Combination therapy with immuno-DASH inhibitor and PGE2 antagonist

Abstract

Methods for enhancing the immune response against tumors are provided. The present invention discloses a combination therapy comprising the administration of an I-DASH inhibitor and a PGE2 antagonist, and the use of such therapy in the treatment of cell proliferative disorders.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U.S. Provisional Patent Application No. 62 / 384,403, filed September 7, 2016; U.S. Provisional Patent Application No. 62 / 384,407, filed September 7, 2016; and U.S. Provisional Patent Application No. 62 / 482,750, filed April 7, 2017. [Background technology]

[0002] Immuno-DASH (I-DASH) inhibitors, potent inhibitors of the post-proline cleaving enzymes DPP4, DPP8, and DPP9, act as checkpoint inhibitors of a newly described immune checkpoint involving DASH enzymes. Inhibition of these target enzymes, including both intracellular and extracellular targets, results in (among other things) pyroptosis of tumor-associated macrophages and the release of IL-1β and possibly other immunostimulatory cytokines. The effects of I-DASH inhibitor treatment include redistribution and altered activity of tumor-associated MDSCs, enhanced priming of T cells and dendritic cells, and enhanced trafficking of T cells and other immune cells to tumors. Treatment with valine-boroproline (Val-boroPro) (talabostat, PT-100), an early prototype I-DASH inhibitor, has been reported to result in immune-related adverse events (irAEs), including pneumonia. See Non-Patent Documents 1 and 2.

[0003] Talabostat was originally designed, together with other aminoboronic acid dipeptides, as a high-affinity competitive inhibitor of the enzyme dipeptidyl peptidase IV (DPP-IV or CD26). The compound was found to stimulate hematopoiesis and antitumor immune responses through cytokine upregulation. Subsequently, in addition to DPP-IV, dipeptidyl peptidases 8 and 9 (DPP-8 and DPP-9) and fibroblast activation protein (FAP) were shown to be sensitive to inhibition by talabostat. See Non-Patent Document 3. Based on similarities in protein structure and substrate specificity, DPP-8, DPP-9, and FAP are classified as members of the DPP-IV-like family of post-prolyl-cleaving serine proteases.

[0004] DPP-8 and DPP-9 are cytosolic proteases, and their inhibition by talabostat has been shown to activate caspase-1 and induce IL-1β in macrophages both in vitro and in tumor-bearing mice, which in turn leads to the upregulation of cytokines and chemokines that characterize the response to talabostat. The biological activity of cytokines and chemokines upregulated by talabostat suggests that both innate and adaptive immunity are induced. In animal models, talabostat enhances cytokine production in tumor tissue and lymphoid organs, thereby enhancing tumor-specific T cell-dependent and T cell-independent immunity. These antitumor responses were enhanced by combination therapy with chemotherapeutic agents such as cisplatin, gemcitabine, paclitaxel, 5-fluorouracil, and the monoclonal antibody rituximab.

[0005] Based on its efficacy in animal models, Val-boroPro entered Phase I human clinical trials, where the compound was deemed well-tolerated and showed some activity. In the Phase I trial, five of 13 patients receiving combination therapy with immunosuppressive chemotherapy showed improvement in grade 3 neutropenia and most significant increases in serum cytokine levels. A Phase I trial of talabostat and rituximab in rituximab-resistant lymphoma showed increases in cytokine levels in most patients, including partial responses in three patients. However, in a subsequent Phase II trial in combination with standard cytotoxic chemotherapy, Val-boroPro failed to meet efficacy endpoints.

[0006] However, dose-limiting toxicities ultimately restricted the maximum dose that could be administered to patients in subsequent studies, and the most commonly reported adverse events associated with talabostat were edema / peripheral swelling, hypotension, or dehydration / hypovolemia, originally suspected to be the result of IL-6 stimulation or other immunomodulatory effects. Phase III trials administering talabostat in combination with either docetaxel or pemetrexed to patients with advanced NSCLC were ultimately halted at interim evaluation. As reported in Non-Patent Document 4, these trials were terminated early because neither the primary nor secondary endpoints were met, and furthermore, the patient group in the docetaxel combination study appeared to have a lower survival rate than the placebo group. Thus, despite promising preclinical results in tumor models, talabostat was ultimately withheld from clinical trials primarily as a result of administration toxicities that prevented the drug from being administered to levels that might have been effective.

[0007] The present invention is based on the discovery that talabostat, like other immuno-DASH inhibitors, can be used as part of an anti-cancer therapy when administered in combination with a PGE2 antagonist, such as a cyclooxygenase inhibitor, and is based in part on the observations described herein that combining an immuno-DASH inhibitor with a PGE2 antagonist results in a significant increase in the safety of certain immuno-DASH inhibitors (increasing the maximum tolerated dose), and in some cases results in a synergistic improvement in the anti-tumor efficacy of the immuno-DASH inhibitor, and further increases the therapeutic range of these drugs to a point where they are more amenable to patient treatment, even in cases where dose-limiting toxicities previously hindered efficacy and led to the abandonment of talabostat as a drug candidate. [Prior art documents] [Non-patent literature]

[0008] [Non-Patent Document 1] Cunningham 2007 Journal Expert Opinion on Investigational Drugs 16:1459-1465 [Non-patent document 2] Uprichard et al. (2005) Journal of Clinical Oncology 23:7563 [Non-patent document 3] Jones B, Uprichard MJ. PT-100 Investigator's Brochure. 2004 [Non-patent document 4] Wall Street Journal, Kennedy VB. “Point Thera puts talabostat trial on hold” Market Watch. 2007 Summary of the Invention [Means for solving the problem]

[0009] One aspect of the present invention relates to a method for enhancing a cellular immune response against cancer, comprising administering to a mammal in need thereof therapeutically effective amounts of an immuno-DASH (I-DASH) inhibitor and a PGE2 antagonist (i.e., a PGE2 pathway inhibitor), wherein the I-DASH inhibitor inhibits the enzymatic activity of DPP8, DPP9, and DPP-4, and optionally FAP, and wherein the combination of the immuno-DASH inhibitor and the PGE2 antagonist induces and / or enhances a T cell-mediated immune response against the tumor.

[0010] In some embodiments, the subject immuno-DASH inhibitor and PGE2 antagonist are combined. For example, the subject immuno-DASH inhibitor is combined with a PEG2 antagonist, such as a cyclooxygenase inhibitor. In a preferred embodiment, the subject immuno-DASH inhibitor is combined with a PEG2 antagonist, such as a cyclooxygenase inhibitor, for oral administration, i.e., in a single dosage formulation. In a preferred embodiment, the immuno-DASH inhibitor and PGE2 antagonist are combined in a form suitable for once-daily or twice-daily administration, such as a tablet or capsule.

[0011] In certain preferred embodiments, the PGE2 antagonist increases the maximum tolerated dose (MID) of the I-DASH inhibitor by at least 30%, more preferably at least 50%, at least 75%, or at least 100%, or by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 40-fold, or even more than 50-fold, compared to the MID of the I-DASH inhibitor in the absence of the PGE2 antagonist.

[0012] In certain preferred embodiments, the PGE2 antagonist improves the efficacy and / or complete remission rate of the I-DASH inhibitor by at least 30%, more preferably at least 50%, at least 75%, or at least 100%, or by at least 2-fold, at least 5-fold, at least 10-fold, at least 20-fold, at least 40-fold, or even more than 50-fold, compared to the efficacy and / or complete remission rate of the I-DASH inhibitor in the absence of the PGE2 antagonist.

[0013] In a preferred embodiment, the PGE2 antagonist reduces the dose of the immuno-DASH inhibitor required to produce a predetermined anti-tumor effect (e.g., mean percent reduction in tumor volume over time compared to placebo and / or mean survival rate compared to placebo) compared to administration of the immuno-DASH inhibitor alone. In one embodiment, the PGE2 antagonist reduces the dose of the immuno-DASH inhibitor required to produce a predetermined anti-tumor effect by 10%, more preferably at least 15%, at least 20%, 30%, at least 40%, at least 50%, or at least 75% compared to administration of the immuno-DASH inhibitor alone. In one embodiment, the PGE2 antagonist reduces the effective dose (ED) of the immuno-DASH inhibitor required to produce a predetermined anti-tumor effect by 10%, more preferably at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 75% compared to administration of the immuno-DASH inhibitor alone. In some embodiments, the PGE2 antagonist reduces the minimum effective dose of the immuno-DASH inhibitor required to produce a predetermined anti-tumor effect by 10%, more preferably at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 75% compared to administration of the immuno-DASH inhibitor alone. In some embodiments, the PGE2 antagonist reduces the maximum effective dose of the immuno-DASH inhibitor required to produce a predetermined anti-tumor effect by 10%, more preferably at least 15%, at least 20%, at least 30%, at least 40%, at least 50%, or at least 75% compared to administration of the immuno-DASH inhibitor alone.

[0014] In certain preferred embodiments, the PEG2 antagonist increases the therapeutic index (or therapeutic index) of the immuno-DASH inhibitor by at least 2-fold, more preferably at least 5-fold, at least 10-fold, at least 15-fold, at least 20-fold, at least 25-fold, at least 30-fold, at least 40-fold, at least 50-fold, at least 75-fold, or at least 100-fold compared to administration of the immuno-DASH inhibitor alone.

[0015] In one embodiment of the present invention, the PEG2 antagonist is a cyclooxygenase (COX) inhibitor, i.e., an inhibitor of COX-1, COX-2, or both. In one preferred embodiment, the COX inhibitor is a COX-2 selective inhibitor. In one preferred embodiment, the COX inhibitor is selected from the group consisting of celecoxib, deracoxib, parecoxib, valdecoxib, rofecoxib, lumiracoxib, etoricoxib, meloxicam, and mixtures and prodrugs thereof.

[0016] In one embodiment of the invention, the PEG2 antagonist does not bind to or alter PPARγ activity at pharmacologically relevant concentrations in combination with an I-DASH inhibitor. In one embodiment of the invention, the PEG2 antagonist is not indomethacin.

[0017] In another embodiment, the PEG2 antagonist is a phospholipase A2 inhibitor, more preferably an inhibitor of cytosolic phospholipase A2 (cPLA2).

[0018] In certain preferred embodiments of the present invention, the immuno-DASH inhibitor has an intracellular IC for DPP8 and DPP9 inhibition of less than 100 nM. 50 , in vitro IC for DPP4 inhibition less than 100 nM 50 , IC for inducing pyroptosis in cell culture macrophages less than 100 nM 50 , and 1x10 -4 k for interaction with DPP4 less than 1 / sec off Has speed.

[0019] In certain preferred embodiments of the methods of the present invention, the I-DASH inhibitor has IC50 values ​​for the inhibition of DPP4, DPP8, and DPP9 that are within two orders of magnitude of each other. 50 It has a value.

[0020] In one embodiment, the immuno-DASH inhibitor has: i) an in vivo IC50 for DPP4 inhibition of less than 200 nM 50 and ii) an intracellular IC for DPP8 and DPP9 inhibition of less than 200 nM. 50 In one embodiment, the in vivo IC 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM. In certain embodiments, the in vitro cell-free IC 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM. In one embodiment, the EnPlex IC 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, or 0.001 nM.

[0021] In one embodiment, the in vivo IC 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, 0.01 nM, or less than 0.001 nM. In certain embodiments, the in vitro cell-free IC 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM. In one embodiment, the EnPlex IC 50is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, less than 0.001 nM (1 picomolar (pM)), or less than 0.0001 nM (100 femtomolar (fM)). In certain embodiments, the K for DPP4 inhibition is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, less than 0.001 nM (1 pM), or less than 0.0001 nM (100 fM).

[0022] In one embodiment, in vitro cell-free IC50 for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, or less than 0.001 nM. In one embodiment, the EnPlex IC 50 is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, less than 0.001 nM (1 pM), or less than 0.0001 nM (100 fM). In certain embodiments, the K for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) is less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, less than 0.001 nM (1 pM), or less than 0.0001 nM (100 fM).

[0023] In one embodiment, in vitro cell-free IC50 for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) 50 IC for DPP4 inhibition 50 In one embodiment, the in vitro cell-free IC50 for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) is within 100-fold of 50 IC for DPP4 inhibition 50 and more preferably, at least 5-fold smaller (stronger inhibition) than 50at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000-fold less (strong inhibition) than

[0024] In one embodiment, EnPlex IC for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) 50 IC for DPP4 inhibition 50 In one embodiment, the EnPlex IC for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) is within 100-fold of 50 IC for DPP4 inhibition 50 and more preferably, at least 5-fold smaller (stronger inhibition) than 50 at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000-fold less (strong inhibition) than

[0025] In one embodiment, the K for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) is greater than the IC for inhibition of DPP4. 50 In one embodiment, the K for inhibition of DPP8 and / or DPP9 (preferably both DPP8 and DPP) is within 100-fold of the IC for inhibition of DPP4. 50 and more preferably, at least 5-fold smaller (stronger inhibition) than 50 at least 10-fold, at least 50-fold, at least 100-fold, at least 500-fold, or at least 1000-fold less (strong inhibition) than

[0026] In certain embodiments, the subject immuno-DASH inhibitors also inhibit fibroblast activation protein (FAP) within the concentration range of the drug that is an effective antitumor agent, e.g., the immuno-DASH inhibitors have a K for FAP inhibition of less than 100 nM, less than 10 nM, less than 1.0 nM, less than 0.1 nM, less than 0.01 nM, less than 0.001 nM (1 pM), or less than 0.0001 nM (100 fM).

[0027] In certain embodiments, I-DASH inhibitors exhibit slow binding inhibition kinetics.

[0028] In one embodiment, the I-DASH inhibitor is present in a dose of 1x10 -4 / sec, preferably less than 5x10 -5 / sec, less than 3x10 -5 / sec or less than 1x10 -5 k for interaction with DPP4 less than / sec off Has speed.

[0029] In one embodiment, the I-DASH inhibitor, when administered as a single oral dose, exhibits a C max C in human patients or mice that is less than 80% of max and even more preferably, the C provided by oral administration of 10 mg of immediate release Val-boroPro. max Less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20% of C max It has.

[0030] In one embodiment, the I-DASH inhibitor, when administered as a single oral dose, exhibits the same C as that produced by oral administration of Val-boroPro formulated as a 10 mg immediate release formulation. max C in human patients or mice, which is less than 80% of the max and even more preferably, the C provided by oral administration of 10 mg of immediate release Val-boroPro. max Less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, or less than 20% of C max It has.

[0031] In certain embodiments, the I-DASH inhibitor is administered in an amount that results in at least a 100% increase in mean plasma levels of one or more of G-CSF, IL-6, IL-8, and / or IL-18, more preferably an increase of at least a 150%, at least a 200%, at least a 250%, at least a 300%, at least a 400%, or at least a 500% increase in mean plasma levels of one or more of G-CSF, IL-6, IL-8, and / or IL-18, within 6 hours of administration.

[0032] In certain embodiments, the I-DASH inhibitor is administered in an amount that results in an increase in mean plasma levels of G-CSF by at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% within 6 hours of administration.

[0033] In certain embodiments, the single-dose formulation comprises an amount of an I-DASH inhibitor that results in an increase in mean plasma levels of G-CSF of at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, at least 400%, or at least 500% within 6 hours of administration.

[0034] In certain embodiments, the I-DASH inhibitor is administered to the patient in an amount sufficient to cause an increase in the serum concentration of CXCL10.

[0035] In certain embodiments, the I-DASH inhibitor is administered to the patient in an amount sufficient to cause a reduction in the number of tumor-associated macrophages.

[0036] In certain embodiments, the I-DASH inhibitor is administered to the patient in an amount sufficient to reduce monocytic myeloid-derived immunosuppressive cells in the tumor.

[0037] In certain embodiments, the I-DASH inhibitor is administered to the patient in an amount sufficient to reduce the T cell suppressive activity of granulocytic myeloid-derived immunosuppressive cells in the tumor.

[0038] In certain embodiments, the I-DASH inhibitor causes complete tumor regression at a therapeutically effective amount, and the therapeutically effective amount is less than the maximum tolerated dose of the immuno-DASH inhibitor.

[0039] In certain embodiments, the I-DASH inhibitor has a therapeutic index of at least 10, more preferably at least 20, 40, 60, 80, or at least 100.

[0040] In one embodiment, the I-DASH inhibitor has a maximum tolerated dose in C57BL / 6 mice of at least 50 mg, more preferably at least 100 mg, at least 150 mg, at least 200 mg, at least 250 mg, or at least 300 mg, and is capable of inducing complete tumor regression in C57BL / 6 mice at a dose less than the maximum tolerated dose, preferably less than 75% of the maximum tolerated dose, and even more preferably less than 50%, less than 25%, less than 10%, or less than 5% of the maximum tolerated dose.

[0041] In one embodiment, an I-DASH inhibitor, alone or in combination with a PGE2 inhibitor, induces a C of at least 50 nM in Sprague Dawley rats, more preferably at least 100 nM, at least 500 nM, at least 1000 nM, at least 1500 nM, at least 2000 nM, at least 3000 nM, at least 5000 nM, at least 10,000 nM, or at least 20,000 nM. max and in C57BL / 6 mice, at serum concentrations below the maximum tolerated dose in those mice, preferably at C less than 75% of the maximum tolerated dose. max and even more preferably, a C of less than 50%, less than 25%, less than 10%, or less than 5% of the maximum tolerated dose. max At doses resulting in a complete tumor regression can be induced.

[0042] In one embodiment, the immuno-DASH inhibitor used in the methods of the invention has the following general formula: [ka] During the ceremony, A represents a 4-8 membered heterocycle containing N and Cα carbons; Z represents C or N; W is -CN, -CH=NR5, [ka] represents; R1 is a C-terminally linked amino acid residue or amino acid analogue, or a C-terminally linked peptide or peptide analogue, or an amino protecting group, or [ka] represents; R2 is absent or represents one or more substituents for ring A, each of which is independently selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamido, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m - may be R7; When X is N, R3 represents hydrogen, and when X is C, R3 represents hydrogen or halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamide, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m - represents R7; R5 is H, alkyl, alkenyl, alkynyl, -C(X1)(X2)X3, -(CH2) m -R7, -(CH2) n -OH, -(CH2) n -O-alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-Alkyl, -(CH2) n -S-alkenyl, -(CH2) n -S-alkynyl, -(CH2) n -S-(CH2) m -R7, -C(O)C(O)NH2, -C(O)C(O)OR'7; R6 is hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m-O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m - represents R7; R7, at each occurrence, represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R7', at each occurrence, represents hydrogen or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; and Y1 and Y2, independently or together, may be OH or a group that can be hydrolyzed to a hydroxyl group, including cyclic derivatives in which Y1 and Y2 are connected by a ring having 5 to 8 atoms in the ring structure (such as pinacol); R50 represents O or S; R51 represents N3, SH2, NH2, NO2 or OR'7; R52 represents hydrogen, lower alkyl, amine, OR'7, or a pharmaceutically acceptable salt, or R51 and R52 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent hydrogen or halogen; m is zero or an integer ranging from 1 to 8; and n is an integer ranging from 1 to 8.

[0043] Another aspect of the present invention relates to an immunoDASH inhibitor represented by Formula I or a pharmaceutical salt thereof: [ka] During the ceremony Ring A represents a 3- to 10-membered ring structure; Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] represents; X is O or S; X 1 represents a halogen; Y 1 and Y 2 are independently OH, or represent a group that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached, or form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached; R 1 is absent or is selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, cyano, nitro, azide, sulfate, sulfonate, sulfonamide, -CF3, -(CH2) m -R 3 , -(CH2) m OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, or -(CH) n -S-(CH2) m -R 3 represents; R 2 is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n -O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R 5 represents O or S; R 6 is N3, SH, NH2, NO2 or OR 8 represents; R 7 is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8 represents hydrogen or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 9 and R 10are each independently absent or represent one, two or three substituents on ring A or ring Z to which they are attached, and the substituents are each independently halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CH m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3.

[0044] Another aspect of the present invention relates to an immunoDASH inhibitor represented by Formula II or a pharmaceutical salt thereof: [ka] During the ceremony, Ring A is R 1a together represent a 7-12 membered polycyclic ring structure; Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] represents; X is O or S; X 1 represents a halogen; Y is C or N; Y 1 and Y 2 are independently OH, or represent a group that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached, or form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached; R 1a is lower alkyl, -(CH2) m -, -(CH2) m -O-(CH2) m -;-(CH2) m -N-(CH2) m -; or -(CH2) m -S-(CH2) m - represents; R 2 is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3 represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n -O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2)n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R 5 represents O or S; R 6 is N3, SH, NH2, NO2 or OR 8 represents; R 7 is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8 represents hydrogen or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 9 and R 10 are each independently absent or represent one, two or three substituents on ring A or ring Z to which they are attached, and the substituents are each independently halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CH m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and p is 1, 2 or 3.

[0045] Another aspect of the present invention relates to an immunoDASH inhibitor represented by Formula III or a pharmaceutical salt thereof: [ka] Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] represents; X is O or S; X 2 represents either absent, halogen or lower alkyl; Y 1 and Y 2 are independently OH, or represent a group that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached, or form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached; R 1 is independently selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamido, -CF3, -(CH2) m -R 3 , -(CH2) m OH, -(CH2) m -O-lower alkyl, -(CH2)m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, or -(CH) n -S-(CH2) m -R 3 represents; R 2 is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3 represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n -O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R 5 represents O or S; R6 is N3, SH, NH2, NO2 or OR 8 represents; R 7 is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8 represents hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 10 represents either no substituents or 1 to 3 substituents on the ring Z to which it is attached, each of which independently represents halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CH m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3.

[0046] Another aspect of the present invention relates to an immunoDASH inhibitor represented by Formula IV or a pharmaceutical salt thereof: [ka] During the ceremony, Ring A represents a 3- to 10-membered ring structure containing N; Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] represents; X is O or S; X 1 represents a halogen; Y 1 and Y 2 are independently OH, or represent a group that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached, or form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached; R 1 is absent or is selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, cyano, nitro, azide, sulfate, sulfonate, sulfonamide, -CF3, -(CH2) m -R 3 , -(CH2) m OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, or -(CH) n -S-(CH2) m -R 3 represents; R 2is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3 represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n -O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R 5 represents O or S; R 6 is N3, SH, NH2, NO2 or OR 8 represents; R 7 is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8represents hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 9 and R 10 are each independently absent or 1 to 3 substituents on ring A or ring Z to which they are attached, and the substituents are each independently selected from halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azide, sulfate, sulfonate, sulfonamide, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3.

