorphonuclear-type (PMN-type) collagenase; 2135 MMP-9, also known as gelatinase B or 92 kDa Type IV collagenase; 2136 MMP-10, also known as stromelysin-2; 2137 MMP-11, also known as stromelysin-3; 2138 MMP-12, also known as metalloelastase; 2139 MMP-13, also known as collagenase-3; 2140 MMP-14, also known as membrane-type (MT) 1-MMP or MT1-MMP; 2141 MMP-15, also known as MT2-MMP; 2142 MMP-16, also known as MT3-MMP; 2143 MMP-17, also known as MT4-MMP; 2144 MMP-18; and 2145 MMP-19. 2146 Other known MMPs include MMP-26 (Matrilysin-2). 2147 The invention provides combinations which comprise an allosteric carboxylic inhibitor of MMP-13. An allosteric carboxylic inhibitor of MMP-13 is any compound that contains a carboxylic ester linker i.e., C(O)OC or COC(O)- or 2148 carboxylic amide linker i.e., 44

2149 and that binds to, coordinates to, or ligates a site in an MMP-13 enzyme that is at a location other than the enzyme's catalytically active site, wherein the catalytically active site is the site where the catalytic zinc cation of the MMP-13 enzyme binds, ligates, or coordinates a natural substrate(s). Thus an allosteric carboxylic inhibitor of MMP-13 is any carboxylic-containing inhibitor of an MMP-13 that does not bind to, coordinate to, or ligate, either directly or indirectly via a bridging water molecule, the catalytic zinc cation of a MMP-13. 2150 Further, an allosteric carboxylic inhibitor of MMP-13, as used in the present invention, is a compound that does not ligate, coordinate to, or bind to the catalytic zinc cation of MMP-13, or a truncated form thereof, and is 5 times more potent in vitro versus MMP-13, or a truncated form thereof, than versus at least 2 other matrix metalloproteinase enzymes, including MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-11, MMP-12, MMP-14, MMP-17, MMP-18, MMP-19, MMP-21, and MMP-26, and tumor necrosis factor alpha convertase (TACE). A preferred aspect of the present invention is combinations comprising allosteric carboxylic inhibitors of MMP-13 that are selective inhibitors of MMP-13 over MMP-1. 2151 Other aspects of the present invention are allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, that are 10, 20, 50, 100, or 1000 times more potent versus MMP-13 than versus at least two of any other MMP enzyme or TACE. 2152 Still other aspects of the present invention are allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, that are selective inhibitors of MMP-13 versus 2, 3, 4, 5, 6, or 7 other MMP enzymes, or versus TACE and 1, 2, 3, 4, 5, 6, or 7 other MMP enzymes. 2153 It should be appreciated that selectivity of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, is a multidimensional characteristic that includes the number of other MMP enzymes and TACE over which selectivity for MMP-13 inhibition is present and the degree of selectivity of inhibition of MMP-13 over another particular MMP or TACE, as measured by, for example, the IC50 in micromolar concentration of inhibitor for the inhibition of the other MMP enzyme or TACE divided by the IC50 in micromolar concentration of inhibitor for the inhibition of MMP-13. 2154 The term IC50 means the concentration of a compound, usually expressed as micromolar or nanomolar, required to inhibit an enzyme's catalytic activity by 50%. 2155 The term ED40 means the concentration of a compound, usually expressed as micromolar or nanomolar, required to treat a disease in about 40% of a patient group. 2156 The term ED30 means the concentration of a compound, usually expressed as micromolar or nanomolar, required to treat a disease in 30% of a patient group. 2157 The phrase pharmaceutical composition means a composition suitable for administration in medical or veterinary use. 2158 The term admixed and the phrase in admixture are synonymous and mean in a state of being in a homogeneous or heterogeneous mixture. Preferred is a homogeneous mixture. 2159 As used herein, the phrase cartilage damage means a disorder of hyaline cartilage and subchondral bone characterized by hypertrophy of tissues in and around the involved joints, which may or may not be accompanied by deterioration of hyaline cartilage surface. 2160 The phrase treating, which is related to the terms treat and treated, means administration of an invention combination as defined above that inhibits the progress, prevents further progress, or reverses progression, in part or in whole, of any one or more symptoms of any one of the diseases and disorders listed above. 2161 The term comprising, which is synonymous with the terms including, containing, or characterized by, is inclusive or open-ended, and does not exclude additional, unrecited elements or method steps from the scope of the invention that is described following the term. 2162 The phrase consisting of is closed-ended, and excludes any element, step, or ingredient not specified in the description of the invention that follows the phrase. 2163 The phrase consisting essentially of limits the scope of the invention that follows to the specified elements, steps, or ingredients, and those further elements, steps, or ingredients that do not materially affect the basic and novel characteristics of the invention. 2164 The invention combination also includes isotopically-labelled compounds, which are identical to those recited above, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F and 36Cl, respectively. Compounds of the present invention and pharmaceutically acceptable salts of said compounds which contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of this invention. Certain isotopically labelled compounds of the present invention, for example those into which radioactive isotopes such as 3H and 14C are incorporated, are useful in drug and/or substrate tissue distribution assays. Tritiated, i.e., 3H and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. Isotopically labelled compounds of those described above in this invention can generally be prepared by carrying out the procedures incorporated by reference above or disclosed in the Schemes and/or in the Examples and Preparations below, by substituting a readily available isotopically labelled reagent for a non-isotopically labelled reagent. 2165 One of ordinary skill in the art will appreciate that the combinations of the invention are useful in treating a diverse array of diseases. One of ordinary skill in the art will also appreciate that when using the combinations of the invention in the treatment of a specific disease that the combinations of the invention may be combined with various existing therapeutic agents used for that disease. 2166 For the treatment of rheumatoid arthritis, the combinations of the invention may be combined with agents such as TNF- inhibitors such as anti-TNF monoclonal antibodies and TNF receptor immunoglobulin molecules (such as Enbrel), low dose methotrexate, lefunimide, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold. 2167 The combinations of the invention can also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Suitable agents to be used in combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAfD's) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic acid, indomethacin, sulindac, apazone, pyrazolones such as phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such as celecoxib and rofecoxib, analgesics and intraarticular therapies such as corticosteroids and hyaluronic acids such as hyalgan and synvisc. 2168 This invention also relates to a method of or a pharmaceutical composition for treating inflammatory processes and diseases comprising administering a combination of this invention to a mammal, including a human, cat, livestock or dog, wherein said inflammatory processes and diseases are defined as above and said inhibitory combination is used in combination with one or more other therapeutically active agents under the following conditions: 2169 A.) where a joint has become seriously inflamed as well as infected at the same time by bacteria, fungi, protozoa and/or virus, said inhibitory combination is administered in combination with one or more antibiotic, antifungal, antiprotozoal and/or antiviral therapeutic agents; 2170 B.) where a multi-fold treatment of pain and inflammation is desired, said inhibitory combination is administered in combination with inhibitors of other mediators of inflammation, comprising one or more members independently selected from the group consisting essentially of: 2171 (1) NSAIDs; 2172 (2) H1-receptor antagonists; 2173 (3) kinin-B1- and B2-receptor antagonists; 2174 (4) prostaglandin inhibitors selected from the group consisting of PGD-, PGF- PGI2- and PGE-receptor antagonists; 2175 (5) thromboxane A2 (TXA2-) inhibitors; 2176 (6) 5-, 12- and 15-lipoxygenase inhibitors; 2177 (7) leukotriene LTC4, LTD4/LTE4- and LTB4-inhibitors; 2178 (8) PAF-receptor antagonists; 2179 (9) gold in the form of an aurothio group together with one or more hydrophilic groups; 2180 (10) immunosuppressive agents selected from the group consisting of cyclosporine, azathioprine and methotrexate; 2181 (11) anti-inflammatory glucocorticoids; 2182 (12) penicillamine; 2183 (13) hydroxychloroquine; 2184 (14) anti-gout agents including colchicine; xanthine oxidase inhibitors including allopurinol; and uricosuric agents selected from probenecid, sulfinpyrazone and benzbromarone; 2185 C. where older mammals are being treated for disease conditions, syndromes and symptoms found in geriatric mammals, said inhibitory combination is administered in combination with one or more members independently selected from the group consisting essentially of: 2186 (1) cognitive therapeutics to counteract memory loss and impairment; 2187 (2) anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, hypertension, myocardial ischemia, angina, congestive heart failure and myocardial infarction, selected from the group consisting of: 2188 a. diuretics; 2189 b. vasodilators; 2190 c. -adrenergic receptor antagonists; 2191 d. angiotensin-II converting enzyme inhibitors (ACE-inhibitors), alone or optionally together with neutral endopeptidase inhibitors; 2192 e. angiotensin II receptor antagonists; 2193 f. renin inhibitors; 2194 g. calcium channel blockers; 2195 h. sympatholytic agents; 2196 i. 2-adrenergic agonists; 2197 j. -adrenergic receptor antagonists; and 2198 k. HMG-CoA-reductase inhibitors (anti-hypercholesterolemics); 2199 (3) antineoplastic agents selected from: 2200 a. antimitotic drugs selected from: 2201 i. vinca alkaloids selected from: 2202 1 vinblastine and 2203 2 vincristine; 2204 (4) growth hormone secretagogues; 2205 (5) strong analgesics; 2206 (6) local and systemic anesthetics; and 2207 (7) H2-receptor antagonists, proton pump inhibitors and other gastroprotective agents. 2208 The active ingredient of the present invention may be administered in combination with inhibitors of other mediators of inflammation, comprising one or more members selected from the group consisting essentially of the classes of such inhibitors and examples thereof which include, matrix metalloproteinase inhibitors, aggrecanase inhibitors, TACE inhibitors, leucotriene receptor antagonists, IL-1 processing and release inhibitors, ILra, H1-receptor antagonists; kinin-B1- and B2-receptor antagonists; prostaglandin inhibitors such as PGD-, PGF- PGI2- and PGE-receptor antagonists; thromboxane A2 (TXA2-) inhibitors; 5- and 12-lipoxygenase inhibitors; leukotriene LTC4-, LTD4/LTE4- and LTB4-inhibitors; PAF-receptor antagonists; gold in the form of an aurothio group together with various hydrophilic groups; immunosuppressive agents, e.g., cyclosporine, azathioprine and methotrexate; anti-inflammatory glucocorticoids; penicillamine; hydroxychloroquine; anti-gout agents, e.g., colchicine, xanthine oxidase inhibitors, e.g., allopurinol and uricosuric agents, e.g., probenecid, sulfinpyrazone and benzbromarone. 2209 The combinations of the present invention may also be used in combination with anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as Adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine and antimetabolites such as methotrexate. 