[0047] In certain preferred embodiments, the immuno-DASH inhibitors are boronic acid inhibitors of the DASH enzymes DPP8 and DPP9 (and optionally also DPP-4 and / or FAP).

[0048] In a preferred embodiment, the immuno-DASH inhibitor is a dipeptide boronic acid inhibitor of the DASH enzymes DPP8 and DPP9 (and optionally DPP-4 and / or FAP). In a preferred embodiment, the dipeptide boronic acid immuno-DASH inhibitor has a proline or proline analog at the P1 position. The subject immuno-DASH inhibitors can mediate tumor regression through immune-mediated mechanisms. The subject I-DASH inhibitors induce macrophage pyroptosis and have other activities, such as directly or indirectly modulating immunogenicity, sensitizing tumor cells to antigen-specific CTL killing, altering immune cell subsets and function, accelerating T cell priming via modulation of dendritic cell trafficking, and generalizing T cell-mediated anti-tumor activity.

[0049] In certain embodiments, the subject immuno-DASH inhibitor and PGE2 antagonist combination may be administered as part of a treatment that includes one or more other chemotherapeutic agents, such as tumor vaccines, adoptive cell therapy, gene therapy, oncolytic virus therapy, and the like.

[0050] In a preferred embodiment, the combination of a PGE2 antagonist and an immuno-DASH inhibitor can be administered as part of a broader combination therapy with other cancer immunotherapies, such as, for example, PD-1 antagonists (such as anti-PD-1 and anti-PD-L1 antibodies, and small molecule antagonists of PD-1 / PD-L1 signaling), CTLA-4 antagonists (such as anti-CTLA4 antibodies), VEGF antagonists (such as anti-VEGF-2, such as Cyramza), EGFr antagonists (such as necitumumab), and the like. anti-EGFr antibodies such as pembrolizumab), IDO inhibitors (such as NLG919), IDO1 inhibitors (such as epacadostat), anti-B7-H3 antibodies (such as MGA271), anti-GITR antibodies (such as MK-4166), HDAC inhibitors (such as entiostat), anti-CD137 antibodies (such as urelumab or PF-05082566), anti-CD20 antibodies (such as ublituximab or Gazyva), PI3K delta (δ) inhibitors (TGR-12 02), IL-15 agonists (such as IL15Ra-Fc fusion protein ALT-803), CXCR4 antagonists (such as Ulocuplumab, Plerixafor, and BL-8040), CXCL12 antagonists (such as Spiegelmer NOX-A12), DNMT inhibitors (such as azacitidine), anti-LAG3 antibodies (such as BMS-986016 or LAG525), interleukin-21, anti-KIR antibodies (such as Lirilumab ), anti-CD27 antibodies (such as Varlilumab), anti-CSF-1R antibodies (such as FPA008 or RO5509554), anti-CCR4 antibodies (such as Mogamulizumab), GMCSF (such as sargamostim), anti-PS antibodies (such as Bavituximab), anti-CD30 antibody-auristatin E conjugates (such as Adcetris), anti-CD19 antibodies (such as MEDI-551), CD40 agonists (such as RO7009789), and anti-CEAExamples of antibodies include IL-2 antibodies (such as RG7813), anti-OX40 antibodies (such as RG7888 or MEDI-6469), OX40 agonists (such as MEDI6383), anti-NY-ESO-1 antibodies (such as CDX-1401), anti-NKG2A antibodies (such as IPH2201), STING agonists, NRLP1 and / or NRLP3 agonists, or anti-CD73 antibodies (such as MEDI9447).

[0051] Another aspect of the present invention relates to a method for enhancing a cellular immune response against cancer, comprising administering to a mammal in need thereof therapeutically effective amounts of a PD-1 inhibitor and a PGE2 antagonist (i.e., a PGE2 pathway inhibitor). [Brief explanation of the drawings]

[0052] [Figure 1] Illustrates immune mechanisms mediated by the extracellular and intracellular targets of the subject immunoDASH inhibitors, where up and down arrows (and associated letters) represent inhibition or stimulation / prolongation of specific effects (direct or indirect). MDSC = myeloid-derived immunosuppressive cells. TAM = tumor-associated macrophages. Immune wheel adapted from Chen and Mellman 2013, Immunity 39(1):1-10. [Figure 2] Depicting tumor-associated macrophages (TAMs) as central immune regulators of the tumor microenvironment. Adapted from Noy and Pollard. Immunity (2014) 41, 49-81. [Figure 3] This is a simple explanation of the interplay between DPP8 and DPP9 inhibition as an induction event and DPP4 inhibition as a prolongation event. [Figure 4] Figure 1 shows the correlation developed between the potency (intracellular IC50 or IIC50) for inhibiting DPP8 and DPP9 when used to treat whole cells and the IC50 for inducing pyroptosis in cell cultured macrophages. [Figure 5]Schematic diagram showing the caspase-1-dependent pyroptosis pathway and IL-1β release that I-DASH inhibitors are understood to induce, as well as induction of the prostaglandin pathway, consistent with the dose-limiting toxicity of talabostat. [Figure 6] Figure 1 shows the results (single dose) of a maximum tolerated dose (MTD) study in Sprague-Dawley rats treated with Val-boroPro (valine-boroproline) in combination with or without the cyclooxygenase inhibitors celecoxib (a COX-2-selective nonsteroidal anti-inflammatory drug), indomethacin (a nonselective inhibitor of COX-1 and COX-2), and SC-560. The bar indicates the MTD single dose in SD rats prior to animal death. Adding a cyclooxygenase inhibitor to an l-DASH inhibitor increases the MTD dose by 47-75-fold, based on serum drug levels. See also Figure 17 for a similar comparison using a cPLA2 inhibitor instead of a COX inhibitor. [Figure 7] This figure shows the results of treating MB49 tumor-bearing mice with Val-boroPro (valine-boroproline) in combination with or without celecoxib. Tumor volume measured over time is shown. Treatment with vehicle (control) or Val-boroPro began 3 days after tumor inoculation and was administered on days 4-8, 11-15, and 18-22. [Figure 8] Figure 1 shows the results of treating MB49 tumor-bearing mice with Val-boroPro (valine-boroproline) in combination with or without celecoxib. Tumor volume measured over time is shown. Treatment with vehicle (control) or Val-boroPro began 3 days after tumor implantation and was administered on days 4-8, 11-15, and 18-22. [Figure 9] Figure 1 shows the results of treating MB49 tumor-bearing mice with Val-boroPro (valine-boroproline) in combination with or without celecoxib. Tumor volume measured over time is shown. Treatment with vehicle (control) or Val-boroPro began 3 days after tumor implantation and was administered on days 4-8, 11-15, and 18-22. [Figure 10]Figure 1 shows the results of treating MB49 tumor-bearing mice with Val-boroPro (valine-boroproline) in combination with or without celecoxib. Tumor growth curves for individual animals in the Val-boroPro (+ / - celecoxib) treatment group are shown. Treatment with vehicle (control) or Val-boroPro began 3 days after tumor implantation and was administered on days 4-8, 11-15, and 18-22. [Figure 11] ARI-5544, ARI-4175CH, ARI-3102C, ARI-5836, ARI-4175, ARI-3102A, ARI-2107, and ARI-2054 show high potency as inhibitors of DPP8 / 9 (IC50<50pM for DPP9) as measured by EnPlex. [Figure 12] Figure 1 shows that ARI-4268 exerts antitumor activity in the MB49 mouse tumor model at doses that demonstrate an improved therapeutic index—even at a truncated dose schedule. [Figure 13] 1 shows the antitumor activity of ARI-5870 alone or in combination with Celebrex (a COX inhibitor) or an anti-PD-1 antibody, or both, in the MB49 mouse tumor model. [Figure 14] 1 shows the antitumor activity of ARI-5870 alone or in combination with Celebrex (a COX inhibitor) or an anti-PD-1 antibody, or both, in the MB49 mouse tumor model. [Figure 15] 1 shows the antitumor activity of ARI-4268 alone or in combination with Celebrex (a COX inhibitor) or an anti-PD-1 antibody, or both, in the MB49 mouse tumor model. [Figure 16] 1 shows the antitumor activity of ARI-4268 alone or in combination with Celebrex (a COX inhibitor) or an anti-PD-1 antibody, or both, in the MB49 mouse tumor model. [Figure 17]

[0033] Figure 1 shows the results (single dose) of a maximum tolerated dose (MTD) study in Sprague Dawley rats treated with Val-boroPro (valine-boroproline) in combination with or without the cPLA2 inhibitors pyrophenone and AACOCF3. The bar represents the MTD single dose in SD rats prior to animal death. The addition of a cPLA2 inhibitor to an I-DASH inhibitor increases the MTD dose by at least 20-fold, based on serum drug levels.

[0053] Of the animals shown to have "regression" in Figures 10, 12, 14, and 16, over 80% of the animals maintained immunity to the MB49 tumor and did not grow new tumors when re-inoculated with MB49 tumor cells 30 days after the final dose of the I-DASH inhibitor, indicating that a T cell-mediated immune response was induced by treatment containing the I-DASH inhibitor. DETAILED DESCRIPTION OF THE INVENTION

[0054] 1. overview The immuno-DASH (I-DASH) inhibitors of the present combination therapy are multimediator cancer immunotherapeutic agents that target novel checkpoint pathways associated with macrophages through inhibition of DPP8 and DPP9, as well as chemokine / cytokine signaling pathways (such as CXCL10) through inhibition of DPP4 and (potentially) FAP.

[0055] Figure 1 shows the direct and indirect effects on tumor-targeted immune responses resulting from treatment with immuno-DASH inhibitors of the invention. For example, and by way of example only, immuno-DASH inhibitors of the invention can: Selective induction of programmed cell death in macrophages; · Reduce monocytic MDSCs in tumors; · Reduces the T cell suppressive activity of granulocytic MDSCs; ·Enhancing trafficking of key effector immune cells; Increases NK and dendritic cell levels; Accelerate the expansion of tumor-specific T cells; ·Increasing the sensitivity of carcinoma cells to CTL killing; · Induce the expression of cell surface proteins on tumor cells that enhance immune reactivity, such as increased expression of MHC class I proteins, calreticulin, and / or tumor cell antigens; Induction of immunostimulatory cytokines and chemokines; and Stabilizes the biologically active forms of several key cytokines and chemokines, including CXCL10.

[0056] In cell culture, only macrophages (and macrophage-derived cells, such as AML cells) are killed by I-DASH inhibitors and through a mechanism involving pyroptosis. I-DASH inhibitors are not directly harmful to non-macrophage normal cells or tumor cells. As shown in Figure 2, tumor-associated macrophages (TAMs) express a series of effector molecules that inhibit antitumor immune responses; these include cell surface receptors, cytokines, chemokines, and enzymes. Without being bound by theory, by selectively targeting tumor-associated macrophages to undergo pyroptosis based on the selectivity of these cells for DPP8 / DPP9 inhibition compared to other cells, immuno-DASH inhibitors can ablate multiple immune checkpoints in the tumor microenvironment.

[0057] The proposed mechanism of action is potent and long-lasting (long K off Inhibition of DPP8 and DPP9 (at a high rate) induces the release of immunostimulatory cytokines such as IL-1β, potentially associated with programmed cell death of macrophages via pyroptosis, resulting in stimulation of the immune response and the release of immunosuppressive effects of tumor-associated macrophages. While inhibition of DPP8 and DPP9 represents an induction mechanism, inhibition of DPP4 and (potentially) FAP represents an extension mechanism, extending the serum half-life of chemokines and cytokines such as CXCL10, which enhances immune cell trafficking to tumor cells. See Figure 3.

[0058] FIG. 4 shows that by optimizing inhibitors according to the intracellular IC50 ("IIC50") for DPP8 and DPP9 inhibition, and (again, without being bound by any particular theory) the potency of the agent to induce pyroptosis in macrophages in vitro, more effective and potentially safer immunoDASH inhibitors can be identified.

[0059] However, at the time of clinical trials of talabostat, the underlying mechanism of action causing dose-limiting toxicity was unknown, and it was not even understood whether the toxicity was the result of on-target or off-target effects of the drug. The present invention is based on the discovery of an antitumor mechanism of action of I-DASH inhibitors, which involves selective pyroptosis of macrophages. As shown in Figure 5, inhibition of DPP8 / 9 activity in macrophages selectively triggers a caspase-1-mediated immunogenic cell death phenomenon known as pyroptosis, which results in the release of various antitumor cytokines that are understood to trigger / enhance the T cell-mediated immune response against tumors observed with I-DASH inhibitors. The present invention is based on the following additional findings: (i) induction of pyroptosis also leads to activation of the eicosanoid production pathway, which, in other circumstances, links cyclooxygenase and phospholipase enzymes to the production of inflammatory eicosanoids such as prostaglandin E2 (PGE2); (ii) retrospective analysis of clinical trials of talabostat revealed two features: dose-limiting toxicity was consistent with the release of inflammatory eicosanoids (especially PGE2); and one phase 2 study including two different drug dose cohorts showed signs of potential efficacy (albeit modest) among the measured secondary endpoints, indicating that talabostat could have been administered at two-, five-, or even ten-fold higher concentrations, which could have mitigated the dose-limiting toxicity and further met the primary and secondary endpoints of the study.

[0060] However, a priori, it was neither clear nor predictable what effect the addition of a PGE2 antagonist, such as a COX inhibitor, would have on the antitumor activity of an I-DASH inhibitor. Until the findings herein, those skilled in the art would not have understood to what extent, if any, prostaglandin release and / or activity of enzymes such as cyclooxygenase and phospholipase were required for the antitumor activity of an I-DASH inhibitor, or whether the PEG2 pathway could be successfully inhibited without impairing antitumor activity—particularly, the ability of an I-DASH inhibitor to induce complete tumor regression and T cell-dependent immunity against tumor rechallenge.

[0061] Figure 6 shows the results (single dose) of a maximum tolerated dose study in Sprague-Dawley rats treated with Val-boroPro (valine-boroproline) with or without various cyclooxygenase inhibitors, including celecoxib (a COX-2-selective nonsteroidal anti-inflammatory drug), indomethacin (a nonselective inhibitor of COX-1 and COX-2), and SC-560. The bars indicate the MTD single dose in SD rats before animal death. Adding a cyclooxygenase inhibitor to an l-DASH inhibitor increases the MTD dose by 47-75-fold, based on serum drug levels.

[0062] These results indicate that the combination of an I-DASH inhibitor with a PGE2 antagonist (especially a COX inhibitor) can provide an enhanced safety profile by increasing the maximum tolerated dose of the I-DASH inhibitor that can be administered to patients. Figures 7-10 demonstrate that the addition of celecoxib not only does not attenuate the antitumor activity of Val-boroPro, but also has a synergistic effect in enhancing the antitumor activity of Val-boroPro. With various concentrations of celecoxib alone, no differences in tumor growth rate were observed compared to the control (vehicle). See Figure 7. However, celecoxib significantly (statistically significantly) and dose-dependently enhanced the antitumor activity of Val-boroPro. See Figures 8 and 9. Considering the individual animal curves (see Figure 10), the combination not only resulted in a dramatic difference in tumor growth rate, but also facilitated the achievement of tumor regression at a dose of 20 μg of Val-boroPro (which produced its effect by itself in this experiment).

[0063] II. definition For convenience, before further description of the present invention, certain terms employed in the specification, examples, and claims are collected here.

[0064] The term "alkyl" refers to the radical of a saturated aliphatic group, including straight-chain alkyl groups, branched-chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl-substituted cycloalkyl groups, and cycloalkyl-substituted alkyl groups. In certain embodiments, a straight-chain or branched-chain alkyl group has 30 or fewer carbon atoms in its backbone (e.g., C1-C for a straight chain). 30 , C3 to C for branched chain 30 ), and more preferably have 20 or fewer carbon atoms. Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure. As used throughout the specification and claims, the term "alkyl" (or "lower alkyl") is meant to include both "unsubstituted alkyls" and "substituted alkyls."

[0065] As used herein, the term "aralkyl" refers to an alkyl group substituted with an aryl group (e.g., an aromatic group). As used herein, the term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl group (eg, a heteroaromatic group).

[0066] The terms "alkenyl" and "alkynyl" refer to unsaturated aliphatic groups similar in length and potential substitution to the alkyls described above, but that contain at least one double or triple bond respectively.

[0067] Unless the number of carbon atoms is otherwise specified, "lower alkyl," as used herein, refers to an alkyl group, as defined above, but having from 1 to 10 carbon atoms in its backbone structure, e.g., from 1 to 4 or 1 to 6 carbon atoms. Similarly, "lower alkenyl" and "lower alkynyl" have similar chain lengths. In some embodiments, an alkyl group is a lower alkyl. In some embodiments, a substituent designated herein as alkyl is a lower alkyl.

[0068] As used herein, the term "aryl" includes 5-, 6- and 7-membered monocyclic aromatic groups, including, for example, benzene. As used herein, the term "heteroaryl" encompasses 5-, 6-, and 7-membered monocyclic aromatic groups containing up to four heteroatoms, including pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, and pyrimidine. These compounds with heteroatoms in the ring structure Hetero An aryl group may also be referred to as an "aryl heterocycle" or a "heteroaromatic". or heteroaromatic ring can be substituted at one or more ring positions with substituents as described above, including, for example, halogen, azido, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxy, silyl, ether, alkylthio, sulfonyl, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF, -CN, and the like. and "heteroaryl" has two or more cyclic rings in which two or more carbons within the rings are shared between two adjacent rings (the rings are "fused rings"), and at least one of the rings is aromatic or heteroaromaticand also encompasses polycyclic ring systems, for example where the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl.

[0069] The terms "heterocyclyl" or "heterocyclic group" refer to 3- to 10-membered ring structures, more preferably 3- to 7-membered rings, whose ring structures include one to four heteroatoms. Heterocycles can be polycyclic. Examples of heterocyclyl groups (heterocyclic groups) include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenarsazine, phenothiazine, furazan, phenoxazine, pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lactones, lactams such as azetidinone and pyrrolidinone, sultams, and sultones. The heterocyclic ring can be substituted at one or more positions with substituents such as those described above, including, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moieties, -CF, -CN, and the like.

[0070] The term "heteroaryl" refers to a monovalent aromatic monocyclic ring system in which at least one ring atom is a heteroatom independently selected from the group consisting of O, N, and S. The term "5-membered heteroaryl" refers to a heteroaryl having 5 ring atoms. Examples of 5-membered heteroaryl groups include pyrrolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, furazanyl, imidazolinyl, and triazolyl.

[0071] The term "heterocycloalkyl" refers to a monocyclic or bicyclic monovalent saturated or non-aromatic unsaturated ring system having one to four ring atoms independently selected from the group consisting of O, N, and S. The term "3- to 10-membered heterocycloalkyl" refers to a heterocycloalkyl having three to ten ring atoms. Examples of 3- to 10-membered heterocycloalkyls include 3- to 6-membered heterocycloalkyls. Bicyclic ring systems include fused, bridged, and spirocyclic ring systems. More specific examples of heterocycloalkyl groups include azepanyl, azetidinyl, aziridinyl, imidazolidinyl, morpholinyl, oxazolidinyl, oxazolidinyl, piperazinyl, piperidinyl, pyrazolidinyl, pyrrolidinyl, quinuclidinyl, and thiomorpholinyl.

[0072] The term "polycyclyl" or "polycyclic group" refers to two or more rings (e.g., cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, and / or heterocyclyl) in which two or more carbons are shared between two adjacent rings, e.g., the rings are "fused rings." Rings that are joined through non-adjacent atoms are referred to as "bridged" rings. Each ring of the polycycle can be substituted at one or more positions with a substituent, as described above, including, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amido, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, -CF, -CN, and the like.

[0073] As used herein, the term "carbocycle" refers to an aromatic or non-aromatic ring in which each atom of the ring is carbon.

[0074] The term "heteroatom" as used herein means an atom of any element other than carbon or hydrogen. Examples of heteroatoms are nitrogen, oxygen, sulfur, and phosphorus.

[0075] As used herein, the term "nitro" means -NO2; the term "halogen" refers to -F, -Cl, -Br, or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; and the term "sulfonyl" means -SO2-.

[0076] "Halogen" or "halo," by itself or as part of another substituent, refers to fluorine, chlorine, bromine, and iodine, or fluoro, chloro, bromo, and iodo. It is understood that "substituted" or "substituted by" includes the implicit proviso that such substitution is in accordance with the allowed valences of the substituted atom and substituent, and that the substitution results in a stable compound that does not spontaneously undergo transformation, such as by rearrangement, cyclization, elimination, and the like.

[0077] As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic substituents of organic compounds. Illustrative substituents include, for example, those described herein above. The permissible substituents can be one or more and the same or different for appropriate organic compounds. Substituents include, for example, halogen, hydroxyl, carbonyl (such as carboxyl, ester, formyl, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), alkoxyl, phosphoryl, phosphonate, phosphinate, amino, amido, amidine, imine, cyano, nitro, azido, sulfhydryl, alkylthio, sulfate, sulfonate, sulfamoyl, sulfonamido, sulfonyl, heterocyclyl, aralkyl, or aromatic or heteroaromatic moieties. It will be understood by those skilled in the art that the moieties substituted on the hydrocarbon chain can themselves be substituted, if appropriate. For example, substituents of substituted alkyl include substituted and unsubstituted forms of amino, azido, imino, amido, phosphoryl (including phosphonates and phosphinates), sulfonyl (including sulfates, sulfonamides, sulfamoyl, and sulfonates), and silyl groups, as well as ethers, alkylthio, carbonyl (including ketones, aldehydes, carboxylates, and esters), -CF3, -CN, and the like. Exemplary substituted alkyls are described below. Cycloalkyls can be further substituted with alkyls, alkenyls, alkoxys, alkylthios, aminoalkyls, carbonyl-substituted alkyls, -CF3, -CN, and the like. For purposes of this invention, heteroatoms such as nitrogen can have hydrogen substituents and / or any permissible substituents of organic compounds described herein that satisfy the valences of the heteroatoms. This invention is not intended to be limited in any manner by the permissible substituents of organic compounds.

[0078] The terms "amino acid residue" and "peptide residue" refer to an amino acid or peptide molecule without its carboxyl group's -OH. In general, the abbreviations used herein to designate amino acids and protecting groups are based on the recommendations of the IUPAC-IUB Commission on Biochemical Nomenclature (see Biochemistry (1972) 11:1726-1732). For example, Met, Ile, Leu, Ala, and Gly represent "residues" of methionine, isoleucine, leucine, alanine, and glycine, respectively. Residue refers to the radical derived from the corresponding α-amino acid by removing the OH moiety of the carboxyl group and the H moiety of the α-amino group. The term "amino acid side chain" refers to the portion of an amino acid excluding the -CH(NH)COOH moiety, as defined by K.D. Kopple, "Peptides and Amino Acids," W.A. Benjamin Inc., New York and Amsterdam, 1966, pages 2 and 33.

[0079] For the most part, the amino acids used in the present application are naturally occurring amino acids found in proteins or naturally occurring anabolic or catabolic products of such amino acids that contain amino and carboxyl groups. Particularly suitable amino acid side chains include those selected from the following amino acids: glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan, as well as the side chains of those amino acids and amino analogs that have been identified as components of peptidylglycan bacterial cell walls.

[0080] The term amino acid residue further includes analogs, derivatives, and congeners of any specific amino acid referred to herein, and by way of example, the subject compounds may include amino acid analogs such as cyanoalanine, canavanine, dienecholic acid, norleucine, 3-phosphoserine, homoserine, dihydroxy-phenylalanine, 5-hydroxytryptophan, 1-methylhistidine, 3-methylhistidine, diaminopimelic acid, ornithine, or diaminobutyric acid. Other naturally occurring amino acid metabolites or precursors having side chains suitable herein will be recognized by those of skill in the art and are encompassed within the scope of the present invention.

[0081] Also included are (D) and (L) stereoisomers of amino acids, if the structure of the amino acid allows for such stereoisomeric forms. The configuration of amino acids and amino acid residues herein is designated by the appropriate symbol (D), (L), or (DL); further, if the configuration is not explicitly stated, the amino acid or residue may have the (D), (L), or (DL) configuration. It should be noted that the structures of some of the compounds of the present invention include asymmetric carbon atoms. It should be understood, therefore, that isomers arising from such asymmetry are also included within the scope of the present invention. Such isomers can be obtained in substantially pure form by traditional separation techniques and by stereocontrolled synthesis. For purposes of this application, unless expressly stated to the contrary, a named amino acid should be construed to encompass both the (D) and (L) stereoisomers.

[0082] As noted above, certain compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, R and S enantiomers, diastereomers, (D) isomers, (L) isomers, racemic mixtures thereof, and other mixtures thereof, as being within the scope of the present invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers, as well as mixtures thereof, are intended to be included in the present invention.

[0083] For example, if a specific enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, followed by separation of the resulting diastereomeric mixture and cleavage of the auxiliary group to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, diastereomeric salts can be formed with an appropriate optically active acid or base, followed by resolution of the diastereomers so formed by fractional crystallization or chromatographic means well known in the art, followed by recovery of the pure enantiomers.

[0084] As used herein, the term "prodrug" encompasses compounds that are converted into therapeutically active agents under physiological conditions. A common method for making a prodrug is to include selected moieties that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by enzymatic activity in the host animal.

[0085] The term “IC 50 " refers to the concentration of inhibitor at which the response (or binding) is reduced by half and can be measured in whole cells, animals, or in vitro cell-free (purified enzyme) systems. Cell-free enzyme inhibition can also be reported as a K value using apparent reaction rate measurements.

[0086] The term “ICIC 50 " or "IIC 50 " is a measure of DPP8 and DPP9 inhibition in a whole cell context, as cell permeability is a factor (DPP8 and DPP9 are cell permeable and purified enzymes are IC 50 (eliminating the cell permeability requirement for measurements of

[0087] The term "DPP4" refers to the protein dipeptidyl peptidase 4.

[0088] The term "DPP8" refers to the protein dipeptidyl peptidase 8.

[0089] The term "DPP9" refers to the protein dipeptidyl peptidase 9.

[0090] For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, inside cover of the Handbook of Chemistry and Physics, 67th Ed., 1986-87. Also for purposes of this invention, the term "hydrocarbon" is intended to include all permissible compounds having at least one hydrogen and one carbon atom. In a broad aspect, permissible hydrocarbons include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and nonaromatic organic compounds, which may be substituted or unsubstituted.

[0091] The term "EnPlex" refers to a purified enzyme activity assay described by Bachovchin et al. Nature Chemical Biology 10, 656-663 (2014). Briefly, purified enzymes are coupled to Luminex microspheres, each with a different bead color. The multi-bead complex is incubated with the compound and then treated with a biotinylated activity-based probe and streptavidin R-phycoerythrin conjugate (SAPE). The mixture is scanned in a Luminex flow cytometer, with one laser detecting the bead color (enzyme identity) and a second laser detecting the R-phycoerythrin signal (enzyme activity). Enzyme concentrations are calculated assuming 100% protein is bound to the beads.

[0092] "Enplex IC 50 " is the IC for enzyme inhibition measured using EnPlex 50 is.

[0093] In the case of a dipeptide (or dipeptide analog), the terms "P1 position" and "P2 position" refer to the carboxy- and amino-terminal residues, respectively. In the case of a subject I-DASH inhibitor, the P1 position is an amino acid (or amino acid analog) in which a boronic acid is substituted at the carboxy-terminus.

[0094] III. Illustrative Embodiments One aspect of the present invention is a method for enhancing a cellular immune response to cancer, comprising administering to a mammal in need thereof therapeutically effective amounts of an immuno-DASH (I-DASH) inhibitor and a PD-1 antagonist, wherein the I-DASH inhibitor inhibits the enzymatic activity of DPP8, DPP9, and DPP4, and wherein the I-DASH inhibitor has IC50 values ​​for the inhibition of DPP4, DPP8, and DPP9 that are within two orders of magnitude of each other. 50 The present invention relates to a method for treating tumors having therapeutic value, wherein the combination of an immuno-DASH inhibitor with a PD-1 pathway inhibitor induces and / or enhances a cellular immune response against tumors.

[0095] In certain preferred embodiments of the present invention, the immuno-DASH inhibitor has an intracellular IC for DPP8 and DPP9 inhibition of less than 100 nM. 50 , in vivo IC for DPP4 inhibition less than 100 nM 50 , with an IC<100 nM for inducing pyroptosis in macrophages in cell culture 50 , and 1x10 -4 k for interaction with DPP4 less than 1 / sec off Has speed.

[0096] Another aspect of the invention is a method for treating a cancer, the method comprising administering to a patient a therapeutically effective amount of the ... any one of the aforementioned methods, wherein the cancer is selected from the group consisting of breast cancer, testicular cancer, thyroid cancer, uterine cancer, and urinary system cancer.

[0097] Another embodiment of the present invention relates to any one of the aforementioned methods, wherein the maximum tolerated dose of the immunoDASH inhibitor in C57BL / 6 mice is at least 10 mg / kg; and the immunoDASH inhibitor causes complete cancer regression in C57BL / 6 mice at a dose less than the maximum tolerated dose in C57BL / 6 mice.

[0098] In some embodiments, the immuno-DASH inhibitor is administered orally or parenterally.

[0099] In some embodiments, the immuno-DASH inhibitor is administered orally.

[0100] In some embodiments, the immuno-DASH inhibitor is administered parenterally.

[0101] In some embodiments, the immuno-DASH inhibitor is administered locally.

[0102] In some embodiments, the immuno-DASH inhibitor is administered in a solid dosage form.

[0103] In some embodiments, the solid dosage form is a tablet, capsule, or pill.

[0104] In some embodiments, the solid dosage form is a tablet.

[0105] In some embodiments, the immuno-DASH inhibitor is administered in an amount sufficient to stimulate the immune system without dose-limiting toxicity.

[0106] A. Exemplary ImmunoDASH Inhibitors A representative class of immunoDASH inhibitors for use in the methods of the present invention is represented by the following general formula: [ka] During the ceremony, A represents a 4-8 membered heterocycle containing N and Cα carbons; Z represents C or N; W is -CN, -CH=NR5, [ka] represents; R1 is a C-terminally linked amino acid residue or amino acid analogue, or a C-terminally linked peptide or peptide analogue, or an amino protecting group, or [ka] represents; R2 is absent or represents one or more substituents for ring A, each of which independently represents a halogen, a lower alkyl, a lower alkenyl, a lower alkynyl, a carbonyl (such as a carboxyl, an ester, a formate, or a ketone), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an amino, an acylamino, an amido, a cyano, a nitro, an azido, a sulfate, a sulfonate, a sulfonamide, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m-SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m - may be R7; When X is N, R3 represents hydrogen, and when X is C, R3 represents hydrogen or halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamide, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m - represents R7; R5 is H, alkyl, alkenyl, alkynyl, -C(X1)(X2)X3, -(CH2) m -R7, -(CH2) n -OH, -(CH2) n -O-alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-Alkyl, -(CH2) n -S-alkenyl, -(CH2) n -S-alkynyl, -(CH2) n -S-(CH2) m -R7, -C(O)C(O)NH2, -C(O)C(O)OR'7; R6 is hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m - represents R7; R7, at each occurrence, represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R7', at each occurrence, represents hydrogen or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; and Y1 and Y2, independently or together, may be OH or a group that can be hydrolyzed to a hydroxyl group, including cyclic derivatives in which Y1 and Y2 are connected by a ring having 5 to 8 atoms in the ring structure (such as pinacol); R50 represents O or S; R51 represents N3, SH2, NH2, NO2 or OR'7; R52 represents hydrogen, lower alkyl, amine, OR'7, or a pharmaceutically acceptable salt, or R51 and R52 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; X1 represents a halogen; X2 and X3 each represent hydrogen or halogen; m is zero or an integer ranging from 1 to 8; and n is an integer ranging from 1 to 8.

[0107] In preferred embodiments, ring A is a 5-, 6-, or 7-membered ring, for example, as represented by the formula: [ka] More preferably, it is a 5- or 6-membered ring (ie, n is 1 or 2, although n can also be 3 or 4). The ring may optionally be further substituted.

[0108] In a preferred embodiment, W is [ka] Represents.

[0109] In a preferred embodiment, W is [ka] Represents.

[0110] In a preferred embodiment, R1 is [ka] wherein R36 is a small hydrophobic group (e.g., lower alkyl or halogen) and R38 is hydrogen, or R36 and R37 together form a 4-7 membered heterocycle containing the N and Cα carbons, as defined above for A; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. In a preferred embodiment, R36 is a lower alkyl (C1-C6) such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group, and R38 and R40 are each hydrogen. In a preferred embodiment, R1 is a valine amino acid residue. In a preferred embodiment, R1 is a t-butylglycine residue.

[0111] In preferred embodiments, R2 is absent or represents a small hydrophobic group such as a lower alkyl or halogen.

[0112] In preferred embodiments, R3 is hydrogen or a small hydrophobic group such as a lower alkyl or halogen.

[0113] In preferred embodiments, R5 is hydrogen or halogenated lower alkyl.

[0114] In a preferred embodiment, X1 is fluorine, and X2 and X3, when halogen, are fluorine.

[0115] Any compound that can be converted by hydrolysis to any of the above-mentioned compounds, including boronic esters and halides, as well as carbonyl equivalents, including acetals, hemiacetals, ketals, and hemiketals, and cyclic dipeptide analogs, are also contemplated as equivalents.

[0116] In certain preferred embodiments, the present methods utilize boronic acid analogs of amino acids as immuno-DASH inhibitors. For example, the present invention contemplates the use of boro-prolyl derivatives in the present methods. Exemplary boronic acid-derived inhibitors of the present invention are represented by the following general formula: [ka] During the ceremony, R1 is a C-terminally linked amino acid residue or amino acid analogue, or a terminally linked peptide or peptide analogue, or [ka] represents; R6 is hydrogen, halogen, alkyl, alkenyl, alkynyl, aryl, -(CH2) m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R7, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R7, [ka] represents; R7 represents an aryl, cycloalkyl, cycloalkenyl, or heterocycle; R8 and R9 are each independently hydrogen, alkyl, alkenyl, -(CH2) m -R7, -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, -C(=O)-(CH2) m represents -R7, or R8 and R9 together with the N atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure; R11 and R12 each independently represent hydrogen, alkyl, or a pharmaceutically acceptable salt, or R11 and R12 together with the OBO atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; m is zero or an integer ranging from 1 to 8; and n is an integer ranging from 1 to 8.

[0117] In one preferred embodiment, R1 is [ka] wherein R36 is a small hydrophobic group (e.g., lower alkyl or halogen) and R38 is hydrogen, or R36 and R37 together form a 4-7 membered heterocycle containing the N and Cα carbons, as defined above for A; and R40 represents a C-terminally linked amino acid residue or amino acid analog, or a C-terminally linked peptide or peptide analog, or an amino-protecting group. In a preferred embodiment, R36 is a lower alkyl (C1-C6) such as a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl group, and R38 and R40 are each hydrogen. In a preferred embodiment, R1 is a valine amino acid residue. In a preferred embodiment, R1 is a t-butylglycine residue.

[0118] In some embodiments, the immuno-DASH inhibitor is a peptide or peptidomimetic that contains a propyl group or analog thereof at the P1 specificity position and a nonpolar (and preferably hydrophobic) amino acid at the P2 specificity position, such as alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan, or methionine, or an analog thereof. In other embodiments, the P2 position is an amino acid with a charged side chain, such as arginine, lysine, aspartic acid, or glutamic acid. For example, the immuno-DASH inhibitor contains an Ala-Pro or Val-Pro dipeptide sequence or its equivalent, and can be represented by the following general chemical formula: [ka]

[0119] In preferred embodiments, ring A is a 5-, 6-, or 7-membered ring, for example, as represented by the formula: [ka]

[0120] In certain preferred embodiments, R32 is a small hydrophobic group (eg, lower alkyl or halogen).

[0121] In certain preferred embodiments, R32 is -lower alkyl-guanidine, -lower alkyl-amine, lower alkyl-C(O)OH, e.g., -(CH2) m -NH-C(=N)(NH2), -(CH2) m -NH2 or -(CH2) m -COOH (where m is 1 to 6, preferably 1 to 3), and the like.

[0122] In a preferred embodiment, R30 represents a C-terminally attached amino acid residue or amino acid analogue, or a C-terminally attached peptide or peptide analogue, or an amino protecting group.

[0123] In preferred embodiments, R2 is absent or represents a small hydrophobic group such as a lower alkyl or halogen.

[0124] In preferred embodiments, R3 is hydrogen or a small hydrophobic group such as a lower alkyl or halogen.

[0125] In certain embodiments, the immuno-DASH inhibitor of the present method is represented by Formula I or a pharmaceutical salt thereof: [ka] During the ceremony, Ring A represents a 3- to 10-membered ring structure; Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] represents; X is O or S; X 1 represents a halogen; Y 1 and Y 2 are independently OH, or represent a group that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached, or form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached; R 1 is absent or is selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, cyano, nitro, azide, sulfate, sulfonate, sulfonamide, -CF3, -(CH2) m -R 3 , -(CH2) m OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3, -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, or -(CH) n -S-(CH2) m -R 3 represents; R 2 is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3 represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n -O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R 5 represents O or S; R 6 is N3, SH, NH2, NO2 or OR 8 represents; R 7is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8 represents hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 9 and R 10 are each independently absent or represent one, two or three substituents on ring A or ring Z to which they are attached, and the substituents are each independently halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CH m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3.

[0126] In certain embodiments, the immuno-DASH inhibitor of Formula I is represented by Formula Ia or a pharmaceutical salt thereof: [ka] In the formula, X, W, Z, R 1 , R 2 , R 9 and R 10 is as defined above for formula I, and p is 1, 2, or 3.

[0127] In certain preferred embodiments of Formula Ia, R 1 is lower alkyl; R 9 is absent or, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10 represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0128] In certain embodiments, the immuno-DASH inhibitor of Formula I is represented by Formula Ib or a pharmaceutical salt thereof: [ka] In the formula, X, W, R 1 , R 2 , R 9 and R 10 is as defined above for formula I, and p is 1, 2, or 3.

[0129] In certain preferred embodiments of Formula Ib, R 1 is lower alkyl; R 9 is absent or, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0130] In certain embodiments, the immuno-DASH inhibitor of Formula I is represented by Formula Ic or a pharmaceutical salt thereof: [ka] In the formula, X, W, R 1 , R 2 , R 9 and R 10 is as defined above for formula I, and p is 1, 2, or 3.

[0131] In certain preferred embodiments of Formula Ic, R 1 is lower alkyl; R 9 is absent or, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10 represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0132] In some embodiments, the immuno-DASH inhibitor is [ka] It is expressed by:

[0133] Another aspect of the present invention relates to an immunoDASH inhibitor represented by Formula II or a pharmaceutical salt thereof: [ka] During the ceremony, Ring A is R 1a together represent a 7-12 membered polycyclic ring structure; Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] and; X is O or S; X 1 represents a halogen; Y is C or N; Y 1 and Y 2 independently, they are OH, or together with the boron atom to which they are attached, represent a group that can be hydrolyzed to a boronic acid, or together with the boron atom to which they are attached, form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid; R 1a is lower alkyl, -(CH2) m -, -(CH2) m -O-(CH2) m -;-(CH2) m -N-(CH2) m -; or -(CH2) m -S-(CH2) m - represents; R 2 is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3 represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n-O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R 5 represents O or S; R 6 is N3, SH, NH2, NO2 or OR 8 represents; R 7 is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8 represents hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 9 and R 10 are each independently absent or represent one, two or three substituents on ring A or ring Z to which they are attached, and the substituents are each independently halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CHm -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3; and p is 1, 2 or 3.

[0134] In certain embodiments, the immuno-DASH inhibitor of Formula II is represented by Formula IIa or a pharmaceutical salt thereof: [ka] In the formula, X, W, Z, R 2 , R 9 and R 10 is as defined above with respect to Formula II.

[0135] In certain preferred embodiments of Formula IIa, R 9 is, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10 represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0136] In certain embodiments, the immuno-DASH inhibitor of Formula II is represented by Formula IIb or a pharmaceutical salt thereof: [ka] In the formula, X, W, R 2 , R 9 and R 10 is as defined above with respect to Formula II.

[0137] In certain preferred embodiments of Formula IIb, R 9 is, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10 represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0138] In certain embodiments, the immuno-DASH inhibitor of Formula II is represented by Formula IIc or a pharmaceutical salt thereof: [ka] In the formula, X, W, R 2 , R 9 and R 10 is as defined above with respect to Formula II.

[0139] In certain preferred embodiments of Formula IIc, R 9 is, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10 represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0140] In certain embodiments, the immuno-DASH inhibitor of Formula II is represented by Formula IId or a pharmaceutical salt thereof: [ka] In the formula, X, W, R 2 , R 9 and R 10 is as defined above with respect to Formula II.

[0141] In certain preferred embodiments of Formula IId, R 9 is, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10 represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0142] In certain embodiments, the immuno-DASH inhibitor of Formula II is represented by Formula IIe or a pharmaceutical salt thereof: [ka] In the formula, X, W, Z, R 2 , R 9 and R 10 is as defined above with respect to Formula II.

[0143] In certain preferred embodiments of Formula IIe, R 9 is, independently at each occurrence, lower alkyl, —OH, —NH, —N, —(lower alkyl)-C(O)OH, —O-lower alkyl, —O-(lower alkyl)-C(O)OH, -guanidinyl; X is O; each R 2 is hydrogen; R 10represents absent or a single substitution by -OH, -NH2, -CN, or -N3; ​​Z is a pyrrolidine or piperidine ring (more preferably a pyrrolidine ring); and W is -B(OH)2 or -CN (more preferably -B(OH)2).

[0144] In some embodiments, the immuno-DASH inhibitor is one of the following: [ka]

[0145] Another aspect of the present invention relates to an immunoDASH inhibitor represented by Formula III or a pharmaceutical salt thereof: [ka] During the ceremony, Ring Z represents a 4- to 10-membered heterocycle containing N and Cα carbons; W is -CN, -CH=NR 4 , a functional group that reacts with the target active site residue, or [ka] represents; X is O or S; X 2 represents either absent, halogen or lower alkyl; Y 1 and Y 2 are independently OH, or represent a group that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached, or form a 5- to 8-membered ring that can be hydrolyzed to a boronic acid together with the boron atom to which they are attached; R 1 is independently selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamido, -CF3, -(CH2) m -R 3 , -(CH2) m OH, -(CH2)m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, or -(CH) n -S-(CH2) m -R 3 represents; R 2 is, at each occurrence, hydrogen, lower alkyl, lower alkynyl, -(CH2) m -R 3 , -C(=O)-alkyl, -C(=O)-alkenyl, -C(=O)-alkynyl, or -C(=O)-(CH2) m -R 3 represents; R 3 represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 4 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH2) m -R 3 , -(CH2) n -OH, -(CH2) n -O-lower alkyl, -(CH2) n -O-alkenyl, -(CH2) n -O-alkynyl, -(CH2) n -O-(CH2) m -R7, -(CH2) n -SH, -(CH2) n -S-lower alkyl, -(CH2) n -S-lower alkenyl, -(CH2) n -S-lower alkynyl, -(CH2) n -S-(CH2) m -R 3 , -C(O)C(O)NH2, or -C(O)C(O)OR 8 represents; R5 represents O or S; R 6 is N3, SH, NH2, NO2 or OR 8 represents; R 7 is hydrogen, lower alkyl, amine, OR 8 or a pharmaceutically acceptable salt thereof, or R 5 and R 6 together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R 8 represents hydrogen, substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 10 represents either no substituents or 1 to 3 substituents on the ring Z to which it is attached, each of which independently represents halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as carboxyl, ester, formate, or ketone), thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CH m -R7, -(CH2) m -OH, -(CH2) m -O-lower alkyl, -(CH2) m -O-lower alkenyl, -(CH2) n -O-(CH2) m -R 3 , -(CH2) m -SH, -(CH2) m -S-lower alkyl, -(CH2) m -S-lower alkenyl, -(CH2) n -S-(CH2) m -R 3 may be; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3.

[0146] In a preferred embodiment, X2 is F or Cl, more preferably F, R1 and R2 are each lower alkyl, more preferably a methyl group, Z is a 5-membered ring, R10 is absent, W is -B(OH)2, X is O, and each occurrence of R2 is hydrogen.