2210 The combinations of the present invention may also be used in combination with anti-hypertensives and other cardiovascular drugs intended to offset the consequences of atherosclerosis, including hypertension, myocardial ischemia including angina, congestive heart failure and myocardial infarction, selected from vasodilators such as hydralazine, -adrenergic receptor antagonists such as propranolol, calcium channel blockers such as nifedipine, 2-adrenergic agonists such as clonidine, -adrenergic receptor antagonists such as prazosin and HMG-CoA-reductase inhibitors (anti-hypercholesterolemics) such as lovastatin or atorvastatin. 2211 The combination of the present invention may also be administered in combination with one or more antibiotic, antifungal, antiprotozoal, antiviral or similar therapeutic agents. 2212 The combinations of the present invention may also be used in combination with CNS agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as L-dopa, requip, mirapex, MAOB inhibitors such as selegine and rasagiline, comP inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotine agonists, dopamine agonists and inhibitors of neuronal nitric oxide synthase) and anti-Alzheimer's drugs such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate. 2213 The combinations of the present invention may also be used in combination with osteoporosis agents such as roloxifene, lasofoxifene, droloxifene or fosomax and immunosuppressant agents such as FK-506 and rapamycin. 2214 The present invention also relates to the formulation of the combination of the present invention alone or with one or more other therapeutic agents which are to form the intended combination, including wherein said different drugs have varying half-lives, by creating controlled-release forms of said drugs with different release times which achieves relatively uniform dosing; or, in the case of non-human patients, a medicated feed dosage form in which said drugs used in the combination are present together in admixture in the feed composition. There is further provided in accordance with the present invention co-administration in which the combination of drugs is achieved by the simultaneous administration of said drugs to be given in combination; including co-administration by means of different dosage forms and routes of administration; the use of combinations in accordance with different but regular and continuous dosing schedules whereby desired plasma levels of said drugs involved are maintained in the patient being treated, even though the individual drugs making up said combination are not being administered to said patient simultaneously. 2215 The term drugs, which is synonymous with the phrases active components, active compounds, and active ingredients, includes celecoxib, or a pharmaceutically acceptable salt thereof, valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and may further include one or two of the other therapeutic agents described above. 2216 The invention method is useful in human and veterinary medicines for treating mammals suffering from one or more of the above-listed diseases and disorders. 2217 The term mammal includes humans, companion animals such as cats and dogs, primates such as monkeys and chimpanzees, and livestock animals such as horses, cows, pigs, and sheep. 2218 The phrase livestock animals as used herein refers to domesticated quadrupeds, which includes those being raised for meat and various byproducts, e.g., a bovine animal including cattle and other members of the genus Bos, a porcine animal including domestic swine and other members of the genus Sus, an ovine animal including sheep and other members of the genus Ovis, domestic goats and other members of the genus Capra; domesticated quadrupeds being raised for specialized tasks such as use as a beast of burden, e.g., an equine animal including domestic horses and other members of the family Equidae, genus Equus, or for searching and sentinel duty, e.g., a canine animal including domestic dogs and other members of the genus Canis; and domesticated quadrupeds being raised primarily for recreational purposes, e.g., members of Equus and Canis, as well as a feline animal including domestic cats and other members of the family Felidae, genus Felis. 2219 All that is required to practice the method of this invention is to administer a combination of celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, in an amount that is therapeutically effective for preventing, inhibiting, or reversing the condition being treated. The invention combination can be administered directly or in a pharmaceutical composition as described below. 2220 A therapeutically effective amount, or, simply, effective amount, of an invention combination will generally be from about 1 to about 300 mg/kg of subject body weight of valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, and from about 1 to about 300 mg/kg of subject body weight of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. Typical doses will be from about 10 to about 5000 mg/day for an adult subject of normal weight for each component of the combination. In a clinical setting, regulatory agencies such as, for example, the Food and Drug Administration (FDA) in the U.S. may require a particular therapeutically effective amount. 2221 In determining what constitutes an effective amount or a therapeutically effective amount of an invention combination for treating, preventing, or reversing one or more symptoms of any one of the diseases and disorders described above that are being treated according to the invention methods, a number of factors will generally be considered by the medical practitioner or veterinarian in view of the experience of the medical practitioner or veterinarian, including the Food and Drug Administration guidelines, or guidelines from an equivalent agency, published clinical studies, the subject's (e.g., mammal's) age, sex, weight and general condition, as well as the type and extent of the disease, disorder or condition being treated, and the use of other medications, if any, by the subject. As such, the administered dose may fall within the ranges or concentrations recited above, or may vary outside them, ie, either below or above those ranges, depending upon the requirements of the individual subject, the severity of the condition being treated, and the particular therapeutic formulation being employed. Determination of a proper dose for a particular situation is within the skill of the medical or veterinary arts. Generally, treatment may be initiated using smaller dosages of the invention combination that are less than optimum for a particular subject. Thereafter, the dosage can be increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day, if desired. 2222 Pharmaceutical compositions, described briefly here and more fully below, of an invention combination may be produced by formulating the invention combination in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. Alternatively, the active components of the invention combination may be formulated separately. 2223 Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch; cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. 2224 The compositions to be employed in the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents commonly employed to treat any of the above-listed diseases and disorders. 2225 The percentage of the active ingredients of celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, combination in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a total concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredients are present, for example, up to about 95%. 2226 Preferred routes of administration of an invention combination are oral or parenteral. However, another route of administration may be preferred depending upon the condition being treated. For exampled, topical administration or administration by injection may be preferred for treating conditions localized to the skin or a joint. Administration by transdermal patch may be preferred where, for example, it is desirable to effect sustained dosing. 2227 It should be appreciated that the different routes of administration may require different dosages. For example, a useful intravenous (IV) dose is between 5 and 50 mg, and a useful oral dosage is between 20 and 800 mg, both for each of celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. The dosage is within the dosing range used in treatment of the above-listed diseases, or as would be determined by the needs of the patient as described by the physician. 2228 The invention combination may be administered in any form. Preferably, administration is in unit dosage form. A unit dosage form of the invention combination to be used in this invention may also comprise other compounds useful in the therapy of diseases described above. A further description of pharmaceutical formulations useful for administering the invention combinations is provided below. 2229 The active components of the invention combination, including celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and other compounds as described above, if any, may be formulated together or separately and may be administered together or separately. The particular formulation and administration regimens used may be tailored to the particular patient and condition being treated by a practitioner of ordinary skill in the medical or pharmaceutical arts. 2230 The advantages of using an invention combination comprising celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, in a method of the instant invention include the nontoxic nature of the compounds which comprise the combination at and substantially above therapeutically effective doses, their ease of preparation, the fact that the compounds are well-tolerated, and the ease of topical, IV, or oral administration of the drugs. 2231 Another important advantage is that the present invention combinations more effectively target a particular disease that is responsive to inhibition of MMP-13 with fewer undesirable side effects than similar combinations that contain MMP-13 inhibitors that are not allosteric carboxylic inhibitors of MMP-13. This is so because the instant allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, do not directly, or indirectly via a bridging water molecule, ligate, coordinate to, or bind to the catalytic zinc cation of MMP-13, but instead bind at a different location from where natural substrate binds to MMP-13. The binding requirements of an allosteric MMP-13 binding site are unique to MMP-13, and account for the specificity of the instant allosteric carboxylic inhibitors of MMP-13 for inhibiting MMP-13 over any other MMP enzyme. This binding mode has not been reported in the art. Indeed, prior art inhibitors of MMP-13 bind to the catalytic zinc cations of other MMP enzymes as well as to the catalytic zinc cation of MMP-13 and, and are consequently significantly less selective inhibitors of MMP-13 enzyme. 2232 The instant allosteric carboxylic inhibitors of MMP-13 are thus therapeutically superior to other inhibitors of MMP-13, or even tumor necrosis factor-alpha converting enzyme (TACE), because of fewer undesirable side effects from inhibition of the other MMP enzymes or TACE. For example, virtually all prior art MMP inhibitors tested clinically to date have exhibited an undesirable side effect known as muscoloskeletal syndrome (MSS). MSS is associated with administering an inhibitor of multiple MMP enzymes or an inhibitor of a particular MMP enzyme such as MMP-1. MSS will be significantly reduced in type and severity by administering the invention combination instead of any combination of a prior art MMP-13 inhibitor with celecoxib or valdecoxib, or a pharmaceutically acceptable salt thereof. The invention combinations are superior to similar combinations that include a COX-2 selective inhibitor with an MMP inhibitor that interacts with the catalytic zinc cation of the MMP-13 enzyme as discussed above, even if that inhibitor shows some selectivity for the MMP-13. 