[0147] B. Representative PGE2 antagonists In one embodiment, the immuno-DASH inhibitor is administered in combination with a substance that inhibits PGE2 production. The PGE2 synthesis process involves phospholipase A2 (PLA2) family members, which mobilize arachidonic acid from the cell membrane, cyclooxygenase (constitutive COX1 and inducible COX2), which converts arachidonic acid to prostaglandin H2 (PGH2), and prostaglandin E synthase (PGES), which is required for the final formation of PGE2. Although the rate of PGE2 synthesis and the resulting inflammatory process can be affected by additional factors, such as the local availability of AA, in most physiological conditions, the rate of PGE2 synthesis is controlled by the local expression and activity of COX2.

[0148] In other embodiments, a subject immuno-DASH inhibitor is administered in combination with an agent that promotes PGE2 degradation. The rate of PGE2 degradation is controlled by 15-hydroxyprostaglandin dehydrogenase (15-PGDH), suggesting that the rate of PGE2 breakdown, in addition to the rate of PGE2 synthesis, also constitutes a target for therapeutic intervention in a subject immuno-DASH inhibitor combination.

[0149] In yet other embodiments, the subject immuno-DASH inhibitors are administered in combination with an agent that reduces PGE2 responsiveness. The four distinct PGE2 receptors are EP1, EP2, EP3, and EP4. sSignaling through the coupled receptors EP2 and EP4 is mediated by the adenylate cyclase-induced cAMP / PKA / CREB pathway and mediates the predominant anti-inflammatory and inhibitory activity of PGE2. While EP2 is thought to signal largely in a cAMP-dependent manner, EP4 also activates the PI3K-dependent ERK1 / 2 pathway. However, both EP2 and EP4 have been shown to activate the GSK3 / β-catenin pathway. As seen in patients with idiopathic pulmonary fibrosis, EP2 expression and the resulting response to PGE2 can be suppressed by hypermethylation. These findings raise the possibility that, in addition to regulating PGE2 production and its degradation, modulation of PGE2 responses at the expression level of individual PGE2 receptors may also contribute to the pathogenesis of human disease and be useful in its treatment. In support of this possibility, the use of synthetic inhibitors that preferentially affect EP2, EP3, or EP4 signaling allows for differential inhibition of different aspects of PGE2 activity.

[0150] Substances that reduce PGE2 responses also include prostaglandin (PG) signaling inhibitors. Prostaglandins signal through multiple receptors, and their key immunosuppressive effects are mediated by activation of adenylate cyclase, resulting in increased intracellular cyclic (c)AMP and PKA, and downstream activation of the PKA / CREB pathway.

[0151] Another level of interference with the PG response involves interfering with their binding to PG receptors. In the case of PGE2, the two key cAMP-activated receptors are EP2 and EP4, for which many specific inhibitors exist.

[0152] The increase in cAMP levels induced by prostaglandins or other factors can be blocked by phosphodiesterases (PDEs; there are six known types, PDE1-PDE5 and PDE10, which reduce intracellular cAMP levels. PDEs can be controlled by phosphodiesterase inhibitors, including xanthines (caffeine, aminophylline, IBMX, pentoxifylline, theobromine, theophylline, or paraxanthine), which all increase intracellular cAMP levels, as well as more selective synthetic and natural agents such as vinpocetine, cilostazol, inamrinone, cilostazol, mesembrine, rolipram, ibudilast, drotaverine, piclamilast, sildenafil, tadalafil, vardenafil, or papaverine.

[0153] Furthermore, interference with PGE2 signaling (or signaling of other factors that increase cAMP levels, such as histamine, β-adrenergic agonists) can be achieved by inhibiting downstream signals of cAMP, such as PKA or CREB.

[0154] Cyclooxygenase inhibitors In a preferred embodiment, the subject immuno-DASH inhibitor is administered in combination with one or more prostaglandin (PG) synthesis inhibitors. The inhibitors inhibit the synthesis of PGs in general or inhibit the synthesis of specific types of PGs. PG synthesis inhibitors include non-selective inhibitors of COX-1 and COX-2, two key enzymes in the PG synthesis pathway, as well as selective inhibitors of COX-2, which are thought to be more specific to COX-2 and less toxic. Examples of non-selective PG inhibitors include aspirin, indomethacin, or ibuprofen (Advil, Motrin). Examples of COX-2 selective inhibitors include celecoxib (Celebrex) and rofecoxib (Vioxx). An example of a COX-1 specific inhibitor is sulindac (Clinoril). Other drugs that inhibit prostaglandin synthesis include steroids (e.g., hydrocortisone, cortisol, prednisone, or dexamethasone) and acetaminophen (Tylenol, Panadol), which is commonly used as an anti-inflammatory, analgesic, and antipyretic. Examples of the most commonly used selective COX2 inhibitors include celecoxib, alecoxib, valdecoxib, and rofecoxib. In one embodiment, the PEG2 antagonist is not indomethacin.

[0155] Examples of the most commonly used non-selective COX1 and COX2 inhibitors include acetylsalicylic acid (aspirin) and other salicylates, acetaminophen (Tylenol), ibuprofen (Advil, Motrin, Nuprin, Rufen), naproxen (Naprosyn, Aleve), nabumetone (Relafen), or diclofenac (Cataflam).

[0156] A component of the present invention is a Cox-2 inhibitor. The terms "cyclooxygenase-2 inhibitor" or "Cox-2 inhibitor" may be used interchangeably herein and include compounds that inhibit the Cox-2 enzyme, regardless of the degree of inhibition of the Cox-1 enzyme, including pharmaceutically acceptable salts of such compounds. Thus, for purposes of the present invention, a compound that inhibits the Cox-2 enzyme is considered a Cox-2 inhibitor, regardless of whether the compound inhibits the Cox-2 enzyme to the same extent, a greater extent, or a lesser extent than the Cox-1 enzyme.

[0157] In one aspect of the present invention, the Cox-2 inhibitor compound is preferably a nonsteroidal anti-inflammatory drug (NSAID). Accordingly, preferred materials useful as Cox-2 inhibitors of the present invention include nonsteroidal anti-inflammatory compounds, their pharmaceutically acceptable salts, or their pure (-) or (+) optical isomers.

[0158] NDAID compounds useful in the present invention include acemetacin, acetylsalicylic acid, alcofenac, aluminoprofen, azapropazone, benorylate, benoxaprofen, bucloxic acid, carprofen, choline magnesium trisalicylate, clidanac, clopinac, dapsone, diclofenac, diflunisal, droxicam, etodolac, fenoprofen, fenbufen, fenclofenac, fentiazac, floctafenine, flufenisal, flurbiprofen, (r)-flubiprofen, (s)-flubiprofen, furofenac, feprazone, flufenamic acid, fluprofen, ibufenac, ibuprofen, indomethacin, isoxacin, and isoxacin. These include cepak, isoxicam, ketoprofen, miroprofen, piroxicam, meloxicam, mefenamic, mefenamic acid, meclofenamic acid, meclofen, nabumetone, naproxen, niflumic acid, oxaprozin, oxypinac, oxyphenbutazone, phenylbutazone, podophyllotoxin derivatives, proglumetacin, piprofen, pirprofen, pranoprofen, salicylic acid, salicylates, sudoxicam, suprofen, sulindac, tenoxicam, tiaprofenic acid, thiopinac, tioxaprofen, tolfenamic acid, tolmetin, zidometacin, zomepirac, and 4-(nitrooxy)butyl ester of 2-fluoro-α-methyl[1,1′-biphenyl]-4-acetic acid.

[0159] In a preferred embodiment, the Cox-2 inhibitor is a COX-2 selective inhibitor. The term "Cox-2 selective inhibitor" encompasses compounds that selectively inhibit the Cox-2 enzyme over the Cox-1 enzyme, including pharmaceutically acceptable salts and prodrugs of such compounds.

[0160] In practice, the selectivity of Cox-2 inhibitors varies depending on the conditions under which the test is performed and the inhibitor being tested. However, for purposes of this specification, the selectivity of a Cox-2 inhibitor is defined as the in vitro or in vivo IC of Cox-1 inhibition. 50 IC values ​​for Cox-2 inhibition 50Ratio divided by Cox-1 IC 50 / Cox-2 IC 50 Cox-2 selective inhibitors can be measured as Cox-1 IC 50 Cox-2 IC 50 is any inhibitor for which the ratio of β to β is greater than 1. In preferred embodiments, this ratio is greater than 2, more preferably greater than 5, even more preferably greater than 10, even more preferably greater than 50, and even more preferably greater than 100.

[0161] As used herein, the term "IC 50 " refers to the concentration of a compound required to produce a 50% inhibition of cyclooxygenase activity. Preferred Cox-2 selective inhibitors of the present invention have a Cox-2 IC of less than about 1 μM, more preferably less than about 0.5 μM, and even more preferably less than about 0.2 μM. 50 It has.

[0162] Preferred Cox-2 selective inhibitors have a Cox-1 IC of greater than about 1 μM, more preferably greater than 20 μM. 50 Such favorable selectivity may represent an ability to reduce the occurrence of common side effects caused by NSAIDs.

[0163] Compounds that act as prodrugs of Cox-2 selective inhibitors are also within the scope of the present invention. As used herein in connection with Cox-2 selective inhibitors, the term "prodrug" refers to a chemical compound that can be converted into an active Cox-2 selective inhibitor in a subject's body by metabolic or simple chemical processes. One example of a prodrug of a COX-2 selective inhibitor is parecoxib, which is a therapeutically effective prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib. A preferred example of a prodrug of a Cox-2 selective inhibitor is parecoxib sodium. One class of prodrugs of Cox-2 inhibitors is described in U.S. Patent No. 5,932,598 (incorporated by reference).

[0164] The Cox-2 selective inhibitor of the present invention may be, for example, the Cox-2 selective inhibitor meloxicam (CAS Registry Number 71125-38-7), or a pharmaceutically acceptable salt or prodrug thereof. [ka]

[0165] In another embodiment of the present invention, the Cox-2 selective inhibitor may be the Cox-2 selective inhibitor RS57067, i.e., 6-[[5-(4-chlorobenzoyl)-1,4-dimethyl-1H-pyrrol-2-yl]methyl]-3(2H)-pyridazinone (CAS Registry Number 179382-91-3), or a pharmaceutically acceptable salt or prodrug thereof. That's fine. [ka]

[0166] As used herein, the term "alkyl," alone or within other terms such as "haloalkyl" or "alkylsulfonyl," encompasses linear or branched radicals having from 1 to about 20 carbon atoms. Lower alkyl radicals have from 1 to about 10 carbon atoms. The number of carbon atoms may also be expressed as, for example, "C1-C5." Examples of lower alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hexyl, octyl, and the like.

[0167] The term "alkenyl" refers to a linear or branched unsaturated acyclic hydrocarbon radical, provided that it contains at least one double bond. The alkenyl radical may be optionally substituted with groups such as those described below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3-hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like.

[0168] The term "alkynyl" refers to a linear or branched unsaturated acyclic hydrocarbon radical, provided that it contains one or more triple bonds; such radicals preferably contain from 2 to about 6 carbon atoms, more preferably from 2 to about 3 carbon atoms. Alkynyl radicals may be optionally substituted with groups such as those described below. Examples of suitable alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyl-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl groups, and the like.

[0169] The term "oxo" refers to a single double-bonded oxygen.

[0170] The terms "hydride," "-H," or "hydrogen" refer to a single hydrogen atom (H). This hydride radical can be attached, for example, to an oxygen atom to form a hydroxyl radical, or two hydride radicals can be attached to a carbon atom to form a methylene (-CH-) radical.

[0171] The term "halo" refers to halogens such as fluorine, chlorine, bromine, or iodine atoms. The term "haloalkyl" encompasses radicals in which any one or more of the alkyl carbon atoms is substituted with a halo as defined above. Specifically, it encompasses monohaloalkyl, dihaloalkyl, and polyhaloalkyl radicals. A monohaloalkyl radical, for example, may have a bromo, chloro, or fluoro atom within the radical. A dihaloalkyl radical may have two or more of the same halo atom or a combination of different halo radicals, and a polyhaloalkyl radical may have more than two of the same halo atom or a combination of different halo radicals.

[0172] The term "hydroxyalkyl" embraces linear or branched alkyl radicals having from 1 to about 10 carbon atoms, any one of which may be substituted with one or more hydroxyl radicals.

[0173] The terms "alkoxy" and "alkoxyalkyl" include linear or branched oxy-containing radicals having alkyl portions of 1 to about 10 carbon atoms, respectively, such as a methoxy radical. The term "alkoxyalkyl" also includes alkyl radicals having two or more alkoxy radicals attached to the alkyl radical, i.e., forming monoalkoxyalkyl and dialkoxyalkyl radicals. An "alkoxy" or "alkoxyalkyl" radical may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to form a "haloalkoxy" or "haloalkoxyalkyl" radical. Examples of "alkoxy" radicals include methoxy, butoxy, and trifluoromethoxy.

[0174] The term "aryl," whether used alone or with other terms, refers to a carbocyclic aromatic system containing one, two, or three rings, which may be pendantly attached or fused together. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indane, biphenyl, and the like. The term "heterocyclyl" refers to a saturated or unsaturated monocyclic or polycyclic carbocyclic ring in which one or more carbon atoms are replaced by N, S, P, or O. This includes, for example, structures such as: [ka] In the formula, Z, Z 1 , Z 2 , or Z 3 is C, S, P, O, or N, except for Z, Z 1 , Z 2 , or Z 3is other than carbon, but if it is attached to another Z atom by a double bond or to another O or S atom, it is not O or S. Further, optional substituents include Z, Z 1 , Z 2 , or Z 3 It is understood that the heterocycle is attached to the ring only when it is C. The term "heterocycle" also includes fully saturated ring structures such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolizinyl, piperidinyl, thiazolidinyl, and the like.

[0175] The term "heteroaryl" encompasses unsaturated heterocyclic radicals. Examples of unsaturated heterocyclic radicals include thienyl, pyrryl, furyl, pyridyl, pyrimidinyl, pyrazinyl, pyrazolyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, pyranyl, and tetrazolyl. This term also encompasses radicals in which a heterocyclic radical is fused to an aryl radical. Examples of such fused bicyclic radicals include benzofuran, benzothiophene, and the like.

[0176] The term "sulfonyl," whether used alone or linked to other terms, such as alkylsulfonyl, refers to the divalent radical -SO2-. "Alkylsulfonyl" embraces alkyl radicals attached to a sulfonyl radical, where alkyl is defined above. The term "arylsulfonyl" embraces sulfonyl radicals substituted with an aryl radical. The term "aminosulfonyl" refers to a sulfonyl radical substituted with an amine radical to form a sulfonamide (-SO2-NH2).

[0177] The terms "carboxy" or "carboxyl," whether used alone or with other terms, such as "carboxyalkyl," refer to -CO2-H. The term "carboxyalkyl" encompasses radicals in which a carboxy radical, as defined above, is attached to an alkyl radical. The term "carbonyl," whether used alone or with other terms, such as "alkylcarbonyl," refers to -(C=O)-. The term "alkylcarbonyl" encompasses radicals in which a carbonyl radical is substituted with an alkyl radical. An example of an "alkylcarbonyl" radical is CH3-(CO)-. The term "alkoxycarbonyl" refers to a radical comprising an alkoxy radical, as defined above, attached to a carbonyl (C=O) radical through an oxygen atom. Examples of such "alkoxycarbonyl" radicals include (CH3)3-COC=O)- and (O=)C-OCH3. The term "amino," whether used alone or with other terms, such as "aminocarbonyl," refers to -NH2.

[0178] The term "heterocycloalkyl" embraces heterocycle-substituted alkyl radicals such as pyridylmethyl and thienylmethyl. The term "aralkyl" or "arylalkyl" embraces aryl-substituted alkyl radicals such as benzyl, diphenylmethyl, triphenylmethyl, phenylethyl, and diphenylethyl. The terms benzyl and phenylmethyl are interchangeable. The term "cycloalkyl" embraces radicals having 3 to 10 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. The term "cycloalkenyl" embraces unsaturated radicals having 3 to 10 carbon atoms such as cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, and cycloheptenyl.

[0179] The term "alkylthio" embraces radicals containing a linear or branched alkyl radical of 1 to 10 carbon atoms, attached to a divalent sulfur atom. An example of an "alkylthio" is methylthio (CH3-S-). The term "alkylsulfinyl" embraces radicals containing a linear or branched alkyl radical of 1 to 10 carbon atoms, attached to a divalent -S(-O)- atom. The term "acyl," whether used alone or within terms such as "acylamino," refers to the radical provided by the residue after removal of the hydroxyl from an organic acid.

[0180] The term "cyano," whether used alone or with other terms, such as "cyanoalkyl," refers to C≡N. The term "nitro" refers to -NO2.

[0181] In one embodiment of the present invention, the Cox-2 selective inhibitor is of the class of chromene / chroman structures, including substituted benzopyrans or substituted benzopyran analogs, as well as substituted benzothiopyrans, dihydroquinolines, or dihydronaphthalenes, as well as diastereomers, enantiomers, racemates, tautomers, salts, esters, amides, and prodrugs thereof, having a structure according to any one of the general formulas shown below:

[0182] Benzopyrans that may serve as Cox-2 selective inhibitors of the present invention include the substituted benzopyran derivatives described in U.S. Patent Nos. 6,271,253 and 6,492,390 (both of which are incorporated by reference). Compounds of this class are defined by the general formula shown below, or an isomer or pharmaceutically acceptable salt thereof: [ka] In the formula, X 1 are O, S, CR c R b and NR a Selected from; R ais selected from hydrido, C1-C3-alkyl, (optionally substituted phenyl)-C1-C3-alkyl, acyl, and carboxy-C1-C6-alkyl; R b and R c are each independently selected from hydrido, C1-C3-alkyl, phenyl-C1-C3-alkyl, C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6-alkoxy, nitro, cyano, and cyano-C1-C3-alkyl, or CR b R c forms a 3- to 6-membered cycloalkyl ring; R 1 is selected from carboxyl, aminocarbonyl, C1-C6-alkylsulfonylaminocarbonyl and C1-C6-alkoxycarbonyl; R 2 is selected from hydrido, phenyl, thienyl, C1-C6-alkyl, and C2-C6-alkenyl; R 3 is selected from C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6-alkoxy, nitro, cyano, and cyano-C1-C3-alkyl, R 4is hydrido, halo, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C2-C6-alkynyl, aryl-C1-C3-alkyl, aryl-C2-C6-alkynyl, aryl-C2-C6-alkenyl, C1-C6-alkoxy, methylenedioxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1-C6-alkoxy-C1-C6-alkyl , aryl-C1-C6-alkyloxy, heteroaryl-C1-C6-alkyloxy, aryl-C1-C6-alkoxy-C1-C6-alkyl, C1-C6-haloalkyl, C1-C6-haloalkoxy, C1-C6-haloalkylthio, C1-C6-haloalkylsulfinyl, C1-C6-haloalkylsulfonyl, C1-C3-(haloalkyl-1-C3-hydroxyalkyl, C1-C6-hydroxyalkyl, hydroxyimino-C1-C6-alkyl, C1-C6- one or more radicals independently selected from alkylamino, arylamino, aryl-C1-C6-alkylamino, heteroarylamino, heteroaryl-C1-C6-alkylamino, nitro, cyano, amino, aminosulfonyl, C1-C6-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C1-C6-alkylaminosulfonyl, heteroaryl-C1-C6-alkylaminosulfonyl, heterocyclylsulfonyl, C1-C6-alkylsulfonyl, aryl-C1-C6-alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C1-C6-alkylcarbonyl, heteroaryl-C1-C6-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C1-C1-alkoxycarbonyl, formyl, C1-C6-haloalkylcarbonyl and C1-C6-alkylcarbonyl; Ring atom A of A 1 , A 2 , A 3 , and A 4 are independently selected from carbon and nitrogen, with the proviso that A 1 , A2 , A 3 , and A 4 at least two of which are carbon; Or R 4 together with ring A form a radical selected from naphthyl, quinolyl, isoquinolyl, quinolidinyl, quinoxalinyl, and dibenzofuryl.

[0183] Another class of benzopyran derivatives that may serve as Cox-2 selective inhibitors of the present invention includes compounds having the following structure, or an isomer or pharmaceutically acceptable salt thereof: [ka] During the ceremony, X 2 are O, S, CR c R b , and NR a Selected from; R a is selected from hydrido, C1-C3-alkyl, (optionally substituted phenyl)-C1-C3-alkyl, alkylsulfonyl, phenylsulfonyl, benzylsulfonyl, acyl, and carboxy-C1-C6-alkyl; R b and R c are each independently selected from hydrido, C1-C3-alkyl, phenyl-C1-C3-alkyl, C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6-alkoxy, nitro, cyano, and cyano-C1-C3-alkyl, or CR c R b forms a cyclopropyl ring; R 5 is selected from carboxyl, aminocarbonyl, C1-C6-alkylsulfonylaminocarbonyl, and C1-C6-alkoxycarbonyl; R 6 is selected from hydrido, phenyl, thienyl, C2-C6-alkynyl, and C2-C6-alkenyl; R 7is selected from C1-C3-perfluoroalkyl, chloro, C1-C6-alkylthio, C1-C6-alkoxy, nitro, cyano, and cyano-C1-C3-alkyl; R 8 is hydrido, halo, C1-C6-alkyl, C2-C6-alkenyl, C2-C6-alkynyl, halo-C2-C6-alkynyl, aryl-C1-C3-alkyl, aryl-C2-C6-alkynyl, aryl-C2-C6-alkenyl, C1-C6-alkoxy, methylenedioxy, C1-C6-alkylthio, C1-C6-alkylsulfinyl, -O(CF2)2O-, aryloxy, arylthio, arylsulfinyl, heteroaryloxy, C1-C6-alkoxy-C1 ~C6-Alkyl, aryl-C1~C6-alkyloxy, heteroaryl-C1~C6-alkyloxy, aryl-C1~C6-alkoxy-C1~C6-alkyl, C1~C6-haloalkyl, C1~C6-haloalkoxy, C1~C6-haloalkylthio, C1~C6-haloalkylsulfinyl, C1~C6-haloalkylsulfonyl, C1~C3-(haloalkyl-C1~C3-hydroxyalkyl), C1~C6-hydroxyalkyl, hydroxyimino-C1~C6-alkyl , C1-C6-alkylamino, arylamino, aryl-C1-C6-alkylamino, heteroarylamino, heteroaryl-C1-C6-alkylamino, nitro, cyano, amino, aminosulfonyl, C1-C6-alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aryl-C1-C6-alkylaminosulfonyl, heteroaryl-C1-C6-alkylaminosulfonyl, heterocyclylsulfonyl, C1-C6-alkylsulfonyl, aryl-C1-C6-alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aryl-C1-C6-alkylcarbonyl, heteroaryl-C1-C6-alkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, C1-C6-alkoxycarbonyl, formyl, C1-C6-haloalkylcarbonyl and C1-C6-alkylcarbonyl; Ring atom D 1 , D 2 , D 3 , and D 4 are independently selected from carbon and nitrogen, with the proviso that D 1 , D 2 , D 3 , and D 4 at least two of are carbon, or R 8 together with ring D form a radical selected from naphthyl, quinolyl, isoquinolyl, quinolidinyl, quinoxalinyl, and dibenzofuryl.

[0184] Other benzopyran Cox-2 selective inhibitors useful in the practice of the present invention are described in U.S. Patent Nos. 6,034,256 and 6,077,850 (both of which are incorporated by reference). The general formula of these compounds is as follows: or an isomer or pharmaceutically acceptable salt thereof, including diastereomers, enantiomers, racemates, tautomers, salts, esters, amides, and prodrugs thereof: [ka] In the formula, X 3 is O or S or NR a selected from the group consisting of: R a is alkyl; R 9 is selected from the group consisting of H and aryl; R 10 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl, and alkoxycarbonyl; R 11 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl, which may be optionally substituted with one or more radicals selected from alkylthio, nitro, and alkylsulfonyl; R 12is selected from the group consisting of one or more radicals selected from H, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, hydroxyarylcarbonyl, nitroaryl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or R 12 forms a naphthyl radical together with ring E.

[0185] A related class of compounds useful in the present invention as Cox-2 selective inhibitors is represented by the following structure, or an isomer or pharmaceutically acceptable salt thereof: [ka] During the ceremony, X 4 is O or S or NR a Selected from; R a is alkyl; R 13 is selected from carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl, and alkoxycarbonyl; R 14 is selected from haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl, which may optionally be substituted with one or more radicals selected from alkylthio, nitro, and alkylsulfonyl; R 15is one or more radicals selected from hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; Or R 15 forms a naphthyl radical together with ring G.

[0186] Another related class of compounds useful in the present invention as Cox-2 selective inhibitors is represented by the structure below, or an isomer or pharmaceutically acceptable salt thereof: [ka] During the ceremony, X 5 is O or S or NR b selected from the group consisting of: R b is alkyl, R 16 is selected from the group consisting of carboxyl, aminocarbonyl, alkylsulfonylaminocarbonyl, and alkoxycarbonyl; R 17 is selected from the group consisting of haloalkyl, alkyl, aralkyl, cycloalkyl, and aryl, each of which is optionally substituted independently with one or more radicals selected from the group consisting of alkylthio, nitro, and alkylsulfonyl; R 18is one or more radicals selected from the group consisting of hydrido, halo, alkyl, aralkyl, alkoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroaralkyloxy, haloalkyl, haloalkoxy, alkylamino, arylamino, aralkylamino, heteroarylamino, heteroarylalkylamino, nitro, amino, aminosulfonyl, alkylaminosulfonyl, arylaminosulfonyl, heteroarylaminosulfonyl, aralkylaminosulfonyl, heteroaralkylaminosulfonyl, heterocyclosulfonyl, alkylsulfonyl, optionally substituted aryl, optionally substituted heteroaryl, aralkylcarbonyl, heteroarylcarbonyl, arylcarbonyl, aminocarbonyl, and alkylcarbonyl; or R 18 forms a naphthyl radical together with ring A.

[0187] Cox-2 selective inhibitors are compounds of the above formula: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl, and lower alkoxycarbonyl; R 17 is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; R 18is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, t-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, t-butyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl, and phenyl; or R 2 may be a compound, or an isomer or a pharmaceutically acceptable salt thereof, in which:

[0188] Cox-2 selective inhibitors are compounds of the above formula: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is carboxyl, R 17 is lower haloalkyl; R 18 is one or more radicals selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkyl, lower haloalkoxy, lower alkylamino, amino, aminosulfonyl, lower alkylaminosulfonyl, 5-membered heteroarylalkylaminosulfonyl, 6-membered heteroarylalkylaminosulfonyl, lower aralkylaminosulfonyl, lower alkylsulfonyl, 6-membered nitrogen-containing heterocyclosulfonyl, optionally substituted phenyl, lower aralkylcarbonyl, and lower alkylcarbonyl; or R 18may be a compound, or an isomer or a pharmaceutically acceptable salt thereof, in which:

[0189] Cox-2 selective inhibitors are compounds of the above formula: X 5 is selected from the group consisting of oxygen and sulfur; R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl, and lower alkoxycarbonyl; R 17 is selected from the group consisting of fluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluoroethyl, difluoropropyl, dichloroethyl, dichloropropyl, difluoromethyl, and trifluoromethyl; R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, butyl, isobutyl, pentyl, hexyl, methoxy, ethoxy, isopropyloxy, tert-butyloxy, trifluoromethyl, difluoromethyl, trifluoromethoxy, amino, N,N-dimethylamino, N,N-diethylamino, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, nitro, N,N-dimethylaminosulfonyl, aminosulfonyl, N-methylaminosulfonyl, N-ethylsulfonyl, 2,2-dimethylethylaminosulfonyl, N,N-dimethylaminosulfonyl, N-(2-methylpropyl)aminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, 2,2-dimethylpropylcarbonyl, phenylacetyl, and phenyl; or R 2 may be a compound, or an isomer or a pharmaceutically acceptable salt thereof, in which:

[0190] Cox-2 selective inhibitors are compounds of the above formula: X 5is selected from the group consisting of oxygen and sulfur; R 16 is selected from the group consisting of carboxyl, lower alkyl, lower aralkyl, and lower alkoxycarbonyl; R 17 is selected from the group consisting of trifluoromethyl and pentafluoroethyl; R 18 is one or more radicals selected from the group consisting of hydrido, chloro, fluoro, bromo, iodo, methyl, ethyl, isopropyl, tert-butyl, methoxy, trifluoromethyl, trifluoromethoxy, N-phenylmethylaminosulfonyl, N-phenylethylaminosulfonyl, N-(2-furylmethyl)aminosulfonyl, N,N-dimethylaminosulfonyl, N-methylaminosulfonyl, N-(2,2-dimethylethyl)aminosulfonyl, dimethylaminosulfonyl, 2-methylpropylaminosulfonyl, N-morpholinosulfonyl, methylsulfonyl, benzylcarbonyl, and phenyl; or R 15 may be a compound, or an isomer or prodrug thereof, in which:

[0191] The Cox-2 selective inhibitor of the present invention may be a compound having the following structure, or an isomer or prodrug thereof: [ka] During the ceremony, X 6 is selected from the group consisting of O and S; R 19 is a lower haloalkyl; R 20 is selected from the group consisting of hydrido and halo; R 21is selected from the group consisting of hydrido, halo, lower alkyl, lower haloalkoxy, lower alkoxy, lower aralkylcarbonyl, lower dialkylaminosulfonyl, lower alkylaminosulfonyl, lower aralkylaminosulfonyl, lower heteroaralkylaminosulfonyl, 5-membered nitrogen-containing heterocyclosulfonyl, and 6-membered nitrogen-containing heterocyclosulfonyl; R 22 is selected from the group consisting of hydrido, lower alkyl, halo, lower alkoxy, and aryl; R 23 is selected from the group consisting of hydrido, halo, lower alkyl, lower alkoxy, and aryl.

[0192] Cox-2 selective inhibitors are compounds having the structure of the above formula: X 6 is selected from the group consisting of O and S; R 19 is selected from the group consisting of trifluoromethyl and pentafluoroethyl; R 20 is selected from the group consisting of hydrido, chloro, and fluoro; R 21 is selected from the group consisting of hydrido, chloro, bromo, fluoro, iodo, methyl, tert-butyl, trifluoromethoxy, methoxy, benzylcarbonyl, dimethylaminosulfonyl, isopropylaminosulfonyl, methylaminosulfonyl, benzylaminosulfonyl, phenylethylaminosulfonyl, methylpropylaminosulfonyl, methylsulfonyl, and morpholinosulfonyl; R 22 is selected from the group consisting of hydrido, methyl, ethyl, isopropyl, tert-butyl, chloro, methoxy, diethylamino, and phenyl; R 23 is selected from the group consisting of hydrido, chloro, bromo, fluoro, methyl, ethyl, tert-butyl, methoxy, and phenyl, or an isomer or prodrug thereof.

[0193] Examples include: [ka] [ka] [ka] [ka] [ka]

[0194] In a preferred embodiment, the chromene Cox-2 inhibitor is selected from (S)-6-chloro-7-(1,1-dimethylethyl)-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, (2S)-6,8-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-6-chloro-8-methyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (2S)-8-ethyl-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, (S)-6,8-dichloro-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylic acid, (2S)-6-chloro-5,7-dimethyl-2-(trifluoromethyl)-2H-chromene-3-carboxylic acid, and mixtures thereof.

[0195] In a preferred embodiment of the present invention, the Cox-2 inhibitor may be selected from the class of tricyclic Cox-2 selective inhibitors represented by the following general structure or a prodrug thereof: [ka] During the ceremony, Z 1 is selected from the group consisting of partially unsaturated or unsaturated heterocyclyl and partially unsaturated or unsaturated carbocyclic ring; R 24is selected from the group consisting of heterocyclyl, cycloalkyl, cycloalkenyl, and aryl; R 24 is optionally substituted, in substitutable positions, with one or more radicals selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; R 25 is selected from the group consisting of methyl or amino; R 26 is H, halo, alkyl, alkenyl, alkynyl, oxo, cyano, carboxyl, cyanoalkyl, heterocyclyloxy, alkyloxy, alkylthio, alkylcarbonyl, cycloalkyl, aryl, haloalkyl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, acyl, alkylthioalkyl, hydroxyalkyl, alkoxycarbonyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, aralkoxyalkyl, alkoxyaralkoxyalkyl, alkoxycarbonylalkyl, aminocarbonyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkoxy and alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, carboxyalkyl, alkylamino, N-arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, N-alkyl-N-arylaminosulfonyl.

[0196] In a preferred embodiment of the present invention, the Cox-2 selective inhibitor represented by the above formula is selected from the group of compounds including celecoxib (B-21), valdecoxib (B-22), deracoxib (B-23), rofecoxib (B-24), etoricoxib (MK-663, B-25), JTE-522 (B-26), or a prodrug thereof.

[0197] Additional information about select examples of Cox-2 selective inhibitors discussed above can be found as follows: celecoxib (CAS Registry Numbers 169590-42-5, C-2779, SC-58653, and U.S. Pat. No. 5,466,823), deracoxib (CAS Registry Number 169590-41-4), rofecoxib (CAS Registry Number 162011-90-7), Compound B-24 (U.S. Pat. No. 5,840,924), Compound B-26 (WO 00 / 25779), and etoricoxib (CAS Registry Numbers 202409-33-4, MK-663, SC-86218, and WO 98 / 03484, all of which are incorporated by reference). Structural formula [ka]

[0198] In a more preferred embodiment of the present invention, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, rofecoxib, and etoricoxib.

[0199] In a preferred embodiment, parecoxib (see U.S. Pat. No. 5,932,598, incorporated by reference), which has the structure shown as B-27 and is a therapeutically active prodrug of the tricyclic Cox-2 selective inhibitor valdecoxib, i.e., B-22 (see U.S. Pat. No. 5,633,272, incorporated by reference), can be advantageously used as the Cox-2 inhibitor of the present invention. [ka]

[0200] The preferred form of parecoxib is parecoxib sodium.

[0201] Another tricyclic Cox-2 selective inhibitor useful in the present invention is the compound ABT-963, having formula B-28 shown below, which is described in WO 00 / 24719 (incorporated by reference). [ka]

[0202] In another embodiment of the present invention, the Cox-2 inhibitor may be selected from the class of phenylacetic acid derivative Cox-2 selective inhibitors represented by the following general structure: [ka] During the ceremony, R 27 is methyl, ethyl, or propyl; R 28 is chloro or fluoro, R 29 is hydrogen, fluoro, or methyl; R 30 is hydrogen, fluoro, chloro, methyl, ethyl, methoxy, ethoxy, or hydroxyl; R 31 is hydrogen, fluoro, or methyl; R 32 is chloro, fluoro, trifluoromethyl, methyl, or ethyl; However, R 28 , R 29 , R 30 , and R 31 is R 27 is ethyl and R 30 If is H, then they will not all be fluoro.

[0203] Exemplary phenylacetic acid derivative Cox-2 selective inhibitors described in WO 99 / 11605 include: R27 is ethyl, R 28 and R 30 is chloro, R 29 and R 31 is hydrogen, R 32 is methyl, It is a compound having the structure shown in the above formula.

[0204] Another phenylacetic acid derivative Cox-2 selective inhibitor is R 27 is propyl, R 28 and R 30 is chloro, R 29 and R 31 is methyl, R 32 is ethyl, It is a compound having the structure shown in the above formula.

[0205] Another phenylacetic acid derivative Cox-2 selective inhibitor disclosed in WO 02 / 20090 is R 27 is methyl, R 28 is fluoro, R 32 is chloro, R 29 , R 30 , and R 31 is hydrogen, The compound is called COX-189 (also known as lumiracoxib, CAS Registry Number 220991-20-8), which has the structure shown in the formula above.

[0206] Compounds having a structure similar to that shown in the above formula that may serve as Cox-2 selective inhibitors of the present invention are described in U.S. Pat. Nos. 6,451,858, 6,310,099, 6,291,523, and 5,958,978 (all of which are incorporated by reference).

[0207] Other Cox-2 selective inhibitors that can be used in the present invention have the general structure shown below, where the J group is a carbocyclic or heterocyclic ring. A preferred embodiment has the structure: [ka] During the ceremony, X 7 is O, J is 1-phenyl, and R 33 is 2-NHSO2CH3, and R 34 is 4-NO2, and R 35 The group is null (nimesulide), or X 7 is O, J is 1-oxo-inden-5-yl, and R 33 is 2-F and R 34 is 4-F and R 35 is 6-NHSO2CH3 (flosulide), or X 7 is O, J is cyclohexyl, and R 33 is 2-NHSO2CH3, and R 34 is 5-NO2, and R 35 The group is absent (NS-398), or X 7 is S, J is 1-oxo-inden-5-yl, and R 33 is 2-F and R 34 is 4-F and R 35 is 6-N - SO2CH3.Na + (L-745337), or X 7 is S, J is thiophen-2-yl, and R 33 is 4-F and R 34 The group is none, R 35 is 5-NHSO2CH3 (RWJ-63556), or X 7 is O, J is 2-oxo-5(R)-methyl-5-(2,2,2-trifluoroethyl)furan-(5H)-3-yl, and R 33 is 3-F and R 34 is 4-F and R 35is 4-(p-SO2CH3)C6H4 (L-784512).

[0208] The Cox-2 selective inhibitor NS-398 is also known as N-(2-cyclohexyloxynitrophenyl)methanesulfonamide (CAS Registry Number 123653-11-2), having the structure shown in Formula B-29 below, and is described, for example, in Yoshimi, N. et al., in Japanese J. Cancer Res., 90(4):406-412 (1999). [ka]

[0209] Evaluation of the anti-inflammatory activity of the Cox-2 selective inhibitor RWJ63556 in a canine inflammation model is described in J Pharmacol Exp Ther 282, 1094-1101 (1997).

[0210] Materials that may serve as Cox-2 selective inhibitors of the present invention include diarylmethylidene furan derivatives described in U.S. Patent No. 6,180,651 (incorporated by reference). Such diarylmethylidene furan derivatives have the general formula shown below, or are isomers or prodrugs thereof: [ka] During the ceremony, rings T and M are independently a phenyl radical, a naphthyl radical, a radical derived from a heterocyclic ring containing 5 to 6 members and having 1 to 4 heteroatoms, or a radical derived from a saturated hydrocarbon ring having 3 to 7 carbon atoms; Substituent Q 1 , Q 2 , L 1 or L 2 At least one of the following is -S(O) nan -R group (where n is an integer equal to 0, 1, or 2, and R is a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms), or a SO2NH2 group, and is located in the para position, and the others are each independently a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a trifluoromethyl radical, or a lower O-alkyl radical having 1 to 6 carbon atoms; or Q 1 and Q 2 or L 1 and L 2 is a methylenedioxy group, R 36 , R 37 , R 38 , and R 39 are independently a hydrogen atom, a halogen atom, a lower alkyl radical having 1 to 6 carbon atoms, a lower haloalkyl radical having 1 to 6 carbon atoms, or an aromatic radical selected from the group consisting of phenyl, naphthyl, thienyl, furyl, and pyridyl; R 36 , R 37 , or R 38 , R 39 is an oxygen atom, or R 36 , R 37 , or R 38 , R 39 together with the carbon atoms to which they are bonded form a saturated hydrocarbon ring having 3 to 7 carbon atoms.

[0211] Specific diarylmethylidenefuran derivatives that may serve as Cox-2 selective inhibitors of the present invention include, for example, N-(2-cyclohexyloxynitrophenyl)methanesulfonamide and (E)-4-[(4-methylphenyl)(tetrahydro-2-oxo-3-furanylidene)methyl]benzenesulfonamide.

[0212] Other Cox-2 selective inhibitors useful in the present invention include dalbuferone (Pfizer), CS-502 (Sankyo), LAS34475 (Almirall Profesfarma), LAS34555 (Almirall Profesfarma), S-33516 (Servier), SD8381 (Pharmacia, described in U.S. Pat. No. 6,034,256), BMS-347070 (Bristol Myers Squibb, described in U.S. Pat. No. 6,180,651), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama Chemical Co., Ltd.), D-1367 (Chiroscience), L-748731 (Merck), CT3 (Atlantic Pharmaceutical), CGP-28238 (Novartis), BF-389 (Biofor / Scherer), GR-253035 (Glaxo Wellcome), 6-dioxo-9H-purin-8-yl-cinnamic acid (Glaxo Wellcome), and S-2474 (Shionogi).

[0213] Compounds that may function as Cox-2 selective inhibitors of the present invention include multimeric compounds containing 2 to 10 ligands covalently attached to one or more linkers, such as those described in U.S. Pat. No. 6,395,724 (incorporated by reference).

[0214] Conjugated linoleic acids, as described in US Pat. No. 6,077,868 (incorporated by reference), are useful in the present invention as selective inhibitors of Cox-2.

[0215] Compounds that may be useful as Cox-2 selective inhibitors in the present invention include the heteroaromatic oxazole compounds described in U.S. Patent Nos. 5,994,381 and 6,362,209 (both of which are incorporated by reference). Such heteroaromatic oxazole compounds have the formula shown below, and pharmaceutically acceptable salts thereof: [ka] During the ceremony, Z 2 is an oxygen atom, R 40 and R 41 One of the expressions [ka] is the basis of During the ceremony, R 43 is lower alkyl, amino, or lower alkylamino; R 44 , R 45 , R 46 , and R 47 are the same or different and each is a hydrogen atom, a halogen atom, a lower alkyl, a lower alkoxy, a trifluoromethyl, a hydroxyl, or an amino, provided that R 44 , R 45 , R 46 , and R 47 at least one of is not a hydrogen atom, and the others are optionally substituted cycloalkyl, optionally substituted heterocyclic group, or optionally substituted aryl; R 30 is lower alkyl or halogenated lower alkyl.

[0216] Cox-2 selective inhibitors useful in the methods and compositions of the present invention include compounds described in U.S. Pat. Nos. 6,080,876 and 6,133,292 (both of which are incorporated by reference) and represented by the following formula: [ka] During the ceremony, Z 3 is selected from the group consisting of linear or branched C1-C6 alkyl, linear or branched C1-C6 alkoxy, unsubstituted, mono-, di-, or tri-substituted phenyl or naphthyl, wherein the substituents are selected from the group consisting of hydrogen, halo, C1-C3 alkoxy, CN, C1-C3 fluoroalkyl, C1-C3 alkyl, and CO2H; R 48is selected from the group consisting of NH2 and CH3; R 49 is selected from the group consisting of C1-C6 alkyl unsubstituted or substituted with C3-C6 cycloalkyl, and C3-C6 cycloalkyl; R 50 is selected from the group consisting of C1-C6 alkyl unsubstituted or substituted with 1, 2, or 3 fluoro atoms, and C3-C6 cycloalkyl; However, R 49 and R 50 are not the same.

[0217] Pyridines described in U.S. Pat. Nos. 6,596,736, 6,369,275, 6,127,545, 6,130,334, 6,204,387, 6,071,936, 6,001,843, and 6,040,450 (all incorporated by reference) and which may serve as Cox-2 selective inhibitors of the present invention have the general formula shown below: [ka] During the ceremony, R 51 is selected from the group consisting of CH3, NH2, NHC(O)CF3, and NHCH3; Z 4 is a mono-, di-, or tri-substituted phenyl or pyridinyl (or an N-oxide thereof), and the substituents are hydrogen, halo, C1-C6 alkoxy, C1-C6 alkylthio, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, N3, -CO2R 53 , hydroxyl, -C(R 54 )(R 55 )-OH, -C1~C6 alkyl-CO2-R 56 , C1-C6 fluoroalkoxy; R 52 is halo, C1-C6 alkoxy, C1-C6 alkylthio, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, N3, -CO2R 57 , hydroxyl, -C(R 58 )(R59 )-OH, -C1~C6 alkyl-CO2-R 60 , C1-C6 fluoroalkoxy, NO2, NR 61 R 62 , and NHCOR 63 selected from the group consisting of R 53 , R 54 , R 55 , R 56 , R 57 , R 58 , R 59 , R 60 , R 61 , R 62 , and R 63 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; Or, R 54 and R 55 , R 58 and R 59 , or R 61 and R 62 together with the atoms to which they are attached form a saturated monocyclic ring of 3, 4, 5, 6, or 7 atoms.