2233 This advantage of the instant combinations will also significantly increase the likelihood that agencies which regulate new drug approvals, such as the United States Food and Drug Administration, will approve the instant combination versus a competing similar combination as discussed above even in the unlikely event that the two combinations behaved similarly in clinical trials. These regulatory agencies are increasingly aware that clinical trials, which test drug in limited population groups, do not always uncover safety problems with a drug, and thus all other things being equal, the agencies will favor the drug with the lowest odds of producing undesirable side effects. 2234 Another important advantage is that the independent anti-inflammatory and pain reducing properties described above for valdecoxib and celecoxib and the disease modifying properties of allosteric carboxylic inhibitors of MMP-13 provide patients suffering from cartilage damage, arthritis, inflammation and/or pain with both relief of symptoms and prevention or inhibition of the underlying disease pathology such as cartilage degradation. 2235 A further advantage of the invention combination is administration of the combination to treat a disease or disorder in a mammal may allow lower doses of valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, and/or an allosteric carboxylic inhibitor of MMP-13 of the combination to be used than would be used if valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic inhibitor of MMP-13 were each administered alone. This advantage is a result of an unexpected synergistic therapeutically beneficial effect on inhibition of cartilage damage or alleviation of pain for the combination over the sum of the therapeutic effects for each component of the combination administered alone. 2236 Some of the compounds utilized in an invention combination are capable of further forming pharmaceutically acceptable salts, including, but not limited to, acid addition and/or base salts. The acid addition salts are formed from basic compounds, whereas the base addition salts are formed from acidic compounds. All of these forms are within the scope of the compounds useful in the invention combination. 2237 Pharmaceutically acceptable acid addition salts of the basic compounds useful in the invention combination include nontoxic salts derived from inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, hydrofluoric, phosphorous, and the like, as well nontoxic salts derived from organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, malate, tartrate, methanesulfonate, and the like. Also contemplated are salts of amino acids such as arginate and the like and gluconate, galacturonate (see, for example, Berge S. M. et al., Pharmaceutical Salts, J. of Pharma. Sci., 1977;66:1). 2238 An acid addition salt of a basic compound useful in the invention combination is prepared by contacting the free base form of the compound with a sufficient amount of a desired acid to produce a nontoxic salt in the conventional manner. The free base form of the compound may be regenerated by contacting the acid addition salt so formed with a base, and isolating the free base form of the compound in the conventional manner. The free base forms of compounds prepared according to a process of the present invention differ from their respective acid addition salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise free base forms of the compounds and their respective acid addition salt forms are equivalent for purposes of the present invention. 2239 A pharmaceutically acceptable base addition salt of an acidic compound useful in the invention combination may be prepared by contacting the free acid form of the compound with a nontoxic metal cation such as an alkali or alkaline earth metal cation, or an amine, especially an organic amine. Examples of suitable metal cations include sodium cation (Na), potassium cation (K), magnesium cation (Mg2), calcium cation (Ca2), and the like. Examples of suitable amines are N,N-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine (see, for example, Berge, supra., 1977). 2240 A base addition salt of an acidic compound useful in the invention combination may be prepared by contacting the free acid form of the compound with a sufficient amount of a desired base to produce the salt in the conventional manner. The free acid form of the compound may be regenerated by contacting the salt form so formed with an acid, and isolating the free acid of the compound in the conventional manner. The free acid forms of the compounds useful in the invention combination differ from their respective salt forms somewhat in certain physical properties such as solubility, crystal structure, hygroscopicity, and the like, but otherwise the salts are equivalent to their respective free acid for purposes of the present invention. 2241 Certain of the compounds useful in the invention combination can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms, including hydrated forms, are equivalent to unsolvated forms and are encompassed within the scope of the present invention. 2242 Certain of the compounds useful in the invention combination possess one or more chiral centers, and each center may exist in the R or S configuration. An invention combination may utilize any diastereomeric, enantiomeric, or epimeric form of a compound useful in the invention combination, as well as mixtures thereof. 2243 Additionally, certain compounds useful in the invention combination may exist as geometric isomers such as the entgegen (E) and zusammen (Z) isomers of 1,2-disubstituted alkenyl groups or cis and trans isomers of disubstituted cyclic groups. An invention combination may utilize any cis, trans, syn, anti, entgegen (E), or zusammen (Z) isomer of a compound useful in the invention combination, as well as mixtures thereof. 2244 Certain compounds useful in the invention combination can exist as two or more tautomeric forms. Tautomeric forms of the compounds may interchange, for example, via enolization/de-enolization, 1,2-hydride, 1,3-hydride, or 1,4-hydride shifts, and the like. An invention combination may utilize any tautomeric form of a compound useful in the invention combination, as well as mixtures thereof. 2245 The syntheses of valdecoxib, or a pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, are well-known in the art, and have even been carried out to produce commercial-scale quantities of compound. The synthesis of allosteric inhibitors of MMP-13 are taught in the patent applications incorporated above by reference. 2246 Intermediates for the synthesis of valdecoxib, or a pharmaceutically acceptable salt thereof, celecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, useful in the invention combination may be prepared by one of ordinary skill in the art of organic chemistry by adapting various synthetic procedures incorporated by reference above or that are well-known in the art of organic chemistry. These synthetic procedures may be found in the literature in, for example, Reagents for Organic Synthesis, by Fieser and Fieser, John Wiley & Sons, Inc, New York, 2000; Comprehensive Organic Transformations, by Richard C. Larock, VCH Publishers, Inc, New York, 1989; the series Compendium of Organic Synthetic Methods, 1989, by Wiley-Interscience; the text Advanced Organic Chemistry, 4th edition, by Jerry March, Wiley-Interscience, New York,1992; or the Handbook of Heterocyclic Chemistry by Alan R. Katritzky, Pergamon Press Ltd, London, 1985, to name a few. Alternatively, a skilled artisan may find methods useful for preparing the intermediates in the chemical literature by searching widely available databases such as, for example, those available from the Chemical Abstracts Service, Columbus, Ohio, or MDL Information Systems GmbH (formerly Beilstein Information Systems GmbH), Frankfurt, Germany. 2247 Preparations of the compounds useful in an invention combination may use starting materials, reagents, solvents, and catalysts that may be purchased from commercial sources or they may be readily prepared by adapting procedures in the references or resources cited above. Commercial sources of starting materials, reagents, solvents, and catalysts useful in preparing invention compounds include, for example, The Aldrich Chemical Company, and other subsidiaries of Sigma-Aldrich Corporation, St. Louis, Mo., BACHEM, BACHEM A. G., Switzerland, or Lancaster Synthesis Ltd, United Kingdom. 2248 Syntheses of some compounds useful in the invention combination may utilize starting materials, intermediates, or reaction products that contain a reactive functional group. During chemical reactions, a reactive functional group may be protected from reacting by a protecting group that renders the reactive functional group substantially inert to the reaction conditions employed. A protecting group is introduced onto a starting material prior to carrying out the reaction step for which a protecting group is needed. Once the protecting group is no longer needed, the protecting group can be removed. It is well within the ordinary skill in the art to introduce protecting groups during a synthesis of valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, or an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and then later remove them. Procedures for introducing and removing protecting groups are known and referenced such as, for example, in Protective Groups in Organic Synthesis, 2nd ed., Greene T. W. and Wuts P. G., John Wiley & Sons, New York: New York, 1991, which is hereby incorporated by reference. 2249 Thus, for example, protecting groups such as the following may be utilized to protect amino, hydroxyl, and other groups: carboxylic acyl groups such as, for example, formyl, acetyl, and trifluoroacetyl; alkoxycarbonyl groups such as, for example, ethoxycarbonyl, tert-butoxycarbonyl (BOC), ,,-trichloroethoxycarbonyl (TCEC), and -iodoethoxycarbonyl; aralkyloxycarbonyl groups such as, for example, benzyloxycarbonyl (CBZ), para-methoxybenzyloxycarbonyl, and 9-fluorenylmethyloxycarbonyl (FMOC); trialkylsilyl groups such as, for example, trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBDMS); and other groups such as, for example, triphenylmethyl (trityl), tetrahydropyranyl, vinyloxycarbonyl, ortho-nitrophenylsulfenyl, diphenylphosphinyl, para-toluenesulfonyl (Ts), mesyl, trifluoromethanesulfonyl, and benzyl. Examples of procedures for removal of protecting groups include hydrogenolysis of CBZ groups using, for example, hydrogen gas at 50 psi in the presence of a hydrogenation catalyst such as 10% palladium on carbon, acidolysis of BOC groups using, for example, hydrogen chloride in dichloromethane, trifluoroacetic acid (TFA) in dichloromethane, and the like, reaction of silyl groups with fluoride ions, and reductive cleavage of TCEC groups with zinc metal. 2250 Preparations of valdecoxib, or a pharmaceutically acceptable salt thereof, or an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, useful in the invention combination are incorporated by reference to the patents, patent applications, and patent application publications described above. 2251 Allosteric carboxylic inhibitors of MMP-13 useful in the present invention combinations may be prepared by one of ordinary skill in the art of synthetic organic chemistry readily adapting known literature methods. Additional methods of preparation are described in co-pending PCT international applications and their corresponding United States nonprovisional application Ser. Nos. 10/071,032; 10/075,918; 10/075,073; 10/075,069; 10/075,954; 10/075,654; 10/074,646; 10/075,909; and 10/071,073, and the related U.S. provisional application Nos. 60/268,780; 60/268,736; 60/268,756; 60/268,821; 60/268,861; 60/268,757; 60/268,782; 60/268,779; and 60/268,781, respectively, all provisional applications filed on Feb. 14, 2001, and from which benefit of priority is claimed. All of the PCT International applications, United States provisional applications, and United States nonprovisional applications have been incorporated herein by reference above.