[0218] Materials that may serve as Cox-2 selective inhibitors of the present invention include diarylbenzopyran derivatives described in U.S. Patent No. 6,340,694 (incorporated by reference). Such diarylbenzopyran derivatives have the following general formula: [ka] During the ceremony, X 8 is an oxygen atom or a sulfur atom, R that is the same or different from each other 64 and R 65 are independently a hydrogen atom, a halogen atom, a C1 to C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a nitro group, a nitrile group, or a carboxyl group, R 66 is the formula S(O) n R 68 wherein n is an integer of 0 to 2, and R 68is a hydrogen atom, a C1-C6 lower alkyl group, or a group of the formula NR 69 R 70 wherein R 69 and R 70 are each independently a hydrogen atom or a C1-C6 lower alkyl group, R 67 is oxazolyl, benzo[b]thienyl, furanyl, thienyl, naphthyl, thiazolyl, indolyl, pyrrolyl, benzofuranyl, pyrazolyl, C1-C6 lower alkyl substituted pyrazolyl, indanyl, pyrazinyl, or the following structure: [ka] is a substituted group represented by In the formula, R 71 From R 75 are independently a hydrogen atom, a halogen atom, a C1-C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a hydroxyalkyl group, a nitro group, a group of the formula S(O) n R 68 A group of formula NR 69 R 70 a group, a trifluoromethoxy group, a nitrile group, a carboxyl group, an acetyl group, or a formyl group, where n, R 68 , R 69 , and R 70 is the above R 66 has the same meaning as defined for R 76 is a hydrogen atom, a halogen atom, a C1 to C6 lower alkyl group, a trifluoromethyl group, an alkoxy group, a hydroxyl group, a trifluoromethoxy group, a carboxyl group, or an acetyl group.

[0219] Materials that may serve as Cox-2 selective inhibitors of the present invention include the 1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines described in U.S. Patent No. 6,376,519 (incorporated by reference). Such 1-(4-sulfamylaryl)-3-substituted-5-aryl-2-pyrazolines have the following formula: [ka] During the ceremony, X 9 is C1-C6 trihalomethyl (preferably trifluoromethyl); C1-C6 alkyl; and optionally substituted or disubstituted phenyl groups of the formula: [ka] [In the formula, R 77 and R 78 are independently selected from the group consisting of hydrogen, halogen, preferably chlorine, fluorine, and bromine; hydroxyl; nitro; C1-C6 alkyl, preferably C1-C3 alkyl; C1-C6 alkoxy, preferably C1-C3 alkoxy; carboxy; C1-C6 trihaloalkyl, preferably trihalomethyl, most preferably trifluoromethyl; and cyano. selected from the group consisting of Z 5 is selected from the group consisting of substituted and unsubstituted aryl.

[0220] Compounds useful as Cox-2 selective inhibitors of the present invention include heterocycles described in U.S. Patent No. 6,153,787 (incorporated by reference). Such heterocycles have the following general formula: [ka] During the ceremony, R 79 is a mono-, di-, or tri-substituted C1-C 12 Alkyl, unsubstituted or mono-, di-, or tri-substituted, linear or branched, C2-C 10 Alkenyl, unsubstituted or mono-, di-, or tri-substituted, linear or branched, C2-C 10 Alkynyl, unsubstituted or mono-, di-, or tri-substituted C3-C 12 Cycloalkenyl or unsubstituted or mono-, di-, or tri-substituted C5-C 12cycloalkynyl, wherein the substituents are selected from the group consisting of halo selected from F, Cl, Br, and I, OH, CF, C-C cycloalkyl, ═O, dioxolane, and CN; R 80 is selected from the group consisting of CH3, NH2, NHC(O)CF3, and NHCH3; R 81 and R 82 is hydrogen and C1 to C 10 alkyl, or R 81 and R 82 together with the carbon to which they are attached form a saturated monocyclic carbocyclic ring of 3, 4, 5, 6, or 7 atoms.

[0221] Another example is the following structure: [ka] In the formula, X 10 is fluoro or chloro.

[0222] Materials that may serve as Cox-2 selective inhibitors of the present invention include the 2,3,5-trisubstituted pyridines described in U.S. Patent No. 6,046,217 (incorporated by reference). Such pyridines have the general formula: [ka] During the ceremony, X 11 is selected from the group consisting of O, S, and a bond; n is 0 or 1, R 83 is selected from the group consisting of CH3, NH2, and NHC(O)CF3; R 84 is halo, C1-C6 alkoxy, C1-C6 alkylthio, CN, C1-C6 alkyl, C1-C6 fluoroalkyl, N3, -CO2R 92 , hydroxyl, -C(R 93 )(R 94)-OH, -C1~C6 alkyl-CO2-R 95 , C1-C6 fluoroalkoxy, NO2, NR 96 R 97 , and NHCOR 98 selected from the group consisting of R 85 ~R 89 are independently selected from the group consisting of hydrogen and C1-C6 alkyl; Or, R 85 and R 89 , or R 89 and R 90 together with the atoms to which they are bonded form a carbon ring of 3, 4, 5, 6, or 7 atoms, or R 85 and R 87 are bonded together.

[0223] Compounds useful as Cox-2 selective inhibitors of the present invention include diaryl bicyclic heterocycles described in U.S. Patent No. 6,329,421 (incorporated by reference). Such diaryl bicyclic heterocycles have the following general formula: [ka] During the ceremony, -A 5 =A 6 -A 7 =A 8 -teeth, (a) -CH=CH-CH=CH-, (b)-CH2-CH2-CH2-C(O)-, -CH2-CH2-C(O)-CH2-, -CH2-C(O)-CH2-CH2, -C(O)-CH2-CH2-CH2, (c)-CH2-CH2-C(O)-, -CH2-C(O)-CH2-, -C(O)-CH2-CH2 (d)-CH2-CH2-OC(O)-, CH2-OC(O)-CH2-, -OC(O)-CH2-CH2-, (e)-CH2-CH2-C(O)-O-, -CH2-C(O)-OCH2-, -C(O)-O-CH2-CH2-, (f)-C(R 105 )2-OC(O)-, -C(O)-OC(R 105 )2-, -OC(O)-C(R 105 )2-, -C(R 105 )2-C(O)-O-, (g) -N=CH-CH=CH-, (h) -CH=N-CH=CH-, (i) -CH=CH-N=CH-, (j) -CH=CH-CH=N-, (k) -N=CH-CH=N-, (l) -N=CH-N=CH-, (m) -CH=N-CH=N-, (n)-S-CH=N-, (o)-SN=CH-, (p)-N=N-NH-, (q) -CH=NS-, and (r)-N=CH-S- selected from the group consisting of: R 99 is selected from the group consisting of S(O)2CH3, S(O)2NH2, S(O)2NHCOCF3, S(O)(NH)CH3, S(O)(NH)NH2, S(O)(NH)NHCOCF3, P(O)(CH3)OH, and P(O)(CH3)NH2; R 100 teeth, (a) C1-C6 alkyl, (b) C3-C7 cycloalkyl, (c) mono- or di-substituted phenyl or naphthyl, wherein the substituents are: (1) Hydrogen, (2) Halo (including F, CI, Br, and I), (3) C1-C6 alkoxy, (4) C1-C6 alkylthio, (5)CN, (6) CF3, (7) C1-C6 alkyl, (8) N3, (9)-CO2H, (10) -CO2-C1-C4 alkyl, (11)-C(R 103 )(R 104 )-OH, (12)-C(R 103 )(R 104 )—O—C1-C4 alkyl, and (13)-C1-C6 alkyl-CO2-R 106 selected from the group consisting of: (d) mono- or di-substituted heteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom that is S, O, or N, and optionally having 1, 2, or 3 additional N atoms; or mono- or di-substituted heteroaryl, wherein the heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom that is N, and optionally having 1, 2, 3, or 4 additional N atoms; wherein the substituents are (1) Hydrogen, (2) halo, including fluoro, chloro, bromo, and iodo; (3) C1-C6 alkyl, (4) C1-C6 alkoxy, (5) C1-C6 alkylthio, (6)CN, (7) CF3, (8) N3, (9)-C(R 103 )(R 104 )-OH, and (10)-C(R 103 )(R 104 )-O-C1~C4 alkyl selected from the group consisting of: (e) Benzoheteroaryl, including benzo-fused analogues of (d) selected from the group consisting of: R 101 and R 102 -A 5 =A 6 -A 7 =A 8 - is a substituent at any position of (a) hydrogen, (b) CF3, (c)CN, (d) C1-C6 alkyl, (e)-Q 3 (Q 3 Q 4 , CO2H, C(R 103 )(R 104 )OH), (f)-OQ 4 , (g)-SQ 4 , and (h) optionally substituted, the substituents being on the alkyl chain, the substituents being C1-C3 alkyl, and Q 3 Q 4 , CO2H, C(R 103 )(R 104 )OH and Q 4 is CO2-C1-C4 alkyl, tetrazolyl-5-yl, or C(R 103 )(R 104 )O—C1-C4 alkyl; (1)-C1-C5 alkyl-Q 3 , (2) -O-C1-C5 alkyl-Q 3 , (3)-S-C1-C5 alkyl-Q 3 , (4)-C1-C3 alkyl-OC 1~3 Alkyl-Q 3 , (5)-C1-C3 alkyl-SC 1~3 Alkyl-Q 3 , (6)-C1-C5 alkyl-OQ 4 , (7)-C1-C5 alkyl-SQ 4 , independently selected from the group consisting of: R 103 , R 104 , and R 105 are each independently selected from the group consisting of hydrogen and C1-C6 alkyl; or R 103 and R 104 together with the carbon to which they are attached form a saturated monocyclic carbocyclic ring of 3, 4, 5, 6, or 7 atoms, or two R on the same carbon105 the groups form a saturated monocyclic carbocyclic ring of 3, 4, 5, 6, or 7 atoms; R 106 is hydrogen or C1-C6 alkyl; R 107 is hydrogen, C1-C6 alkyl, or aryl; X 7 are O, S, NR 107 , CO, C(R 107 )2, C(R 107 )(OH), -C(R 107 )=C(R 107 )-, -C(R 107 )=N-, or N=C(R 107 )-.

[0224] Compounds that may act as selective inhibitors of Cox-2 include salts of 5-amino or substituted amino 1,2,3-triazole compounds described in U.S. Patent No. 6,239,137 (incorporated by reference), which are of the class of compounds of the formula: [ka] During the ceremony, R 108 teeth, [ka] and p is 0 to 2, m is 0 to 4, and n is 0 to 5; X 13 is O, S, SO, SO2, CO, CHCN, CH2, or C=NR 113 (where R 113 is hydrogen, lower alkyl, hydroxyl, lower alkoxy, amino, lower alkylamino, di-lower alkylamino, or cyano; R 111 and R 112are independently halogen, cyano, trifluoromethyl, lower alkanoyl, nitro, lower alkyl, lower alkoxy, carboxy, lower carboalkoxy, trifluoromethoxy, acetamido, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, trichlorovinyl, trifluoromethylthio, trifluoromethylsulfinyl, or trifluoromethylsulfonyl; R 109 is amino, mono- or di-lower alkylamino, acetamido, acetimido, ureido, formamido, or guanidino, R 110 is carbamoyl, cyano, carbazoyl, amidino, or N-hydroxycarbamoyl; Here, lower alkyl, including lower alkyl, lower alkoxy and lower alkanoyl groups contain 1 to 3 carbon atoms.

[0225] Pyrazole derivatives, such as those described in U.S. Patent No. 6,136,831 (incorporated by reference), may serve as Cox-2 selective inhibitors in the present invention. Such pyrazole derivatives have the formula: [ka] During the ceremony, R 114 is hydrogen or halogen, R 115 and R 116 are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxyl, or lower alkanoyloxy; R 117 is lower haloalkyl or lower alkyl, X 14 is sulfur, oxygen, or NH; Z 6 is lower alkylthio, lower alkylsulfonyl, or sulfamoyl.

[0226] Materials that may serve as Cox-2 selective inhibitors of the present invention include substituted derivatives of benzosulfonamides described in U.S. Patent No. 6,297,282 (incorporated by reference). Such benzosulfonamide derivatives have the formula: [ka] During the ceremony, X 15 represents oxygen, sulfur, or NH; R 118 is an optionally unsaturated alkyl or alkyloxyalkyl group, optionally mono-, poly- or mixedly substituted by halogen, alkoxy, oxo or cyano; or a cycloalkyl, aryl or heteroaryl group, optionally mono-, poly- or mixedly substituted by halogen, alkyl, CF3, cyano or alkoxy, R 119 and R 120 are, independently of each other, hydrogen; an optionally polyfluorinated alkyl group; an aralkyl, aryl or heteroaryl group; or a group (CH) n -X 16 represents, or R 119 and R 120 is a 3- to 7-membered heterocyclic ring having, together with the N atom, one or more heteroatoms N, O, or S, which may be saturated, partially unsaturated, or fully unsaturated, optionally containing an oxo, alkyl, alkylaryl, or aryl group, or a group (CH) n -X 16 which may be substituted with X 16 is halogen, NO2, -OR 121 , -COR 121 , -CO2R 121 , -OCO2R 121 , -CN, -CONR 121 OR 122 , -CONR 121 R 122 , -SR121 , -S(O)R 121 , -S(O)2R 121 , -NR 121 R 122 , -NHC(O)R 121 , -NHS(O)2R 121 represents n represents an integer of 0 to 6, R 123 represents a linear or branched alkyl, cycloalkyl, alkylcarboxyl, aryl, aralkyl, heteroaryl or heteroaralkyl group having 1 to 10 C atoms, which may optionally be mono-, poly- or mixedly substituted by halogen or alkoxy, R 124 is a halogen; hydroxyl; a linear or branched alkyl, alkoxy, acyloxy or alkyloxycarbonyl group having 1 to 6 carbon atoms, which may optionally be a halogen, NO2, -OR 121 , -COR 121 , -CO2R 121 , -OCO2R 121 , -CN, -CONR 121 OR 122 , -CONR 121 R 122 , -SR 121 , -S(O)R 121 , -S(O)2R 121 , -NR 121 R 122 , -NHC(O)R 121 , -NHS(O)2R 121 or a polyfluoroalkyl group, R 121 and R 122 represent, independently of each other, hydrogen, alkyl, aralkyl, or aryl; m represents an integer of 0 to 2.

[0227] Compounds useful as Cox-2 selective inhibitors of the present invention include the phenyl heterocycles described in U.S. Patent Nos. 5,474,995 and 6,239,173 (both of which are incorporated by reference). Such phenyl heterocycle compounds have the formula: [ka] During the ceremony, When the b side is a double bond and the a and c sides are single bonds, X 17 -Y 1 -Z 7 -teeth, (a) -CH2CH2CH2-, (b) -C(O)CH2CH2-, (c) -CH2CH2C(O)-, (d)-CR 129 (R 129’ )-OC(O)-, (e)-C(O)-O-CR 129 (R 129’ )-, (f)-CH2-NR 127 -CH2-, (g)-CR 129 (R 129’ )-NR 127 -C(O)-, (h)-CR 128 =CR 128’ -S- (i)-S-CR 128 =CR 128’ -, (j) -SN=CH-, (k) -CH=NS-, (l)-N=CR 128 -O-, (m)-O-CR 128 =N-, (n)-N=CR 128 -NH-, (o)-N=CR 128 -S-, and (p)-S-CR 128 =N-, (q)-C(O)-NR 127 -CR129 (R 129’ )-, (r)R 122 -R under the condition that is not -S(O)2CH3 127 N-CH=CH-, (s)R 125 -CH=CH-NR provided that is not -S(O)2CH3 127 - selected from the group consisting of When the a and c sides are double bonds and the b side is a single bond, X 17 -Y 1 -Z 7 -teeth, (a) =CH-O-CH=, and (b) = CH-NR 127 -CH=, (c)=NS-CH=, (d)=CH-SN=, (e)=NO-CH=, (f)=CH-ON=, (g)=NSN=, (h)=NON= selected from the group consisting of: R 125 teeth, (a)S(O)2CH3, (b) S(O)2NH2, (c) S(O)2NHC(O)CF3, (d) S(O)(NH)CH3, (e) S(O)(NH)NH2, (f) S(O)(NH)NHC(O)CF3, (g) P(O)(CH3)OH, and (h)P(O)(CH3)NH2; selected from the group consisting of: R 126 teeth, (a) C1-C6 alkyl, (b) C3, C4, C5, C6, and C7 cycloalkyl; (c) mono-, di-, or tri-substituted phenyl or naphthyl, where the substituents are: (1) Hydrogen, (2) Halo, (3) C1-C6 alkoxy, (4) C1-C6 alkylthio, (5)CN, (6) CF3, (7) C1-C6 alkyl, (8) N3, (9)-CO2H, (10) -CO2-C1-C4 alkyl, (11)-C(R 129 )(R 130 )-OH, (12)-C(R 129 )(R 130 )—O—C1-C4 alkyl, and (13)-C1-C6 alkyl-CO2-R 129 selected from the group consisting of: (d) mono-, di-, or tri-substituted heteroaryl, wherein the heteroaryl is a monocyclic aromatic ring of 5 atoms, said ring having one heteroatom that is S, O, or N, and optionally having 1, 2, or 3 additional N atoms; or mono-, di-, or tri-substituted heteroaryl, wherein the heteroaryl is a monocyclic ring of 6 atoms, said ring having one heteroatom that is N, and optionally having 1, 2, 3, or 4 additional N atoms; wherein the substituents are (1) Hydrogen, (2) halo, including fluoro, chloro, bromo, and iodo; (3) C1-C6 alkyl, (4) C1-C6 alkoxy, (5) C1-C6 alkylthio, (6)CN, (7) CF3, (8) N3, (9)-C(R 129 )(R 130 )-OH, and (10)-C(R 129 )(R 130 )-O-C1~C4 alkyl selected from the group consisting of: (e) Benzoheteroaryl, including benzo-fused analogues of (d) selected from the group consisting of: R 127 teeth, (a) hydrogen, (b) CF3, (c)CN, (d) C1-C6 alkyl, (e) hydroxyl C1-C6 alkyl, (f) —C(O)—C1-C6 alkyl, (g) optionally substituted, wherein the substituent is on the alkyl and the substituent is C1-C3 alkyl; (1)-C1-C5 alkyl-Q 5 , (2) -C1-C5 alkyl-O-C1-C3 alkyl-Q 5 , (3) -C1-C3 alkyl-S-C1-C3 alkyl-Q 5 , (4)-C1-C5 alkyl-OQ 5 , or (5)-C1-C5 alkyl-SQ 5 , (h)-Q 5 selected from the group consisting of: R 128 and R 128’ teeth, (a) hydrogen, (b) CF3, (c)CN, (d) C1-C6 alkyl, (e)-Q 5 , (f)-OQ 5 ; (g)-SQ 5 , and (h) optionally substituted, wherein the substituent is on the alkyl and the substituent is C1-C3 alkyl; (1)-C1-C5 alkyl-Q 5 , (2) -O-C1-C5 alkyl-Q 5 , (3)-S-C1-C5 alkyl-Q 5 , (4) -C1-C3 alkyl-O-C1-C3 alkyl-Q 5 , (5) -C1-C3 alkyl-S-C1-C3 alkyl-Q 5 , (6)-C1-C5 alkyl-OQ 5 , (7)-C1-C5 alkyl-SQ 5 each independently selected from the group consisting of: R 129 , R 129’ , R 130 , R 131 , and R 132 teeth, (a) hydrogen, (b) C1-C6 alkyl each independently selected from the group consisting of: Or, R 129 and R 130 , or R 131 and R 132 together with the carbon to which they are attached form a saturated monocyclic carbocyclic ring of 3, 4, 5, 6, or 7 atoms; Q 5 is CO2H, CO2-C1-C4 alkyl, tetrazolyl-5-yl, C(R 131 )(R 132 )(OH), or C(R 131 )(R 132 )(O-C1-C4 alkyl); However, XYZ is -S-CR 128 =CR 128’ When R 128 and R 128’ is anything other than CF3.

[0228] An exemplary phenyl heterocycle disclosed in US Pat. No. 6,239,173 is 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(2H)-furanone.

[0229] Bicyclic carbonylindole compounds, such as those described in U.S. Patent No. 6,303,628 (incorporated by reference), are useful as Cox-2 selective inhibitors of the present invention. Such bicyclic carbonylindole compounds have the formula: [ka] During the ceremony, A 9 is C1-C6 alkylene or -NR 133 - and Z 8 is C(=L 3 )R 134 , or SO2R 135 and Z 9 is CH or N, Z 10 and Y 2 is -CH2-, O, S, and NR 133 are independently selected from m is 1, 2, or 3; q and r are independently 0, 1, or 2; X 18 are independently selected from halogen, C1-C4 alkyl, halo-substituted C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, C1-C4 alkylthio, nitro, amino, mono- or di(C1-C4 alkyl)amino, and cyano; n is 0, 1, 2, 3, or 4; L 3 is oxygen or sulfur, R 133 is hydrogen or C1-C4 alkyl, R 134 is hydroxyl, C1-C6 alkyl, halo-substituted C1-C6 alkyl, C1-C6 alkoxy, halo-substituted C1-C6 alkoxy, C3-C7 cycloalkoxy, C1-C4 alkyl (C3-C7 cycloalkoxy), -NR 136 R 137, C1-C4 alkylphenyl-O-, or phenyl-O-, wherein the phenyl is optionally substituted with 1 to 5 substituents independently selected from halogen, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, and nitro; R 135 is C1-C6 alkyl or halo-substituted C1-C6 alkyl, R 136 and R 137 is hydrogen, C 1~6 alkyl, and halo-substituted C1-C6 alkyl.

[0230] Materials that may serve as Cox-2 selective inhibitors of the present invention include the benzimidazole compounds described in U.S. Patent No. 6,310,079 (incorporated by reference). Such benzimidazole compounds have the following formula: [ka] During the ceremony, A 10 is a heteroaryl selected from a 5-membered monocyclic aromatic ring having one heteroatom selected from O, S, and N, and optionally containing 1 to 3 N atoms in addition to the heteroatom; or a 6-membered monocyclic aromatic ring having one N atom and optionally containing 1 to 4 N atoms in addition to the N atom; wherein the heteroaryl is bonded to the nitrogen atom of the benzimidazole via a carbon atom of the heteroaryl ring, X 20is halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [N-(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1-C4 alkanoyl)amino, N-(C1-C4 alkyl)(C1-C4 alkanoyl)amino, N-[(C1-C4 alkyl)s [(halo-substituted C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [N-(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [N-(C1-C4 alkyl)amino]sulfonyl, and [N,N-di(C1-C4 alkyl)amino]sulfonyl; X 21is halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxyl-substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [N-(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1-C4 alkanoyl)amino, N-(C1-C4 alkyl)-N-(C1-C4 alkanoyl)amino, N-[(C1-C4 alkyl)sulfonyl ]amino, N-[(halo-substituted C1-C4 alkyl)sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)hydroxy, carbamoyl, [N-(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [N-(C1-C4 alkyl)amino]sulfonyl, and [N,N-di(C1-C4 alkyl)amino]sulfonyl; R 138is hydrogen; straight-chain or branched C1-C4 alkyl [optionally substituted with 1 to 3 substituents independently selected from halo, hydroxyl, C1-C4 alkoxy, amino, N—(C1-C4 alkyl)amino, and N,N-di(C1-C4 alkyl)amino]; C3-C8 cycloalkyl [optionally substituted with 1 to 3 substituents independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino, N—(C1-C4 alkyl)amino, and N,N-di(C1-C4 C4-C8 cycloalkenyl [optionally substituted with 1 to 3 substituents independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, and N,N-di(C1-C4 alkyl)amino]; phenyl [optionally substituted with 1 to 3 substituents independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkyl, hydroxyl, Substituted C1-C4 alkyl, (C1-C4 alkoxy)C1-C4 alkyl, halo-substituted C1-C4 alkoxy, amino, N-(C1-C4 alkyl)amino, N,N-di(C1-C4 alkyl)amino, [N-(C1-C4 alkyl)amino]C1-C4 alkyl, [N,N-di(C1-C4 alkyl)amino]C1-C4 alkyl, N-(C1-C4 alkanoyl)amino, N-[C1-C4 alkyl)(C1-C4 alkanoyl)]amino, N-[(C1-C4 alkyl)sulfonyl]amino, N-[(halo-substituted C1-C4 alkyl) sulfonyl]amino, C1-C4 alkanoyl, carboxy, (C1-C4 alkoxy)carbonyl, carbamoyl, [N-(C1-C4 alkyl)amino]carbonyl, [N,N-di(C1-C4 alkyl)amino]carbonyl, cyano, nitro, mercapto, (C1-C4 alkyl)thio, (C1-C4 alkyl)sulfinyl, (C1-C4 alkyl)sulfonyl, aminosulfonyl, [N-(C1-C4 alkyl)amino]sulfonyl, and [N,N-di(C1-C4 alkyl)amino]sulfonyl];and heteroaryl selected from a 5-membered monocyclic aromatic ring having one heteroatom selected from O, S, and N, and optionally containing 1 to 3 N atoms in addition to the heteroatom, or a 6-membered monocyclic aromatic ring having one N atom, and optionally containing 1 to 4 N atoms in addition to the N atom, [which are optionally selected from X; 20 and optionally substituted with 1 to 3 substituents selected from R 139 and R 140 are independently selected from hydrogen; halo; C1-C4 alkyl; and phenyl, optionally substituted with 1 to 3 substituents independently selected from halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, amino, N—(C1-C4 alkyl)amino, and N,N-di(C1-C4 alkyl)amino; Or R 138 and R 139 can form a C3-C7 cycloalkyl ring together with the carbon atoms to which they are attached, m is 0, 1, 2, 3, 4, or 5; n is 0, 1, 2, 3, or 4.

[0231] Compounds that can be used as Cox-2 selective inhibitors of the present invention include the indole compounds described in U.S. Patent No. 6,300,363 (incorporated by reference). Such indole compounds have the following formula: and pharmaceutically acceptable salts thereof: [ka] During the ceremony, L 4 is oxygen or sulfur, Y 3 is a direct bond or a C1-C4 alkylidene, Q 6 teeth, (a) C1-C6 alkyl or halo-substituted C1-C6 alkyl, wherein the alkyl is optionally substituted with up to three substituents independently selected from hydroxyl, C1-C4 alkoxy, amino, and mono- or di(C1-C4 alkyl)amino; (b) C3-C7 cycloalkyl [optionally substituted with up to three substituents independently selected from hydroxyl, C1-C4 alkyl, and C1-C4 alkoxy]; (c) phenyl or naphthyl [optionally (c-1) Halo, C1-C4 alkyl, halo-substituted C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, S(O) m R 143 , SO2NH2, SO2N(C1-C4 alkyl)2, amino, mono- or di(C1-C4 alkyl)amino, NHSO2R 143 , NHC(O)R 143 , CN, CO2H, CO2(C1-C4 alkyl), C1-C4 alkyl-OH, C1-C4 alkyl-OR 143 , CONH2, CONH(C1-C4 alkyl), CON(C1-C4 alkyl)2, and -OY-phenyl (phenyl is optionally substituted with halo, C1-C4 alkyl, CF3, hydroxyl, OR 143 , S(O) m R 143 , amino, mono- or di(C1-C4 alkyl)amino, and CN) and optionally substituted with up to four substituents independently selected from (d) a five-atom monocyclic aromatic group having one heteroatom selected from O, S, and N, and optionally containing up to three N atoms in addition to the heteroatom; (d-1) Halo, C1-C4 alkyl, halo-substituted C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, C1-C4 alkyl-OH, S(O) m R 143, SO2NH2, SO2N(C1-C4 alkyl)2, amino, mono- or di(C1-C4 alkyl)amino, NHSO2R 143 , NHC(O)R 143 , CN, CO2H, CO2(C1-C4 alkyl), C1-C4 alkyl-OR 143 , CONH2, CONH(C1-C4 alkyl), CON(C1-C4 alkyl)2, phenyl, and mono-, di-, or tri-substituted phenyl (substituents may be halo, CF3, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, OCF3, SR 143 , SO2CH3, SO2NH2, Amino, C 1~4 Alkylamino and NHSOR 143 (independently selected from and optionally substituted with up to three substituents independently selected from (e) A 6-atom monocyclic aromatic group having one heteroatom that is N, and optionally containing up to three atoms in addition to the heteroatom, substituted with up to three substituents independently selected from group (d-1) above. and R 141 is hydrogen, or C1-C6 alkyl [optionally hydroxyl, OR 143 , nitro, amino, mono- or di(C1-C4 alkyl)amino, CO2H, CO2(C1-C4 alkyl), CONH2, CONH(C1-C4 alkyl), and CON(C1-C4 alkyl)2; R 142 teeth, (a) hydrogen, (b) C1-C4 alkyl, (c)C(O)R 145 and R 145 teeth, (c-1) C1~C 22 Alkyl or C2-C 22 alkenyl [optionally, (c-1-1) Halo, Hydroxyl, OR 143 , S(O) m R143 , nitro, amino, mono- or di(C1-C4 alkyl)amino, NHS02R 143 , CO2H, CO2(C1-C4 alkyl), CONH2, CONH(C1-C4 alkyl), CON(C1-C4 alkyl)2, OC(O)R 143 , thienyl, naphthyl, and groups of the formula [ka] and optionally substituted with up to four substituents independently selected from (c-2) C1~C 22 Alkyl or C2-C 22 alkenyl [optionally substituted with 5 to 45 halogen atoms], (c-3)-Y 5 -C3-C7 cycloalkyl or Y 5 -C3-C7 cycloalkenyl [optionally, (c-3-1) C1-C4 alkyl, hydroxyl, OR 143 , S(O) m R 143 , amino, mono- or di(C1-C4 alkyl)amino, CONH2, CONH(C1-C4 alkyl), and CON(C1-C4 alkyl)2 and optionally substituted with up to three substituents independently selected from (c-4) phenyl or naphthyl [optionally, (c-4-1) Halo, C1-C8 alkyl, C1-C4 alkyl-OH, hydroxyl, C1-C8 alkoxy, halo-substituted C1-C8 alkyl, halo-substituted C1-C8 alkoxy, CN, nitro, S(O) m R 143 , SO2NH2, SO2NH(C1-C4 alkyl), SO2N(C1-C4 alkyl)2, amino, C1-C4 alkylamino, di(C1-C4 alkyl)amino, CONH2, CONH(C1-C4 alkyl), CON(C1-C4 alkyl)2, OC(O)R 143and phenyl, wherein phenyl is optionally substituted with up to three substituents independently selected from halo, C1-C4 alkyl, hydroxyl, OCH3, CF3, OCF3, CN, nitro, amino, mono- or di(C1-C4 alkyl)amino, CO2H, CO2(C1-C4 alkyl), and CONH2. and optionally substituted with up to seven (preferably up to seven) substituents independently selected from (c-5) monocyclic aromatic groups as defined above in (d) and (e) [optionally (c-5-1) Halo, C1-C8 alkyl, C1-C4 alkyl-OH, hydroxyl, C1-C8 alkoxy, CF3, OCF3, CN, nitro, S(O) m R 143 , amino, mono- or di(C1-C4 alkyl)amino, CONH2, CONH(C1-C4 alkyl), CON(C1-C4 alkyl)2, CO2H and CO2(C1-C4 alkyl), and -Y-phenyl (phenyl is halogen, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, CF3, OCF3, CN, nitro, S(O) m R 143 , amino, mono- or di(C1-C4 alkyl)amino, CO2H, CO2(C1-C4 alkyl), CONH2, CONH(C1-C4 alkyl), and CON(C1-C4 alkyl)2). and optionally substituted with up to three substituents independently selected from (c-6) The group of the following formula [ka] is selected from X 22 is halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, halo-substituted C1-C4 alkoxy, S(O) m R 143 , amino, mono- or di(C1-C4 alkyl)amino, NHSO2R 143, nitro, halo-substituted C1-C4 alkyl, CN, CO2H, CO2(C1-C4 alkyl), C1-C4 alkyl-OH, C1-C4 alkyl OR 143 , CONH2, CONH(C1-C4 alkyl), or CON(C1-C4 alkyl)2; R 143 is C1-C4 alkyl or halo-substituted C1-C4 alkyl, m is 0, 1, or 2; n is 0, 1, 2, or 3; p is 1, 2, 3, 4, or 5; and q is 2 or 3; Z 11 is oxygen, sulfur, or NR 144 and R 144 is hydrogen, C1-C6 alkyl, halo-substituted C1-C4 alkyl, or -Y 5 -phenyl, wherein phenyl is optionally halo, C1-C4 alkyl, hydroxyl, C1-C4 alkoxy, S(O) m R 143 , optionally substituted with up to two substituents independently selected from amino, mono- or di(C1-C4 alkyl)amino, CF3, OCF3, CN, and nitro; However, the formula -Y 5 The -Q group is X 22 is hydrogen, L 4 is oxygen, R 141 is hydrogen, R 142 When is acetyl, it is not methyl or ethyl.

[0232] The arylphenylhydrazides described in U.S. Patent No. 6,077,869 (incorporated by reference) may serve as Cox-2 selective inhibitors of the present invention. Such arylphenylhydrazides have the following formula: [ka] During the ceremony, X 23 and Y6 is selected from hydrogen, halogen, alkyl, nitro, amino, hydroxy, methoxy, and methylsulfonyl.

[0233] Materials that may serve as Cox-2 selective inhibitors of the present invention include the 2-aryloxy, 4-arylfuran-2-ones described in U.S. Patent No. 6,140,515 (incorporated by reference). Such 2-aryloxy, 4-arylfuran-2-ones have the following formula: or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R 146 is selected from the group consisting of SCH3, —S(O)2CH3, and S(O)2NH2; R 147 is OR 150 , mono- or di-substituted phenyl or pyridyl, the substituents being selected from the group consisting of methyl, chloro, and F; R 150 is unsubstituted, mono- or disubstituted phenyl or pyridyl, the substituents being selected from the group consisting of methyl, chloro, and F; R 148 is H or C1-C4 alkyl optionally substituted with 1-3 groups of F, Cl, or Br; R 149 is H or C1-C4 alkyl optionally substituted with 1-3 groups of F, Cl, or Br, with the proviso that R 148 and R 149 are not the same thing.

[0234] Materials that may serve as Cox-2 selective inhibitors of the present invention include the bisaryl compounds described in U.S. Patent No. 5,994,379 (incorporated by reference). Such bisaryl compounds have the following formula: or a pharmaceutically acceptable salt, ester, or tautomer thereof: [ka] In the formula, Z 13 is C or N, Z 13 When N, R 151 represents H or is absent, or R as described below 152 Together with Z 13 When C, R 151 represents H, and R 152 is a part having the following characteristics: (a) a linear chain of 3-4 atoms containing 0-2 double bonds and capable of adopting an energetically stable trans configuration, where the double bonds, if present, are in a trans configuration; (b) is lipophilic except for the atom directly attached to ring A, which may be lipophilic or non-lipophilic; and (c) There is an energetically stable configuration that is planar with ring A within a range of approximately 15 degrees. Or R 151 and R 152 are combined to represent a 5- or 6-membered aromatic or non-aromatic ring D fused to ring A, said ring D containing 0 to 3 heteroatoms selected from O, S, and N; ring D is lipophilic except for the atom directly bonded to ring A, which may be lipophilic or non-lipophilic, and ring D is available in an energetically stable configuration that is planar with ring A within about 15 degrees; The ring D may further comprise one or more 1R selected from the group consisting of C1-C2 alkyl, —OC1-C2 alkyl, —NHC1-C2 alkyl, —N(C1-C2 alkyl)2, —C(O)C1-C2 alkyl, —S—C1-C2 alkyl, and C(S)C1-C2 alkyl. a is substituted with a group, Y 7 represents N, CH, or C—O—C alkyl; Z 13 When is N, Y 7 may represent a carbonyl group, R 153 represents H, Br, Cl, or F, R 154represents H or CH3.

[0235] Compounds useful as Cox-2 selective inhibitors of the present invention include the 1,5-diarylpyrazoles described in U.S. Patent No. 6,028,202 (incorporated by reference). Such 1,5-diarylpyrazoles have the following formula and pharmaceutically acceptable salts thereof: [ka] During the ceremony, R 155 , R 156 , R 157 , and R 158 are independently selected from the group consisting of hydrogen, C1-C5 alkyl, C1-C5 alkoxy, phenyl, halo, hydroxyl, C1-C5 alkylsulfonyl, C1-C5 alkylthio, trihaloC1-C5 alkyl, amino, nitro, and 2-quinolinylmethoxy; R 159 is hydrogen, C1-C5 alkyl, trihaloC1-C5 alkyl, phenyl, substituted phenyl wherein the phenyl substituent is halogen, C1-C5 alkoxy, trihaloC1-C5 alkyl, or nitro; or R 159 is a 5- to 7-membered heteroaryl ring in which at least one ring member is nitrogen, sulfur, or oxygen; R 160 is hydrogen, C1-C5 alkyl, phenyl C1-C5 alkyl, substituted phenyl C1-C5 alkyl, wherein the phenyl substituent is halogen, C1-C5 alkoxy, trihalo C1-C5 alkyl, or nitro; or R 160 is C1-C5 alkoxycarbonyl, phenoxycarbonyl, substituted phenoxycarbonyl, wherein the phenyl substituent is halogen, C1-C5 alkoxy, trihaloC1-C5 alkyl, or nitro; R 161 is C1~C 10 Alkyl, substituted C1-C 10alkyl, wherein the substituents are halogen, trihaloC1-C5 alkyl, C1-C5 alkoxy, carboxy, C1-C5 alkoxycarbonyl, amino, C1-C5 alkylamino, diC1-C5 alkylamino, diC1-C5 alkylaminoC1-C5 alkylamino, C1-C5 alkylaminoC1-C5 alkylamino, or a heterocycle containing 4 to 8 ring atoms (optionally substituted with C1-C5 alkyl) in which one or more of the ring atoms is nitrogen, oxygen, or sulfur; or R 161 is phenyl, substituted phenyl, where the phenyl substituents are one or more of C1-C5 alkyl, halogen, C1-C5 alkoxy, trihaloC1-C5 alkyl, or nitro; or R 161 is a heteroaryl having 5 to 7 ring atoms in which one or more atoms are nitrogen, oxygen, or sulfur, a fused heteroaryl in which one or more 5- to 7-membered aromatic rings are fused to the heteroaryl, or R 161 is NR 163 R 164 and R 163 and R 164 is hydrogen and C 1~5 alkyl, or R 163 and R 164 may be taken together with the depicted nitrogen to form a 5-7 membered heteroaryl ring, optionally substituted with C1-C5 alkyl, in which one or more of the ring members is nitrogen, sulfur, or oxygen; R 162 is hydrogen, C1-C5 alkyl, nitro, amino, and halogen.

[0236] Materials that may serve as Cox-2 selective inhibitors of the present invention include the 2-substituted imidazoles described in U.S. Patent No. 6,040,320 (incorporated by reference). Such 2-substituted imidazoles have the following formula, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R164 is phenyl, heteroaryl containing 5 to 6 ring atoms, or substituted phenyl [substituents are C 1~5 independently selected from one or more members of the group consisting of alkyl, halogen, nitro, trifluoromethyl, and nitrile; R 165 is phenyl, heteroaryl containing 5 to 6 ring atoms, substituted heteroaryl, wherein the substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl and halogen, or substituted phenyl, wherein the substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, halogen, nitro, trifluoromethyl, and nitrile; R 166 is hydrogen, 2-(trimethylsilyl)ethoxymethyl), C1-C5 alkoxycarbonyl, aryloxycarbonyl, aryl C1-C5 alkyloxycarbonyl, aryl C1-C5 alkyl, phthalimido C1-C5 alkyl, amino C1-C5 alkyl, diamino C1-C5 alkyl, succinimido C1-C5 alkyl, C1-C5 alkylcarbonyl, arylcarbonyl, C1-C5 alkylcarbonyl C1-C5 alkyl, aryloxycarbonyl C1-C5 alkyl, heteroaryl C1-C5 alkyl wherein the heteroaryl contains 5 or 6 ring atoms, or substituted aryl C1-C5 alkyl, wherein the aryl substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, C1-C5 alkoxy, halogen, amino, C1-C5 alkylamino, and diC1-C5 alkylamino; R 167 is (A 11 ) n -(CH 165 ) q -X 24 and A 11 is sulfur or carbonyl, n is 0 or 1, q is 0 to 9, X 24is hydrogen, hydroxyl, halogen, vinyl, ethynyl, C1-C5 alkyl, C3-C7 cycloalkyl, C1-C5 alkoxy, phenoxy, phenyl, aryl C1-C5 alkyl, amino, C1-C5 alkylamino, nitrile, phthalimide, amido, phenylcarbonyl, C1-C5 alkylaminocarbonyl, phenylaminocarbonyl, aryl C1-C5 alkylaminocarbonyl, C1-C5 alkylthio, C1-C5 alkylsulfonyl, phenylsulfonyl, substituted sulfonamides, wherein the sulfonyl substituents are selected from the group consisting of C1-C5 alkyl, phenyl, arC1-C5 alkyl, thienyl, furanyl, and naphthyl; substituted vinyls, wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine, chlorine, and iodine; substituted ethynyl, wherein the substituents are independently selected from one or more members of the group consisting of fluorine, bromine, chlorine, and iodine; substituted C1-C5 alkyl, wherein the substituents are selected from the group consisting of one or more of C1-C5 alkoxy, trihaloalkyl, phthalimido, and amino; substituted phenyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, halogen, and C1-C5 alkoxy; substituted phenoxy, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, halogen, and C1-C5 alkoxy; substituted C1-C5 alkoxy, wherein the alkyl substituent is selected from the group consisting of phthalimido and amino; substituted aryl C1-C5 alkyl [wherein the alkyl substituent is hydroxyl]; substituted aryl C1-C5 alkyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, halogen, and C1-C5 alkoxy; substituted amides, wherein the carbonyl substituent is selected from the group consisting of C1-C5 alkyl, phenyl, aryl C1-C5 alkyl, thienyl, furanyl, and naphthyl; substituted phenylcarbonyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of C1-C5 alkyl, halogen, and C1-C5 alkoxy; substituted C1-C5 alkylthio, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido; substituted C1-C5 alkylsulfonyl, wherein the alkyl substituent is selected from the group consisting of hydroxyl and phthalimido; substituted phenylsulfonyl, wherein the phenyl substituents are independently selected from one or more members of the group consisting of bromine, fluorine, chlorine, C1-C5 alkoxy, and trifluoromethyl; selected from the group consisting of however, A 11 is sulfur and X 24 is other than hydrogen, C1-C5 alkylaminocarbonyl, phenylaminocarbonyl, arylC1-C5 alkylaminocarbonyl, C1-C5 alkylsulfonyl, or phenylsulfonyl, then q must be 1 or greater; A 11 is sulfur and q is 1, then X 24 cannot be a C1-C2 alkyl, A 11 is carbonyl and q is 0, then X 24 cannot be vinyl, ethynyl, C1-C5 alkylaminocarbonyl, phenylaminocarbonyl, aryl C1-C5 alkylaminocarbonyl, C1-C5 alkylsulfonyl, or phenylsulfonyl; A 11 is carbonyl, q is 0, and X 24 If is H, then R 166 does not become 2-(trimethylsilyl)ethoxymethyl, If n is 0 and q is 0, then X 24 cannot become hydrogen.

[0237] Materials that may serve as Cox-2 selective inhibitors of the present invention include the 1,3- and 2,3-diarylcycloalkano- and cycloalkenopyrazoles described in U.S. Patent No. 6,083,969 (incorporated by reference). Such 1,3- and 2,3-diarylpyrazole compounds have the general formula shown in the following two formulas, as well as pharmaceutically acceptable salts, esters, and prodrug forms thereof: [ka] During the ceremony, R 168 and R 169 are independently selected from the group consisting of hydrogen, halogen, (C1-C6)alkyl, (C1-C6)alkoxy, nitro, amino, hydroxyl, trifluoro, —S(C1-C6)alkyl, —SO(C1-C6)alkyl, and —SO(C1-C6)alkyl; The fused moiety M is an optionally substituted group selected from the group consisting of cyclohexyl and cycloheptyl groups having the formula: [ka] [In the formula, R 170 is selected from the group consisting of hydrogen, halogen, hydroxyl, and carbonyl, or R 170 and R 171 together form a moiety selected from the group consisting of -OCOCH2-, -ONH(CH3)COCH2-, -OCOCH=, and O-; R 171 and R 172 is hydrogen, halogen, hydroxyl, carbonyl, amino, (C1-C6) alkyl, (C1-C6) alkoxy, =NOH, -NR 174 R 175, -OCH3, -OCH2CH3, -OSO2NHCO2CH3, ═CHCO2CH2CH3, -CH2CO2H, -CH2CO2CH3, -CH2CO2CH2CH3, -CH2CON(CH3)2, -CH2CO2NHCH3, -CHCHCO2CH2CH3, -OCON(CH3)OH, -C(COCH3)2, di(C1-C6)alkyl, and di(C1-C6)alkoxy; R 173 is selected from the group consisting of hydrogen, halogen, hydroxyl, carbonyl, amino, (C1-C6) alkyl, (C1-C6) alkoxy, and optionally substituted carboxyphenyl, wherein the substituents on the carboxyphenyl group are selected from the group consisting of halogen, hydroxyl, amino, (C1-C6) alkyl, and (C1-C6) alkoxy; Or R 172 and R 173 together, -O- and [ka] forming a moiety selected from the group consisting of R 174 is selected from the group consisting of hydrogen, OH, —OCOCH3, —COCH3, and (C1-C6) alkyl; R 175 is selected from the group consisting of hydrogen, OH, —OCOCH3, —COCH3, (C1-C6) alkyl, —CONH2, and SO2CH3. However, when M is a cyclohexyl group, R 170 ~R 173 It is impossible for all of the atoms to be hydrogen.