Examples of Allosteric Carboxylic Inhibitors of MMP-13 2252 1. Examples of Thiazolopyrimidinedione Allosteric Inhibitors of MMP-13: 2253 The syntheses of thiazolopyrimidinediones useful as allosteric inhibitors of MMP-13 are described in our co-pending U.S. nonprovisional application Ser. No. 10/071,032, the corresponding PCT International application number PCT/IB02/00313, and the priority application U.S. provisional application No. 60/268,780, filed on Feb. 14, 2001. 2254 One example is named and drawn below: 2255 6-Benzyl-5,7-dioxo-6,7-dihydro-5H-thiazolo3,2-cpyrimidine-2-carboxylic acid benzyl ester 45

2256 It should be appreciated that the compound drawn above has first and second hydrophobic groups and first, second and third hydrogen bond acceptors. The first hydrophobic group locates in the S1 pocket of the enzyme and its hydrophobic aryl ring interacts with the aryl rings of His222 and Tyr244. The second hydrophobic group is open to solvent and forms hydrophobic interactions with the aryl rings of e.g. Phe252 and Tyr246. The three hydrogen bond acceptors interact respectively with Thr245, Thr247 and Met 253. 2257 2. Examples of Isophthalic Acid Allosteric Inhibitors of MMP-13: 2258 The syntheses of isophthalic acid derivatives are described in our co-pending United States nonprovisional application Ser. No. 10/075,918, the corresponding PCT International application number PCT/IB02/00344, and the priority application U.S. provisional application No. 60/268,736, filed on Feb. 14, 2001. 2259 Binding to MMP-13 of a representative example of one of the isophthalic acid derivatives is as described above for Example 1. It will be observed that the compounds of this series have two hydrophobic groups and two hydrogen bond acceptors. 2260 3. Examples of Fused Bicyclic Pyrimidone Allosteric Inhibitors of MMP-13: 2261 The syntheses of fused bicyclic pyrimidone allosteric inhibitors of MMP-13 are described in co-pending United States nonprovisional application Ser. No. 10/075,073, the corresponding PCT International application number PCT/IB02/00204, and the priority application U.S. provisional application No. 60/268,756, filed on Feb. 14, 2001. 2262 Binding to MMP-13 of a representative compound of the fused bicyclic pyrimidone allosteric inhibitors of MMP-13 is through two hydrophobic groups and three hydrogen bond acceptors, the third hydrogen bond acceptor binding to Met 253 and also via a bridging water molecule to the backbone carbonyl of His251. 2263 4. Examples of Substituted Quinazoline Allosteric Inhibitors of MMP-13: 2264 The syntheses of quinazoline allosteric inhibitors of MMP-13 are described in our co-pending United States nonprovisional application Ser. No. 10/075,954, the related PCT International application number PCT/EP02/01979, and the corresponding priority U.S. provisional application No. 60/268,661, filed on Feb. 14, 2001. 2265 Binding to MMP-13 of the compound of Example 35 is based on two hydrophobic groups and three hydrogen bond acceptors. As in the thiazolopyrimidinediones, the third hydrogen bond acceptor binds both to Met 253 and via a bridging water molecule to the backbone carbonyl oxygen of His 251. It will also be noted from the above table that some compounds in this series do not have a second hydrophobic group, but nevertheless bind to MMP-13 and exhibit a useful inhibitory activity. 2266 5. Examples of pyrido2,3-dpyrimidines: 2267 The syntheses of pyrido2,3-dpyrimidine allosteric inhibitors of MMP-13 are also described in our co-pending United States nonprovisional application Ser. No. 10/075,954, the related PCT International application number PCT/EP02/01979, and the corresponding priority U.S. provisional application No. 60/268,661, filed on Feb. 14, 2001. 2268 6. Examples of Fused Triazolo-quinazoline Allosteric Inhibitors of MMP-13: 2269 Syntheses of fused triazolo-quinazoline allosteric inhibitors of MMP-13 are described in our co-pending United States nonprovisional application Ser. No. 10/075,654, the related PCT International application number PCT/FR02/00504, and the priority application U.S. provisional application No. 60/268,757, filed on Feb. 14, 2001. 2270 Binding of a representative compound in the fused triazolo-quinazoline, Example 57 involves first and second hydrophobic groups and first, second and third hydrogen bond acceptors. 2271 7. Examples of 1,1-dioxy-benzo-(1,2,4)-thiadiazine Allosteric Inhibitors of MMP-13: 2272 The syntheses of 1,1-dioxy-benzo-(1,2,4)-thiadiazine allosteric inhibitors of MMP-13 are described in our co-pending United States nonprovisional application Ser. No. 10/074,646, the related PCT International application number PCT/IB02/00083, and the priority application U.S. provisional application No. 60/268,782, filed on Feb. 14, 2001. 2273 For illustration purposes, examples of allosteric carboxylic inhibitors of MMP-13 are described below. The allosteric carboxylic inhibitors of MMP-13 have been evaluated in standard assays for their ability to inhibit the catalytic activity of various MMP enzymes. The assays used to evaluate the MMP biological activity of the invention compounds are well-known and routinely used by those skilled in the study of MMP inhibitors and their use to treat clinical conditions. For example, allosteric carboxylic inhibitors of MMP-13 may be readily identified by assaying a test compound for inhibition of MMP-13 according to Biological Methods 1 or 2, and further assaying the test compound for allosteric inhibition of MMP-13 according to Biological Methods 3 or 4, as described below. 2274 Examples of allosteric carboxylic inhibitors of MMP-13 are provided below. The compounds have been shown to be potent and selective inhibitors of MMP-13 catalytic domain versus full-length MMP-1 and MMP-3 catalytic domain. Potencies with MMP-13 catalytic domain for the allosteric inhibitors of MMP-13 typically range from about 0.001 M to about 1 M. Some compounds were further screened with full-length MMP-2, full-length MMP-7, full-length MMP-9, and MMP-14 catalytic domain, and were found to be selective inhibitors of MMP-13 versus these other MMP enzymes also. Selectivity of the allosteric inhibitors of MMP-13 for MMP-13 catalytic domain versus another MMP enzyme (full-length or catalytic domain), as determined by dividing the IC50 for the inhibitor with a comparator MMP enzyme by the IC50 of the inhibitor with MMP-13 catalytic domain, typically ranged from 5 to 50,000 fold. 2275 The allosteric carboxylic inhibitors of MMP-13 were assayed for inhibition of MMP-13 and for allosteric inhibition of MMP-13 and certain other MMP enzymes according to Biological Methods 1 to 4, which are described immediately below. The assays measure the amount by which a test compound reduces the hydrolysis of a thiopeptolide substrate catalyzed by a matrix metalloproteinase enzyme. Such assays are described in detail by Ye et al., in Biochemistry, 1992;31(45):11231-11235, which is incorporated herein by reference. One such assay is described below in Biological Method 1. 2276 Some of the particular methods described below use the catalytic domain of the MMP-13 enzyme, namely matrix metalloproteinase-13 catalytic domain (MMP-13CD), rather than the corresponding full-length enzyme, MMP-13. It has been shown previously by Ye Qi-Zhuang, Hupe D., and Johnson L. (Current Medicinal Chemistry, 1996;3:407-418) that inhibitor activity against a catalytic domain of an MMP is predictive of the inhibitor activity against the respective full-length MMP enzyme.

Biological Method 1 2277 Thiopeptolide substrates show virtually no decomposition or hydrolysis at or below neutral pH in the absence of a matrix metalloproteinase enzyme. A typical thiopeptolide substrate commonly utilized for assays is Ac-Pro-Leu-Gly-thioester-Leu-Leu-Gly-OEt. A 100 L assay mixture will contain 50 mM of N-2-hydroxyethylpiperazine-N-2-ethanesulfonic acid buffer (HEPES, pH 7.0), 10 mM CaCl2, 100 M thiopeptolide substrate, and 1 mM 5,5-dithio-bis-(2-nitro-benzoic acid) (DTNB). The thiopeptolide substrate concentration may be varied, for example from 10 to 800 M to obtain Km and Kcat values. The change in absorbance at 405 nm is monitored on a Thermo Max microplate reader (molecular Devices, Menlo Park, Calif.) at room temperature (22 C.). The calculation of the amount of hydrolysis of the thiopeptolide substrate is based on E41213600 M1 cm1 for the DTNB-derived product 3-carboxy-4-nitrothiophenoxide. Assays are carried out with and without matrix metalloproteinase inhibitor compounds, and the amount of hydrolysis is compared for a determination of inhibitory activity of the test compounds. 2278 Test compounds were evaluated at various concentrations in order to determine their respective IC50 values, the micromolar concentration of compound required to cause a 50% inhibition of catalytic activity of the respective enzyme. 2279 It should be appreciated that the assay buffer used with MMP-3CD was 50 mM N-morpholinoethane sulfonate (MES) at pH 6.0 rather than the HEPES buffer at pH 7.0 described above.

Biological Method 2 2280 The test described above for the inhibition of MMP-13 was also adapted and used to determine the ability of the allosteric carboxylic inhibitors of MMP-13 to inhibit the matrix metalloproteases MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 and MMP-14. Allosteric carboxylic inhibitors of MMP-13 have been evaluated for their ability to inhibit MMP-13 and other MMPs using, for example, MMP-1FL, which refers to full length interstitial collagenase; MMP-2FL, which refers to full length Gelatinase A; MMP-3CD, which refers to the catalytic domain of stromelysin; MMP-7FL, which refers to full length matrilysin; MMP-9FL, which refers to full length Gelatinase B; MMP-13CD, which refers to the catalytic domain of collagenase 3; and MMP-14CD, which refers to the catalytic domain of MMP-14. Test compounds can be evaluated at various concentrations in order to determine their respective IC50 values, the micromolar concentration of compound required to cause a 50% inhibition of the hydrolytic activity of the respective enzyme. The results obtained show that the allosteric carboxylic inhibitors of MMP-13 generally have IC50 values for MMP-13 which are about 100 times lower than the IC50 values for the same compounds with respect to the other matrix metalloproteases tested. 2281 The results of the above assays with other MMPs establish that the allosteric carboxylic inhibitors of MMP-13 are potent and selective inhibitors of MMP enzymes. Because of this potent and selective inhibitory activity, the compounds are especially useful, in combination with a selective inhibitor of COX-2, to treat diseases mediated by the MMP enzymes and COX-2, and particularly those mediated by MMP-13 and COX-2. 2282 Allosteric carboxylic inhibitors of MMP-13 also may be readily identified by assaying a test compound for inhibition of MMP-13 according to the methods described below in Biological Methods 3 and 4.

Biological Method 3 2283 Fluorigenic peptide-1 substrate based assay for identifying allosteric carboxylic inhibitors of MMP-13CD: 2284 Final Assay Conditions: 2285 50 mM HEPES buffer (pH 7.0) 2286 10 mM CaCl2 2287 10 M fluorigenic peptide-1 (FP1) substrate 2288 0 or 15 mM acetohydroxamic acid (AcNHOH)1 Kd 2289 2% DMSO (with or without inhibitor test compound) 2290 0.5 nM MMP-13CD enzyme 2291 Stock Solutions: 2292 1) 10assay buffer: 500 mM HEPES buffer (pH 7.0) plus 100 mM CaCl2 2293 2) 10 mM FP1 substrate: (Mca)-Pro-Leu-Gly-Leu-(Dnp)-Dpa-Ala-Arg-NH2 (Bachem, M-1895; A novel coumarin-labeled peptide for sensitive continuous assays of the matrix metalloproteinases, Knight C. G., Willenbrock F., and Murphy, G., FEBS Lett., 1992;296:263-266). Prepared 10 mM stock by dissolving 5 mg FP1 in 0.457 mL DMSO. 2294 3) 3 M AcNHOH: Prepared by adding 4 mL H2O and 1 mL 10assay buffer to 2.25 g AcNHOH (Aldrich 15,903-4). Adjusted pH to 7.0 with NaOH. Diluted volume to 10 mL with H2O. Final solution contained 3 M AcNHOH, 50 mM HEPES buffer (pH 7.0), and 10 mM CaCl2. 2295 4) AcNHOH dilution buffer: 50 mM HEPES buffer (pH 7.0) plus 10 mM CaCl2 2296 5) MMP-13CD enzyme: Stock concentration250 nM. 2297 6) Enzyme dilution buffer: 50 mM HEPES buffer (pH 7.0), 10 mM CaCl2, and 0.005% BRIJ 35 detergent (Calbiochem 203728; Protein Grade, 10%) 2298 Procedure (for one 96-well microplate): 2299 A. Prepared assay mixture: 2300 1100 L 10 assay buffer 2301 11 L 10 mM FP1 2302 55 L 3 M AcNHOH or 55 L AcNHOH dilution buffer 2303 8500 L H2O 2304 B. Diluted MMP-13CD to 5 nM working stock: 2305 22 L MMP-13CD (250 nM) 2306 1078 L enzyme dilution buffer 2307 C. Ran kinetic assay: 2308 1. Dispensed 2 L inhibitor test sample (in 100% DMSO) into well. 2309 2. Added 88 L assay mixture and mixed well, avoiding bubbles. 2310 3. Initiated reactions with 10 L of 5 nM MMP-13CD; mixed well, avoiding bubbles. 2311 4. Immediately measured the kinetics of the reactions at room temperature. 2312 Fluorimeter: Fmax Fluorescence Microplate Reader & SOFTMAX PRO Version 1.1 software (Molecular Devices Corporation; Sunnyvale, Calif. 94089). 2Protocol menu:excitation:320 nmemission:405 nmrun time:15 mminterval:29 secRFU min:-10RFU max:200Vmax points:32/32

2313 D. Compared % of control activity and/or IC50 with inhibitor test compound AcNHOH. 2314 Hydrolysis of the fluorigenic peptide-1 substrate, (Mca)Pro-Leu-Gly-Leu-Dpa-Ala-Arg-NH2; Bachem, catalog number M-1895, wherein Mca is (7-methoxy-coumarin-4-yl)acetyl and Dpa is (3-2,4-dinitrophenyl-L-2,3-diaminopropionyl), was used to screen for MMP-13 catalytic domain (CD) inhibitors. (Dpa may also be abbreviated as Dnp.) Reactions (100 L) contained 0.05 M Hepes buffer (pH 7), 0.01 M calcium chloride, 0.005% polyoxyethylene (23) lauryl ether (Brij 35), 0 or 15 mM acetohydroxamic acid, 10 M FP1, and 0.1 mM to 0.5 nM inhibitor in DMSO (2% final). 2315 After recombinant human MMP-13CD (0.5 nM final) was added to initiate the reaction, the initial velocity of FP1 hydrolysis was determined by monitoring the increase in fluorescence at 405 nm (upon excitation at 320 nm) continuously for up to 30 minutes on a microplate reader at room temperature. Alternatively, an endpoint read can also be used to determine reaction velocity provided the initial fluorescence of the solution, as recorded before addition of enzyme, is subtracted from the final fluorescence of the reaction mixture. The inhibitor was assayed at different concentration values, such as, for example, 100 M, 10 M, 1 M, 100 nM, 10 nM, and 1 nM. Then the inhibitor concentration was plotted on the X-axis against the percentage of control activity observed for inhibited experiments versus uninhibited experiments (i.e., (velocity with inhibitor) divided by (velocity without inhibitor)100) on the Y-axis to determine IC50 values. This determination was done for experiments done in the presence, and experiments done in the absence, of acetohydroxamic acid. Data were fit to the equation: percent control activity100/1((I/IC50)slope), where I is the inhibitor concentration, IC50 is the concentration of inhibitor where the reaction rate is 50% inhibited relative to the control, and slope is the slope of the IC50 curve at the curve's inflection point, using nonlinear least-squares curve-fitting equation regression. 2316 Results may be expressed as an IC50 Ratio (/) ratio, which means a ratio of the IC50 of the inhibitor with MMP-13 and a inhibitor to the catalytic zinc of MMP-13, divided by the IC50 of the inhibitor with MMP-13 without the inhibitor to the catalytic zinc of MMP-13. Allosteric carboxylic inhibitors of MMP-13 have an IC50 Ratio (/) ratio of less than 1, and are synergistic with the inhibitor to the catalytic zinc of MMP-13 such as, for example, AcNHOH. Compounds which are not allosteric carboxylic inhibitors of MMP-13 will be inactive in the assay or will have an IC50 Ratio (/) of greater than 1, unless otherwise indicated. Results can be confirmed by kinetics experiments which are well known in the biochemical art.

Biological Method 4 2317 Fluorigenic peptide-1 based assay for identifying allosteric carboxylic inhibitors of matrix metalloproteinase-13 catalytic domain (MMP-13CD): 2318 In a manner similar to Biological Method 3, an assay is run wherein 1, 10-phenanthroline is substituted for acetohydroxamic acid to identify allosteric carboxylic inhibitors of MMP-13CD. 2319 Animal models may be used to establish that the instant allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, or an N-oxide thereof, would be useful for preventing, treating, and inhibiting cartilage damage, and thus for treating osteoarthritis, for example.

Biological Method 5 2320 Selective inhibitors of COX-2 may be identified by screening a test compound in the following assays. 2321 Human In Vitro Assays 2322 Human Cell-Based COX-1 Assay: 2323 Human peripheral blood obtained from healthy volunteers can be diluted to {fraction (1/10)} volume with 3.8% sodium citrate solution. The platelet-rich plasma immediately obtained can be washed with 0.14 M sodium chloride containing 12 mM Tris-HCl (pH 7.4) and 1.2 mM EDTA. Platelets can then be washed with platelet buffer (Hanks buffer (Ca free) containing 0.2% BSA and 20 mM Hepes). Finally, the human washed platelets (HWP) can be suspended in platelet buffer at the concentration of 2.85108 cells/ml and stored at room temperature until use. The HWP suspension (70 l aliquots, final 2.0107 cells/ml) can be placed in a 96-well U bottom plate and 10 l aliquots of 12.6 mM calcium chloride added. Platelets can be incubated with A23187 (final 10 M, Sigma) with test compound (0.1-100 M) dissolved in DMSO (final concentration; less than 0.01%) at 37 C. for 15 minutes. The reaction can be stopped by addition of EDTA (final 7.7 mM) and TxB2 in the supernatant quantitated by using a radioimmunoassay kit (Amersham) according to the manufacturer's procedure. 2324 Human Cell-Based COX-2 Assay: 2325 The human cell based COX-2 assay can be carried out as previously described (Moore et al., Inflamm. Res., 45, 54, 1996). Confluent human umbilical vein endothelial cells (HUVECs, Morinaga) in a 96-well flat bottom plate can be washed with 80 ml of RPMI1640 containing 2% FBS and incubated with hIL-1 (final concentration 300 U/ml, R & D Systems) at 37 C. for 24 hours. After washing, the activated HUVECs can be incubated with test compound (final concentration; 0.1 nM-1 M) dissolved in DMSO (final concentration; less than 0.01%) at 37 C. for 20 minutes and stimulated with A23187 (final concentration 30 mM) in Hanks buffer containing 0.2% BSA, 20 mM Hepes at 37 C. for 15 minutes. 6-Keto-PGF1, stable metabolite of PGI2, in the supernatant can be quantitated by using a radioimmunoassay method (antibody; Preseptive Diagnostics, SPA; Amersham). 2326 Canine In Vitro Assays: 2327 The following canine cell based COX 1 and COX-2 assays have been reported in Ricketts et al., Evaluation of Selective Inhibition of Canine Cyclooxygenase 1 and 2 by Carprofen and Other Nonsteroidal Anti-inflammatory Drugs, American Journal of Veterinary Research, 59 (11), 1441-1446. 2328 Protocol for Evaluation of Canine COX-1 Activity: 2329 Test compounds can be solubilized and diluted the day before the assay can be to be conducted with 0.1 mL of DMSO/9.9 mL of Hank's balanced salts solution (HBSS) and stored overnight at 4 C. On the day that the assay can be carried out, citrated blood can be drawn from a donor dog, centrifuged at 190g for 25 minutes at room temperature and the resulting platelet-rich plasma can then be transferred to a new tube for further procedures. The platelets can be washed by centrifuging at 1500g for 10 minutes at room temperature. The platelets can be washed with platelet buffer comprising Hank's buffer (Ca free) with 0.2% bovine serum albumin (BSA) and 20 mM HEPES. The platelet samples can then be adjusted to 1.5107/mL, after which 50 l of calcium ionophore (A23187) together with a calcium chloride solution can be added to 50 l of test compound dilution in plates to produce final concentrations of 1.7 M A23187 and 1.26 mM Ca. Then, 100 l of canine washed platelets can be added and the samples can be incubated at 37 C. for 15 minutes, after which the reaction can be stopped by adding 20 l of 77 mM EDTA. The plates can then be centrifuged at 2000g for 10 minutes at 4 C., after which 50 l of supernatant can be assayed for thromboxane B2 (TXB2) by enzyme-immunoassay (EIA). The pg/mL of TXB2 can be calculated from the standard line included on each plate, from which it can be possible to calculate the percent inhibition of COX-1 and the IC50 values for the test compounds. 2330 Protocol for Evaluation of Canine COX-2 Activity: 2331 A canine histocytoma (macrophage-like) cell line from the American Type Culture Collection designated as DH82, can be used in setting up the protocol for evaluating the COX-2 inhibition activity of various test compounds. There can be added to flasks of these cells 10 g/mL of LPS, after which the flask cultures can be incubated overnight. The same test compound dilutions as described above for the COX-1 protocol can be used for the COX-2 assay and can be prepared the day before the assay can be carried out. The cells can be harvested from the culture flasks by scraping and can then be washed with minimal Eagle's media (MEM) combined with 1% fetal bovine serum, centrifuged at 1500 rpm for 2 minutes and adjusted to a concentration of 3.2105 cells/mL. To 50 l of test compound dilution there can be added 50 l of arachidonic acid in MEM to give a 10 M final concentration and there can be added as well 100 l of cell suspension to give a final concentration of 1.6105 cells/mL. The test sample suspensions can be incubated for 1 hour and then centrifuged at 1000 rpm for 10 minutes at 4 C., after which 50 l aliquots of each test compound sample can be delivered to EIA plates. The EIA can be performed for prostaglandin E2 (PGE2) and the pg/mL concentration of PGE2 can be calculated from the standard line included on each plate. From this data it can be possible to calculate the percent inhibition of COX-2 and the IC50 values for the test compounds. Repeated investigations of COX-1 and COX-2 inhibition can be conducted over the course of several months. The results are averaged and a single COX-1:COX-2 ratio is calculated. 2332 Whole blood assays for COX-1 and COX-2 are known in the art such as the methods described in C. Brideau, et al., A Human Whole Blood Assay for Clinical Evaluation of Biochemical Efficacy of Cyclooxygenase Inhibitors, Inflammation Research, Vol. 45, pp. 68-74 (1996). These methods may be applied with feline, canine or human blood as needed.

Biological Method 6 2333 Carrageenan Induced Foot Edema in Rats 2334 Male Sprague-Dawley rats (5 weeks old, Charles River Japan) can be fasted overnight. A line can be drawn using a marker above the ankle on the right hind paw and the paw volume (VO) can be measured by water displacement using a plethysmometer (Muromachi). Animals can be given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (2.5 ml per 100 g body weight). One hour later, the animals can then be injected intradermally with -carrageenan (0.1 ml of 1% w/v suspension in saline, Zushikagaku) into right hind paw (Winter et al., Proc. Soc. Exp. Biol. Med., 111, 544, 1962; Lombardino et al., Arzneim. Forsch., 25, 1629, 1975) and three hours later, the paw volume (V3) can be measured and the increase in volume (V3-V0) calculated. Since maximum inhibition attainable with classical NSAIDs is 60-70%, ED30 values can be calculated.

Biological Method 7 2335 Gastric Ulceration in Rats: 2336 The gastric ulcerogenicity of test compound can be assessed by a modification of the conventional method (Ezer et al., J. Pharm. Pharmacol., 28, 655, 1976; Cashin et al., J. Pharm. Pharmacol., 29, 330-336, 1977). Male Sprague-Dawley rats (5 weeks old, Charles River Japan), fasted overnight, can be given orally either vehicle (0.1% methyl cellulose or 5% Tween 80) or a test compound (1 ml per 100 g body weight). Six hours after, the animals can be sacrificed by cervical dislocation. The stomachs can be removed and inflated with 1% formalin solution (10 ml). Stomachs can be opened by cutting along the greater curvature. From the number of rats that showed at least one gastric ulcer or haemorrhaging erosion (including ecchymosis), the incidence of ulceration can be calculated. Animals did not have access to either food or water during the experiment.

Biological Method 8 2337 Canine Whole Blood Ex Vivo Determinations of COX-1 and COX-2 Activity Inhibition 2338 The in vivo inhibitory potency of a test compound against COX-1 and COX-2 activity may be evaluated using an ex vivo procedure on canine whole blood. Three dogs can be dosed with 5 mg/kg of the test compound administered by oral gavage in 0.5% methylcellulose vehicle and three dogs can be untreated. A zero-hour blood sample can be collected from all dogs in the study prior to dosing, followed by 2- and 8-hour post-dose blood sample collections. Test tubes can be prepared containing 2 L of either (A) calcium ionophore A23187 giving a 50 M final concentration, which stimulates the production of thromboxane B2 (TXB2) for COX-1 activity determination; or of (B) lipopolysaccharide (LPS) to give a 10 g/mL final concentration, which stimulates the production of prostaglandin E2 (PGE2) for COX-2 activity determination. Test tubes with unstimulated vehicle can be used as controls. A 500 L sample of blood can be added to each of the above-described test tubes, after which they can be incubated at 37 C. for one hour in the case of the calcium ionophore-containing test tubes and overnight in the case of the LPS-containing test tubes. After incubation, 10 L of EDTA can be added to give a final concentration of 0.3%, in order to prevent coagulation of the plasma which sometimes occurs after thawing frozen plasma samples. The incubated samples can be centrifuged at 4 C. and the resulting plasma sample of 200 L can be collected and stored at 20 C. in polypropylene 96-well plates. In order to determine endpoints for this study, enzyme immunoassay (EIA) kits available from Cayman can be used to measure production of TXB2 and PGE2, utilizing the principle of competitive binding of tracer to antibody and endpoint determination by colorimetry. Plasma samples can be diluted to approximate the range of standard amounts which would be supplied in a diagnostic or research tools kit, i.e., {fraction (1/500)} for TXB2 and {fraction (1/750)} for PGE2. 2339 COX inhibition is observed when the measured percent inhibition is greater than that measured for untreated controls. The percent inhibition in the above table is calculated in a straightforward manner in accordance with the following equation: 1

% Inhibition (2 - hour) = \frac{({PGE}_{2} at t = 0) - ({PGE}_{2} at t = 2)}{({PGE}_{2} at t = 0)}

2340 Data Analysis: 2341 Statistical program packages, SYSTAT (SYSTAT, INC.) and StatView (Abacus Cencepts, Inc.) for Macintosh can be used. Differences between test compound treated group and control group can be tested for using ANOVA. The IC50 (ED30) values can be calculated from the equation for the log-linear regression line of concentration (dose) versus percent inhibition. 2342 The selective COX-2 inhibitors described above have been, or could have been, identified by at least one of the methods described above and show, or would show, IC50 values of 0.001 M to 3 M with respect to inhibition of COX-2 in either the canine or human assays. 2343 As mentioned above, COX-2 selectivity can be determined by ratio in terms of IC50 value of COX-1 inhibition to COX-2 inhibition. In general, it can be said that a compound showing a COX-1/COX-2 inhibition ratio of more than 5 has sufficient COX-2 selectivity. 2344 The newly discovered ability of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, to inhibit cartilage damage, alleviate pain, and treat osteoarthritis may be established in animal models as described below. The activity of an invention combination for treating cartilage damage and pain and/or inflammation may be determined by the procedures of Biological Methods 9 or 10 as described below. 2345 Biological Method 9 2346 Monosodium Iodoacetate-induced Osteoarthritis in Rat Model of Cartilage Damage (MIA Rat): 2347 One end result of the induction of osteoarthritis in this model, as determined by histologic analysis, is the development of an osteoarthritic condition within the affected joint, as characterized by the loss of Toluidine blue staining and formation of osteophytes. Associated with the histologic changes is a concentration-dependent degradation of joint cartilage, as evidenced by affects on hind-paw weight distribution of the limb containing the affected joint, the presence of increased amounts of proteoglycan or hydroxyproline in the joint upon biochemical analysis, or histopathological analysis of the osteoarthritic lesions. 2348 Generally, In the MIA Rat model on Day 0, the hind-paw weight differential between the right arthritic joint and the left healthy joint of male Wistar rats (150 g) are determined with an incapacitance tester, model 2KG (Linton Instrumentation, Norfolk, United Kingdom). The incapacitance tester has a chamber on top with an outwardly sloping front wall that supports a rat's front limbs, and two weight sensing pads, one for each hind paw, that facilitates this determination. Then the rats are anesthetized with isofluorine, and the right, hind leg knee joint is injected with 1.0 mg of mono-iodoacetate (MIA) through the infrapatellar ligament. Injection of MIA into the joint results in the inhibition of glycolysis and eventual death of surrounding chondrocytes. The rats are further administered either an invention combination such as a combination, comprising an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, with celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, or vehicle (in the instant case, water) daily for 14 days or 28 days. Both the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, are, each independently, typically administered at a dose of 30 mg per kilogram of rat per day (30 mg/kg/day), but each component of the combination may independently be administered at other doses such as, for example, 10 mg/kg/day, 60 mg/kg/day, 90-mg/kg/day, or 100 mg/kg/day according to the requirements of the combination being studied. It is well within the level of ordinary skill in the pharmaceutical arts to determine a proper dosage of an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, in this model. Administration of the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, in this model is optionally by oral administration or intravenous administration via an osmotic pump. Further, administration of the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, may be simultaneous as a co-formulation of both drugs, simultaneous by way of independent formulations of each drug of the invention combination alone according to optimal drug delivery profiles, or non-simultaneous such as, sequential administration of an independent formulation of one drug followed by, after some pre-determined period of time, administration of an independent formulation of the other drug of the invention combination. After 7 and 14 days for a two-week study, or 7, 14, and 28 days for a four-week study, the hind-paw weight distribution is again determined. Typically, the animals administered vehicle alone place greater weight on their unaffected left hind paw than on their right hind paw, while animals administered an invention combination show a more normal (i.e., more like a healthy animal) weight distribution between their hind paws. This change in weight distribution was proportional to the degree of joint cartilage damage. Percent inhibition of a change in hind paw joint function is calculated as the percent change in hind-paw weight distribution for treated animals versus control animals. For example, for a two week study, 2

Percent inhibition of a in hind paw joint function = [1 - \frac{(W_{G})}{(W_{C})}] 100

2349 wherein: WC is the hind-paw weight differential between the healthy left limb and the arthritic limb of the control animal administered vehicle alone, as measured on Day 14; and 2350 WG is the hind-paw weight differential between the healthy left limb and the arthritic limb of the animal administered an invention combination, as measured on Day 14. 2351 In order to measure biochemical or histopathological end points in the MIA Rat model, some of the animals in the above study may be sacrificed, and the amounts of free proteoglycan in both the osteoarthritic right knee joint and the contralateral left knee joint may be determined by biochemical analysis. The amount of free proteoglycan in the contralateral left knee joint provides a baseline value for the amount of free proteoglycan in a healthy joint. The amount of proteoglycan in the osteoarthritic right knee joint in animals administered an invention combination, and the amount of proteoglycan in the osteoarthritic right knee joint in animals administered vehicle alone, are independently compared to the amount of proteoglycan in the contralateral left knee joint. The amounts of proteoglycan lost in the osteoarthritic right knee joints are expressed as percent loss of proteoglycan compared to the contralateral left knee joint control. The percent inhibition of proteoglycan loss, may be calculated as (proteoglycan loss from joint (%) with vehicle)(proteoglycan loss from joint with an invention combination)(proteoglycan loss from joint (%) with vehicle)100. 2352 The MIA Rat data that are expected from the analysis of proteoglycan loss would establish that an invention combination is effective for inhibiting cartilage damage and inflammation and/or alleviating pain in mammalian patients, including human. 2353 The results of these studies with oral dosing may be presented in tabular format in the columns labelled IJFL (%/SEM), wherein UFL means Inhibition of Joint Function Limitation, SDCES, wherein SDCES means Significant Decrease In Cartilage Erosion Severity, and S WHLE, wherein SIJWHLE means Significant Increase in Joints Without Hind Limb Erosion. 2354 The proportion of subjects without hind limb erosions may be analyzed via an Exact Sequential Cochran-Armitage Trend test (SAS Institute, 1999). The Cochran-Armitage Trend test is employed when one wishes to determine whether the proportion of positive or Yes responders increases or decreases with increasing levels of treatment. For the particular study, it is expected that the number of animals without joint erosions increased with increasing dose. 2355 The ridit analysis may be used to determine differences in overall erosion severity. This parameter takes into account both the erosion grade (0no erosion, Ierosion extending into the superficial or middle layers, or IIdeep layer erosion), and area (small, medium and large, quantified by dividing the area of the largest erosion in each score into thirds) simultaneously. The analysis recognizes that each unit of severity is different, but does not assume a mathematical relationship between units. 2356 Another animal model for measuring effects of an invention combination on cartilage damage and inflammation and/or pain is described below in Biological Method 10.

Biological Method 10 2357 Induction of Experimental Osteoarthritis in Rabbit (EOA in Rabbit): 2358 Normal rabbits are anaesthetized and anteromedial incisions of the right knees performed. The anterior cruciate ligaments are visualized and sectioned. The wounds are closed and the animals are housed in individual cages, exercised, and fed ad libitum. Rabbits are given either vehicle (water) or an invention combination dosed three times per day with 30-mg/kg/dose or 10-mg/kg/dose each independently determined for the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, but each drug of the combination may independently be administered at other doses such as, for example, 3 times 20 mg/kg/day or 3 times 60 mg/kg/day according to the requirements of the combination being studied. The rabbits are euthanized 8 weeks after surgery and the proximal end of the tibia and the distal end of the femur are removed from each animal. 2359 Macroscopic Grading 2360 The cartilage changes on the femoral condyles and tibial plateaus are graded separately under a dissecting microscope (Stereozoom, Bausch & Lomb, Rochester, N.Y.). The depth of erosion is graded on a scale of 0 to 4 as follows: grade 0normal surface; Grade 1minimal fibrillation or a slight yellowish discoloration of the surface; Grade 2erosion extending into superficial or middle layers only; Grade 3erosion extending into deep layers; Grade 4erosion extending to subchondral bone. The surface area changes are measured and expressed in mm2. Representative specimens may also be used for histologic grading (see below). 2361 Histologic Grading 2362 Histologic evaluation is performed on sagittal sections of cartilage from the lesional areas of the femoral condyle and tibial plateau. Serial sections (5 um) are prepared and stained with safranin-O. The severity of OA lesions is graded on a scale of 0-14 by two independent observers using the histologic-histochemical scale of Mankin et al. This scale evaluates the severity of OA lesions based on the loss of safranin-O staining (scale 0-4), cellular changes (scale 0-3), invasion of tidemark by blood vessels (scale 0-1) and structural changes (scale 0-6). On this latter scale, 0 indicates normal cartilage structure and 6 indicates erosion of the cartilage down to the subchondral bone. The scoring system is based on the most severe histologic changes in the multiple sections. 2363 Representative specimens of synovial membrane from the medial and lateral knee compartments are dissected from underlying tissues. The specimens are fixed, embedded, and sectioned (5 um) as above, and stained with hematoxylin-eosin. For each compartment, two synovial membrane specimens are examined for scoring purposes and the highest score from each compartment is retained. The average score is calculated and considered as a unit for the whole knee. The severity of synovitis is graded on a scale of 0 to 10 by two independent observers, adding the scores of 3 histologic criteria: synovial lining cell hyperplasia (scale 0-2); villous hyperplasia (scale 0-3); and degree of cellular infiltration by mononuclear and polymorphonuclear cells (scale 0-5): 0 indicates normal structure. 2364 Statistical Analysis 2365 Mean values and SEM is calculated and statistical analysis was done using the Mann-Whitney U-test. 2366 The results of these studies would be expected to show that an invention combination would reduce the size of the lesion on the tibial plateaus, and perhaps the damage in the tibia or on the femoral condyles, as well as show pain alleviating effects if measured. In conclusion, these results would show that an invention combination would have significant inhibition effects on the damage to cartilage and pain. 2367 The foregoing studies would establish that an invention combination is effective for the inhibition of cartilage damage and inflammation and/or alleviating pain, and thus useful for the treatment of osteoarthritis or rheumatoid arthritis in human, and other mammalian disorders. Such a treatment offers a distinct advantage over existing treatments that only modify pain or inflammation or and other secondary symptoms. The effectiveness of an invention combination in this model would indicate that the invention combination will have clinically useful effects in preventing and/or treating cartilage damage, pain and/or inflammation. 2368 Administration according to the invention method of celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, to a mammal to treat the diseases listed above is preferably, although not necessarily, accomplished by administering the compound, or a salt thereof, in a pharmaceutical dosage form. 2369 Celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, can be prepared and administered according to the invention method in a wide variety of oral and parenteral pharmaceutical dosage forms. Thus, celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally. Also, celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, can be administered by inhalation, for example, intranasally. Additionally, celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active components celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. The active compounds generally are present in a concentration of about 5% to about 95% by weight of the formulation. 2370 For preparing pharmaceutical compositions from celecoxib, or a pharmaceutically acceptable salt thereof, or valdecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, (i.e., the active components) pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations are preferred. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material. 2371 In powders, the carrier is a finely divided solid which is in a mixture with the finely divided active component. Powders suitable for intravenous administration or administration by injection may be lyophilized. 2372 In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. 2373 The powders and tablets preferably contain from about 5% to about 70%, total, of the active component. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like. The term preparation is intended to include the formulation of the active component with encapsulating material as a carrier providing a capsule in which the active component, with or without other carriers, is surrounded by a carrier, which is thus in association with it. Similarly, cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration. 2374 For preparing suppositories, a low melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted and the active component is dispersed homogeneously therein, as by stirring. The molten homogenous mixture is then poured into convenient sized molds, allowed to cool, and thereby to solidify. 2375 Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution. 2376 Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing, and thickening agents as desired. 2377 Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents. 2378 Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like. 2379 The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing an appropriate quantity of the active component. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules. Also, the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form. 2380 The quantity of active component in a unit dose preparation may be varied or adjusted from 0.01 to 1000 mg, preferably 1 to 500 mg according to the particular application and the potency of the active components. The composition can, if desired, also contain other compatible therapeutic agents. 2381 In therapeutic use as agents to treat the above-listed diseases, the allosteric carboxylic inhibitors of MMP-13, or a pharmaceutically acceptable salt thereof, or a combination of the same with valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, are administered at a dose that is effective for treating at least one symptom of the disease or disorder being treated. The initial dosage of about 1 mg/kg to about 100 mg/kg daily of the active component will be effective. A daily dose range of about 25 mg/kg to about 75 mg/kg of the active component is preferred. The dosages, however, may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the particular allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, being employed in the invention combination. Determination of the proper dosage for a particular situation is within the skill of the art as described above. Typical dosages will be from about 0.1 mg/kg to about 500 mg/kg, and ideally about 25 mg/kg to about 250 mg/kg, such that it will be an amount that is effective to treat the particular disease or disorder being treated. 2382 A preferred composition for dogs comprises an ingestible liquid peroral dosage form selected from the group consisting of a solution, suspension, emulsion, inverse emulsion, elixir, extract, tincture and concentrate, optionally to be added to the drinking water of the dog being treated. Any of these liquid dosage forms, when formulated in accordance with methods well known in the art, can either be administered directly to the dog being treated, or may be added to the drinking water of the dog being treated. The concentrate liquid form, on the other hand, is formulated to be added first to a given amount of water, from which an aliquot amount may be withdrawn for administration directly to the dog or addition to the drinking water of the dog. 2383 A preferred composition provides delayed-, sustained- and/or controlled-release of valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, and the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. Such preferred compositions include all such dosage forms which produce 40% inhibition of cartilage degradation, and result in a plasma concentration of the active component of at least 3 fold the active component's ED40 for at least 2 hours; preferably for at least 4 hours; preferably for at least 8 hours; more preferably for at least 12 hours; more preferably still for at least 16 hours; even more preferably still for at least 20 hours; and most preferably for at least 24 hours. Preferably, there is included within the above-described dosage forms those which produce 40% inhibition of cartilage degradation, and result in a plasma concentration of the active component of at least 5 fold the active component's ED40 for at least 2 hours, preferably for at least 2 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours and most preferably for at least 24 hours. More preferably, there is included the above-described dosage forms which produce 50% inhibition of cartilage degradation, and result in a plasma concentration of the active component of at least 5 fold the active component's ED40 for at least 2 hours, preferably for at least 4 hours, preferably for at least 8 hours, more preferably for at least 12 hours, still more preferably for at least 20 hours and most preferably for at least 24 hours. 2384 The following Formulation Examples 1 to 8 illustrate the invention pharmaceutical compositions wherein the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, are formulated separately, each independently as described, When the formulations comprise the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient, they contain a cartilage damage treating effective amount or an anti-osteoarthritic effective amount of the allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof. When the formulations comprise valdecoxib, or a pharmaceutically acceptable salt thereof, or celecoxib, or a pharmaceutically acceptable salt thereof, they contain a pain alleviating effective amount or an anti-inflammatory effective amount of valdecoxib or celecoxib. The examples are representative only, and are not to be construed as limiting the invention in any respect.

FORMULATION EXAMPLE 12385

3Tablet Formulation:IngredientAmount (mg)An allosteric carboxylic inhibitor of MMP-13, or25celecoxib, or valdecoxibLactose50Cornstarch (for mix)10Cornstarch (paste)10Magnesium stearate (1%)5Total100

2386 The allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib, lactose, and cornstarch (for mix) are blended to uniformity. The cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand screen and dried at 80 C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. Such tablets can be administered to a human from one to four times a day for inhibiting cartilage damage or treating osteoarthritis.

FORMULATION EXAMPLE 2 2387 Coated Tablets: 2388 The tablets of Formulation Example 1 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.

FORMULATION EXAMPLE 3 2389 Injection vials: 2390 The pH of a solution of 500 g of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid. The solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.

FORMULATION EXAMPLE 4 2391 Suppositories: 2392 A mixture of 25 g of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib, 100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured into molds, and allowed to cool. Each suppository contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.

FORMULATION EXAMPLE 5 2393 Solution: 2394 A solution is prepared from 1 g of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib, 9.38 g of NaH2PO4.12H2O, 28.48 g of Na2HPO4.12H2O, and 0.1 g benzalkonium chloride in 940 mL of double-distilled water. The pH of the solution is adjusted to pH 6.8 using 2 M hydrochloric acid. The solution is diluted to 1.0 L with double-distilled water, and sterilized by irradiation. A 25 mL volume of the solution contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.

FORMULATION EXAMPLE 6 2395 Ointment: 2396 500 mg of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib is mixed with 99.5 g of petroleum jelly under aseptic conditions. A 5 g portion of the ointment contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.

FORMULATION EXAMPLE 7 2397 Capsules: 2398 2 kg of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib are filled into hard gelatin capsules in a customary manner such that each capsule contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib.

FORMULATION EXAMPLE 8 2399 Ampoules: 2400 A solution of 2.5 kg of an allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib is dissolved in 60 L of double-distilled water. The solution is sterile filtered, and the filtrate is filled into ampoules. The ampoules are lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 25 mg of the allosteric carboxylic inhibitor of MMP-13, or celecoxib, or valdecoxib. 2401 The following Formulation Examples 9 to 16 illustrate the invention pharmaceutical compositions containing an invention combination in a single formulation with a pharmaceutically acceptable carrier, diluent, or excipient. The examples are representative only, and are not to be construed as limiting the invention in any respect.

FORMULATION EXAMPLE 92402

4Tablet Formulation:IngredientAmount (mg)An allosteric carboxylic inhibitor of MMP-1325Valdecoxib or celecoxib20Lactose50Cornstarch (for mix)10Cornstarch (paste)10Magnesium stearate (1%)5Total120

2403 The allosteric carboxylic inhibitor of MMP-13, valdecoxib or celecoxib, lactose, and cornstarch (for mix) are blended to uniformity. The cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand screen and dried at 80 C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. Such tablets can be administered to a human from one to four times a day for treatment of one of the above-listed diseases.

FORMULATION EXAMPLE 10 2404 Coated Tablets: 2405 The tablets of Formulation Example 9 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant.

FORMULATION EXAMPLE 11 2406 Injection Vials: 2407 The pH of a solution of 250 g of valdecoxib or celecoxib, 500 g of an allosteric carboxylic inhibitor of MMP-13, and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid. The solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 12.5 mg of valdecoxib or celecoxib and 25 mg of the allosteric carboxylic inhibitor of MMP-13.

FORMULATION EXAMPLE 12 2408 Suppositories: 2409 A mixture of 50 g of valdecoxib or celecoxib, 25 g of an allosteric carboxylic inhibitor of MMP-13, 100 g of soya lecithin, and 1400 g of cocoa butter is fused, poured into molds, and allowed to cool. Each suppository contains 50 mg of valdecoxib or celecoxib and 25 mg of the allosteric carboxylic inhibitor of MMP-13.

FORMULATION EXAMPLE 13 2410 Solution: 2411 A solution is prepared from 0.5 g of valdecoxib or celecoxib, 1 g of an allosteric carboxylic inhibitor of MMP-13, 9.38 g of NaH2PO4 12H2O, 28.48 g of Na2HPO4.12H2O, and 0.1 g benzalkonium chloride in 940 mL of double-distilled water. The pH of the solution is adjusted to pH 6.8 using 2 M hydrochloric acid. The solution is diluted to 1.0 L with double-distilled water, and sterilized by irradiation. A 25 mL volume of the solution contains 12.5 mg of valdecoxib or celecoxib and 25 mg of the allosteric carboxylic inhibitor of MMP-13.

FORMULATION EXAMPLE 14 2412 Ointment: 2413 100 mg of valdecoxib or celecoxib, 500 mg of an allosteric carboxylic inhibitor of MMP-13 is mixed with 99.4 g of petroleum jelly under aseptic conditions. A 5 g portion of the ointment contains 5 mg of valdecoxib or celecoxib and 25 mg of the allosteric carboxylic inhibitor of MMP-13.

FORMULATION EXAMPLE 15 2414 Capsules: 2415 2 kg of valdecoxib or celecoxib and 20 kg of an allosteric carboxylic inhibitor of MMP-13 are filled into hard gelatin capsules in a customary manner such that each capsule contains 25 mg of valdecoxib or celecoxib and 250 mg of the allosteric carboxylic inhibitor of MMP-13.

FORMULATION EXAMPLE 16 2416 Ampoules: 2417 A solution of 2.5 kg of valdecoxib or celecoxib and 2.5 kg of an allosteric carboxylic inhibitor of MMP-13 is dissolved in 60 L of double-distilled water. The solution is sterile filtered, and the filtrate is filled into ampoules. The ampoules are lyophilized under sterile conditions and aseptically sealed. Each ampoule contains 25 mg each of valdecoxib or celecoxib and the allosteric carboxylic inhibitor of MMP-13. 2418 While it may be desirable to formulate valdecoxib or celecoxib and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, together in one capsule, tablet, ampoule, solution, and the like, for simultaneous administration, it is not necessary for the purposes of practicing the invention methods. Valdecoxib or celecoxib and an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, of an invention combination alternatively can each be formulated independently in any form such as, for example, those of any one Formulation Examples 1 to 16, and administered to a patient either simultaneously or at different times. 2419 The following examples illustrate the invention pharmaceutical compositions containing discrete formulations of the active components of the invention combination and a pharmaceutically acceptable carrier, diluent, or excipient. The examples are representative only, and are not to be construed as limiting the invention in any respect.

FORMULATION EXAMPLE 172420

5Tablet Formulation of an allostericcarboxylic inhibitor of MMP-13:IngredientAmount (mg)An allosteric carboxylic inhibitor of MMP-1325Lactose50Cornstarch (for mix)10Cornstarch (paste)10Magnesium stearate (1%)5Total100

2421 An allosteric carboxylic inhibitor of MMP-13, lactose, and cornstarch (for mix) are blended to uniformity. The cornstarch (for paste) is suspended in 200 mL of water and heated with stirring to form a paste. The paste is used to granulate the mixed powders. The wet granules are passed through a No. 8 hand screen and dried at 80 C. The dry granules are lubricated with the 1% magnesium stearate and pressed into a tablet. 2422 Injection Vial Formulation of Valdecoxib or Celecoxib: 2423 The pH of a solution of 500 g of valdecoxib or celecoxib and 5 g of disodium hydrogen phosphate is adjusted to pH 6.5 in 3 L of double-distilled water using 2 M hydrochloric acid. The solution is sterile filtered, and the filtrate is filled into injection vials, lyophilized under sterile conditions, and aseptically sealed. Each injection vial contains 25 mg of valdecoxib or celecoxib. 2424 Such tablets containing the allosteric carboxylic inhibitor of MMP-13 can be administered to a human from one to four times a day for treatment of the above-listed diseases, and the injection solutions containing valdecoxib or celecoxib can be administered to a human 1 or 2 times per day, wherein the administration by injection is optionally simultaneous with administration of the tablets or at different times, for the treatment of one of the above-listed diseases.

FORMULATION EXAMPLE 18 2425 Coated Tablets Containing an Allosteric Carboxylic Inhibitor of MMP-13: 2426 The tablets of Formulation Example 17 are coated in a customary manner with a coating of sucrose, potato starch, talc, tragacanth, and colorant. 2427 Capsules Containing Valdecoxib or Celecoxib: 2428 2 kg of valdecoxib or celecoxib are filled into hard gelatin capsules in a customary manner such that each capsule contains 25 mg of valdecoxib or celecoxib. 2429 Such coated tablets containing the allosteric carboxylic inhibitor of MMP-13 can be administered to a human from one to four times a day for treatment of the above-listed diseases, and the capsules containing valdecoxib or celecoxib can be administered to a human 1 or 2 times per day, wherein the administration of the capsules is optionally simultaneous with administration of the tablets or at different times, for the treatment of one of the above-listed diseases. 2430 Still further, it should be appreciated that the invention methods comprising administering an invention combination to a mammal to treat diseases or disorders listed above may be used to treat different diseases simultaneously. For example, administration of valdecoxib or celecoxib in accordance with the invention combination may be carried out as described above to treat inflammation, arthritic pain, pain associated with menstrual cramping, and migraines, while an allosteric carboxylic inhibitor of MMP-13, or a pharmaceutically acceptable salt thereof, may be administered to treat OA or inhibit cartilage damage. 2431 As shown above, the invention method offers a distinct advantage over existing treatments for diseases such as OA that comprise cartilage damage, wherein the existing treatments modify pain or secondary symptoms, but do not show a disease modifying effect. 2432 While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. It is intended, therefore, that the invention be defined by the scope of the claims that follow and that such claims be interpreted as broadly as is reasonable. 2433 Having described the invention method, various embodiments of the invention are hereupon claimed.