[0238] The novel esters derived from indole alkanols and amides derived from indole alkyl amides described in U.S. Patent No. 6,306,890 (incorporated by reference) can serve as selective Cox-2 inhibitors in the present invention. Such compounds have the following general formula: [ka] During the ceremony, R 176 is C1-C6 alkyl, C1-C6 branched alkyl, C4-C8 cycloalkyl, C1-C6 hydroxyalkyl, branched C1-C6 hydroxyalkyl, hydroxyl-substituted C4-C8 aryl, primary, secondary, or tertiary C1-C6 alkylamino, primary, secondary, or tertiary branched C1-C6 alkylamino, primary, secondary, or tertiary C4-C8 arylamino, C1-C6 alkylcarboxylic acid, branched C1-C6 alkylcarboxylic acid, C1-C6 alkylene esters, branched C1-C6 alkyl esters, C4-C8 aryls, C4-C8 arylcarboxylic acids, C4-C8 aryl esters, C4-C8 aryl substituted C1-C6 alkyls, C4-C8 heterocycloalkyl or aryl containing O, N, or S in the ring, alkyl- or aryl-substituted C4-C8 heterocycloalkyl or aryl containing O, N, or S in the ring, or halo-substituted versions thereof, where halo is chloro, bromo, fluoro, or iodo; R 177 is C1-C6 alkyl, C1-C6 branched alkyl, C4-C8 cycloalkyl, C4-C8 aryl, C4-C8 aryl-substituted C1-C6 alkyl, C1-C6 alkoxy, C1-C6 branched alkoxy, C4-C8 aryloxy, or halo-substituted versions thereof; or R 177 is halo, wherein halo is chloro, fluoro, bromo, or iodo; R 178 is hydrogen, C1-C6 alkyl, or C1-C6 branched alkyl; R 179 is C1-C6 alkyl, C4-C8 aroyl, C4-C8 aryl, C4-C8 heterocycloalkyl or aryl containing O, N, or S in the ring, C4-C8 aryl-substituted C1-C6 alkyl, alkyl- or aryl-substituted C4-C8 heterocycloalkyl or aryl containing O, N, or S in the ring, alkyl-substituted C4-C8 aroyl, alkyl-substituted C4-C8 aryl, or halo-substituted versions thereof, where halo is chloro, bromo, or iodo; n is 1, 2, 3, or 4; X 25 is O, NH, or NR 180 and R 180 is C1-C6 or C1-C6 branched alkyl.

[0239] Materials that may serve as Cox-2 selective inhibitors of the present invention include the pyridazinone compounds described in U.S. Patent No. 6,307,047 (incorporated by reference). Such pyridazinone compounds have the following formula: or a pharmaceutically acceptable salt, ester, or prodrug thereof: [ka] During the ceremony, X 26 -O, -S, -NR 185 , -NOR a , and -NNR b R c selected from the group consisting of R 185 is selected from the group consisting of alkenyl, alkyl, aryl, arylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, and heterocyclealkyl; R a , R b , and R c are independently selected from the group consisting of alkyl, aryl, arylalkyl, cycloalkyl, and cycloalkylalkyl; R 181is an alkyl, alkoxy, alkoxyalkyl, alkoxyiminoalkoxy, alkyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhaloalkyl, aryloxyhydroxyalkyl, arylcarbonylalkyl, carboxyalkyl, cyanoalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylidenealkyl, haloalkenyl, haloalkoxyhydroxyalkyl, haloalkyl, haloalkynyl, heterocycle, heterocyclealkoxy, heterocyclealkyl, heterocycleoxy, hydroxyalkyl, hydroxyiminoalkoxy, -(CH2) n C(O)R 186 , -(CH2) n CH(OH)R 186 , -(CH2) n C(NOR d )R 186 , -(CH2) n CH(NOR d )R 186 , -(CH2) n CH(NR d R e )R 186 , -R 187 R 188 , -(CH2) n C≡CR 188 , -(CH2) n [CH(CX 26’ 3)] m (CH2) p R 188 , -(CH2) n (CX 26’ 2) m (CH2) p R 188 , and (CH2) n (CHX 26’ ) m (CH2) m R 188 selected from the group consisting of R 186is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkenyl, haloalkyl, haloalkynyl, heterocycle, and heterocyclealkyl; R 187 is selected from the group consisting of alkenylene, alkylene, halo-substituted alkenylene, and halo-substituted alkylene; R 188 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkenyl, haloalkyl, heterocycle, and heterocyclealkyl; R d and R e is independently selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkenyl, cycloalkyl, haloalkyl, heterocycle, and heterocyclealkyl; X 26’ is a halogen, m is an integer from 0 to 5, n is an integer from 0 to 10, p is an integer from 0 to 10, R 182 , R 183 , and R 184 is hydrogen, alkenyl, alkoxyalkyl, alkoxyiminoalkoxy, alkoxyiminoalkyl, alkyl, alkynyl, alkylcarbonylalkoxy, alkylcarbonylamino, alkylcarbonylaminoalkyl, aminoalkoxy, aminoalkylcarbonyloxyalkoxy, aminocarbonylalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, carboxyalkylcarbonyloxyalkoxy, cyano, cycloalkenyl, cycloalkyl, cycloalkylidenealkyl, haloalkenyloxy, haloalkoxy, haloalkyl, halogen, heterocycle, hydroxyalkoxy, hydroxyiminoalkoxy, hydroxyiminoalkyl, mercaptoalkoxy, nitro, phosphonatoalkoxy, Y 8 , and Z 14 are independently selected from the group consisting of However, R182 , R 183 , or R 184 One of them is Z 14 must be R 182 , R 183 , or R 184 Only one of the 14 and Z 14 teeth, [ka] selected from the group consisting of X 27 is S(O)2, S(O)(NR 191 ), S(O), Se(O)2, P(O)(OR 192 ), and P(O)(NR 193 R 194 ) selected from the group consisting of X 28 is selected from the group consisting of hydrogen, alkenyl, alkyl, alkynyl, and halogen; R 190 is an alkenyl, alkoxy, alkyl, alkylamino, alkylcarbonylamino, alkynyl, amino, cycloalkenyl, cycloalkyl, dialkylamino, -NHNH2, and -NCHN(R 191 )R 192 selected from the group consisting of R 191 , R 192 , R 193 , and R 194 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R 193 and R 194 together with their nitrogen bonding partners, O, S, and NR 188 can form a 3- to 6-membered ring containing one or two heteroatoms selected from the group consisting of Y 8 -OR 195 , -SR 195 , -C(R 197 )(R 198 )R 195 , -C(O)R 195 , -C(O)OR195 , -N(R 197 )C(O)R 195 , -NC(R 197 )R 195 , and -N(R 197 )R 195 selected from the group consisting of R 195 is hydrogen, alkenyl, alkoxyalkyl, alkyl, alkylthioalkyl, alkynyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, hydroxyalkyl, and NR 199 R 200 selected from the group consisting of R 197 , R 198 , R 199 , and R 200 are independently selected from the group consisting of hydrogen, alkenyl, alkoxy, alkyl, cycloalkenyl, cycloalkyl, aryl, arylalkyl, heterocycle, and heterocyclealkyl.

[0240] Benzosulfonamide derivatives described in U.S. Patent No. 6,004,948 (incorporated by reference) are useful as Cox-2 selective inhibitors of the present invention. Such benzosulfonamide derivatives have the following formula: [ka] During the ceremony, A 12 represents oxygen, sulfur, or NH; R 201 represents a cycloalkyl, aryl or heteroaryl group [optionally mono- or polysubstituted with halogen, alkyl, CF3, or alkoxy]; D 5 is the two following expressions: [ka] represents one of the groups: R 202 and R203 are each independently a hydrogen atom, an optionally polyfluorinated alkyl group, an aralkyl group, an aryl group, or a heteroaryl group, or a group (CH2) n -X 29 represents, or R 202 and R 203 is a saturated, partially unsaturated, or fully unsaturated 3- to 7-membered heterocyclic ring containing, together with the N atom, one or more heteroatoms N, O, or S [optionally, an oxo, alkyl, alkylaryl, or aryl group, or a group (CH2) n -X 29 R 202’ is hydrogen, an optionally polyfluorinated alkyl group, an aralkyl group, an aryl group, or a heteroaryl group, or a group (CH2) n -X 29 represents X 29 is halogen, NO2, -OR 204 , -COR 204 , -CO2R 204 , -OCO2R 204 , -CN, -CONR 204 OR 205 , -CONR 204 R 205 , -SR 204 , -S(O)R 204 , -S(O)2R 204 , -NR 204 R 205 , -NHC(O)R 204 , -NHS(O)2R 204 represents Z 15 -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2-CH=CH-, -CH=CH-CH2-, -CH2-CO-, -CO-CH2-, -NHCO-, -CONH-, -NHCH2-, -CH2NH-, -N=CH-, -NHCH-, -CH2-CH2-NH-, -CH=CH-, >NR 203 , >C=O, >S(O) m represents R 204 and R 205represent, independently of each other, hydrogen, alkyl, aralkyl, or aryl; n is an integer from 0 to 6, R 206 is a linear or branched C1-C4 alkyl group, optionally mono- or polysubstituted with halogen or alkoxy, or R 206 represents CF3, m represents an integer of 0 to 2; However, R 206 If represents CF3, then A 12 does not become O.

[0241] Materials that may serve as Cox-2 selective inhibitors of the present invention include the methanesulfonyl-biphenyl derivatives described in U.S. Patent No. 6,583,321 (incorporated by reference). Such methanesulfonyl-biphenyl derivatives have the formula: [ka] During the ceremony, R 207 and R 208 are respectively, hydrogen; C1-C4-alkyl, substituted or not with halogen; C3-C7-cycloalkyl; C1-C5-alkyl containing 1-3 ether bonds and / or aryl substitutions; substituted or unsubstituted phenyl; or a substituted or unsubstituted 5- or 6-membered heteroaryl containing two or more heteroatoms selected from the group consisting of nitrogen, sulfur, and oxygen; wherein phenyl or heteroaryl may be mono- or polysubstituted with substituents selected from the group consisting of hydrogen, methyl, ethyl, and isopropyl.

[0242] Cox-2 selective inhibitors, such as the 1H-indole derivatives described in U.S. Patent No. 6,599,29 (incorporated by reference), are useful in the present invention. Such 1H-indole derivatives have the formula: [ka] During the ceremony, X 30 is -NHSO2R 209 and R 209 represents hydrogen or C1-C3-alkyl, Y 9 is hydrogen, halogen, C1-C3-alkyl [substituted or not with halogen, NO2, NH2, OH, OMe, CO2H or CN], Q 7 is C=O, C=S, or CH2.

[0243] Compounds useful as Cox-2 selective inhibitors of the present invention include prodrugs of the Cox-2 inhibitors described in U.S. Patent Nos. 6,436,967 and 6,613,790 (both of which are incorporated by reference). Such prodrugs of Cox-2 inhibitors have the formula: [ka] During the ceremony, A 13 is a ring substituent selected from partially unsaturated heterocycle, heteroaryl, cycloalkenyl, and aryl; A 13is unsubstituted or is selected from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, cycloalkylalkyl, alkenyl, alkynyl, heterocyclooxy, alkylthio, cycloalkyl, aryl, heterocyclyl, cycloalkenyl, aralkyl, heterocyclylalkyl, alkylthioalkyl, arylcarbonyl, aralkylcarbonyl, aralkenyl, alkoxyalkyl, arylthioalkyl, aryloxyalkyl, aralkylthioalkyl, araalkoxyalkyl, alkoxycarbonylalkenyl. substituted with one or more groups selected from alkyl, aminocarbonylalkyl, alkylaminocarbonyl, N-arylaminocarbonyl, N-alkyl-N-arylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, -arylamino, N-aralkylamino, N-alkyl-N-aralkylamino, N-alkyl-N-arylamino, aminoalkyl, alkylaminoalkyl, N-arylaminoalkyl, N-aralkylaminoalkyl, N-alkyl-N-arylaminoalkyl, aryloxy, aralkoxy, arylthio, aralkylthio, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, N-arylaminosulfonyl, arylsulfonyl, and N-alkyl-N-arylaminosulfonyl; R 210 is selected from heterocyclyl, cycloalkyl, cycloalkenyl, and aryl; R 210 is unsubstituted or substituted with one or more groups selected from alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, arylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; R 211is selected from hydrido and alkoxycarbonylalkyl; R 212 is selected from alkyl, carboxyalkyl, acyl, alkoxycarbonyl, heteroarylcarbonyl, alkoxycarbonylalkylcarbonyl, alkoxycarbonylcarbonyl, an amino acid residue, and alkylcarbonylaminoalkylcarbonyl, with the proviso that A 13 is not tetrazolium or pyridinium; 13 is R 212 is not an indanone when A is alkyl or carboxyalkyl; 13 is R 210 is 4-fluorophenyl, R 211 is a hydride, and R 212 is methyl or acyl, but not thienyl, R 213 is a hydride.

[0244] Specific, non-limiting examples of substituted sulfonamide prodrugs of Cox-2 inhibitors that are useful in the present invention, as disclosed in U.S. Pat. No. 6,436,967 (incorporated by reference), include the following: N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]propanamide; N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]butanamide; N-[[4-[1,5-dimethyl)-3-phenyl-1H-pyrazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-(2-(3-pyridinyl)-4-(trifluoromethyl)-1H-imidazol-1-yl)phenyl]sulfonyl]acetamide; N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]butanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]butanamide; N-[[4-[2-(3-chloro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[3-(3-fluorophenyl)-5-methylisoxazol-4-yl]phenyl]sulfonyl]acetamide; 2-methyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]benzamide; 2,2-dimethyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; N-[[4-5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]butanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl)sulfonyl]pentanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]hexanamide; 3-Methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]propanamide; 2-ethoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; N-[[4-[5-methyl-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1Hpyrazol-1-yl]phenyl]sulfonyl]propanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]butanamide; N-[[4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[3-(difluoromethyl)-6-fluoro-1,5-dihydro-7-methoxy-[2]benzothiopyrano[4,3-c]pyrazol-1-yl)phenyl]sulfonyl]acetamide; N-[[4-[6-fluoro-1,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzothiopyrano[4,3-c]pyrazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]phenyl]sulfonyl]acetamide; N-[[4-(2-methyl-4-phenyloxazol-5-yl)phenyl]sulfonyl]acetamide; Methyl [[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]oxoacetate; 2-Methoxy-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]propanamide; N-[[4-[5-(difluoromethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]butanamide; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]formamide; 1,1-dimethylethyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate; N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine; 2-amino-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; 2-(Acetylamino)-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]acetamide; Methyl 4-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-4-oxobutanoate; Methyl N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]carbamate; N-acetyl-N-[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]glycine, ethyl ester; N-[[4-(5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)phenyl]sulfonyl]acetamide; Methyl 3-[[[4-(5-methyl-3-phenylisoxazol-4-yl)phenyl]sulfonyl]amino]-3-oxopropanoate; 4-[5-(3-bromo-5-fluoro-4-methoxyphenyl)-2-(trifluoromethyl)oxazol-4-yl]-N-methylbenzenesulfonamide; N-(1,1-dimethylethyl)-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]-N-methylbenzenesulfonamide; N-methyl-4-(5-methyl-3-phenylisoxazol-4-yl)benzenesulfonamide; N-[[4-[5-(hydroxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[5-(acetoxymethyl)-3-phenylisoxazol-4-yl]phenyl]sulfonyl]acetamide; N-[[4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl)phenyl]sulfonyl]acetamide; 4-[2-(4-fluorophenyl)-1H-pyrrol-1-yl]-N-methylbenzenesulfonamide; N-[[4-(3,4-dimethyl-1-phenyl-1H-pyrazol-5-yl]phenyl]sulfonyl]propanamide; N-[[4-[2-(2-methylpyridin-3-yl)-4methylfluoromethylimidazol-1-yl]phenyl]sulfonyl]propanamide; 4-[2-(4-fluorophenyl)cyclopenten-1-yl]-N-methylbenzenesulfonamide; and N-[[4-(3-phenyl-2,3-dihydro-2-oxofuran-4-yl)phenyl]sulfonyl]propanamide.

[0245] These prodrugs, disclosed in U.S. Pat. No. 6,613,790 (incorporated by reference), include: A 13is a pyrazole group optionally substituted in substitutable positions with one or more groups independently selected at each occurrence from the group consisting of alkylcarbonyl, formyl, halo, alkyl, haloalkyl, oxo, cyano, nitro, carboxyl, alkoxy, aminocarbonyl, alkoxycarbonyl, carboxyalkyl, cyanoalkyl, hydroxyalkyl, haloalkylsulfonyloxy, alkoxyalkyloxyalkyl, carboxyalkoxyalkyl, alkenyl, alkynyl, alkylthio, alkylthioalkyl, alkoxyalkyl, alkoxycarbonylalkyl, aminocarbonylalkyl, alkylaminocarbonyl, alkylaminocarbonylalkyl, alkylamino, aminoalkyl, alkylaminoalkyl, alkylsulfinyl, alkylsulfonyl, aminosulfonyl, and alkylaminosulfonyl; R 210 is a phenyl group optionally substituted in substitutable positions with one or more groups independently selected at each occurrence from the group consisting of alkyl, haloalkyl, cyano, carboxyl, alkoxycarbonyl, hydroxyl, hydroxyalkyl, haloalkoxy, amino, alkylamino, nitro, alkoxyalkyl, alkylsulfinyl, halo, alkoxy, and alkylthio; R 211 and R 212 is independently selected from the group consisting of hydroxyalkyl and hydride, and R 211 and R 212 is other than hydride, and R 213 is selected from the group consisting of hydride and fluoro; It has the general formula shown above.

[0246] Examples of prodrug compounds disclosed in U.S. Pat. No. 6,613,790 (incorporated by reference) that are useful as Cox-2 inhibitors in the present invention include, but are not limited to, N-(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, N,N-bis(2-hydroxyethyl)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide, or a pharmaceutically acceptable salt thereof.

[0247] Cox-2 selective inhibitors, such as the sulfamoyl heteroaryl pyrazole compounds described in U.S. Patent No. 6,583,321 (incorporated by reference), can serve as Cox-2 inhibitors in the present invention. The sulfamoyl heteroaryl pyrazole compounds have the formula: [ka] During the ceremony, R 214 is furyl, thiazolyl, or oxazolyl; R 215 is hydrogen, fluoro, or ethyl, and X 31 and X 32 is independently hydrogen or chloro.

[0248] Heteroaryl-substituted amidinyl and imidazolyl compounds described in U.S. Patent No. 6,555,563 (incorporated by reference) are useful as Cox-2 selective inhibitors of the present invention. Such heteroaryl-substituted amidinyl and imidazolyl compounds have the formula: [ka] During the ceremony, Z 16 is O or S, R 216 is optionally substituted aryl; R 217is aryl optionally substituted with aminosulfonyl; R 218 and R 219 together form an optionally substituted 5-membered ring.

[0249] Materials that can serve as Cox-2 selective inhibitors of the present invention include the substituted hydroxamic acid derivatives described in U.S. Patent Nos. 6,432,999, 6,512,121, and 6,515,014 (all of which are incorporated by reference). These compounds also act as inhibitors of the lipoxygenase 5 enzyme. Such substituted hydroxamic acid derivatives have the general formula shown in one of the following formulas: [ka]

[0250] Pyrazole-substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,432,999 (incorporated by reference) include: A 14 is pyrazolyl [optionally substituted with substituents selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl]; Y 10 is selected from lower alkenylene and lower alkynylene; R 220 is a substituent selected from 5- and 6-membered heterocyclo; lower cycloalkyl; lower cycloalkenyl; and aryl selected from phenyl, biphenyl, and naphthyl; and R 220is optionally substituted in substitutable positions with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; R 221 is selected from lower alkyl and amino; R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo and lower cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0251] Pyrazole-substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,432,999 (incorporated by reference) include: A 15 is pyrazolyl [optionally substituted with substituents selected from acyl, halo, hydroxyl, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl]; Y 11 is selected from lower alkylene, lower alkenylene, and lower alkynylene; R 223 is a substituent selected from 5- and 6-membered heterocyclo; lower cycloalkyl; lower cycloalkenyl; and aryl selected from phenyl, biphenyl, and naphthyl; and R 223 is optionally substituted in substitutable positions with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylmino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; R 224 is selected from lower alkyl and amino; R 225 is selected from hydrido, lower alkyl; It may have the above formula or a pharmaceutically acceptable salt thereof.

[0252] Heterocyclo-substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,512,121 (incorporated by reference) include: A 14 is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl; A 14 is optionally substituted with substituents selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y 10 is lower alkylene, lower alkenylene, and lower alkynylene; R 220 is a substituent selected from 5- and 6-membered heterocyclo; lower cycloalkyl; lower cycloalkenyl; and aryl selected from phenyl, biphenyl, and naphthyl; and R 220 is optionally substituted in substitutable positions with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; R 221 is selected from lower alkyl and amino; R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo, and lower cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0253] Heterocyclo-substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,512,121 (incorporated by reference) include: A 15 is a ring substituent selected from oxazolyl, furyl, pyrrolyl, thiazolyl, imidazolyl, isothiazolyl, isoxazolyl, cyclopentenyl, phenyl, and pyridyl, and A is optionally substituted with substituents selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl; Y 11 is selected from lower alkyl, lower alkenyl, and lower alkynyl; R 223 is a substituent selected from 5- and 6-membered heterocyclo; lower cycloalkyl; lower cycloalkenyl; and aryl selected from phenyl, biphenyl, and naphthyl; and R 223 is optionally substituted in substitutable positions with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; R 224 is selected from lower alkyl and amino; R 225 is selected from hydride and alkyl; It may have the above formula or a pharmaceutically acceptable salt thereof.

[0254] Thiophene-substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,515,014 (incorporated by reference) include: A 14 is thienyl [optionally substituted with substituents selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl]; Y 10 is ethylene, isopropylene, propylene, butylene, lower alkenylene, and lower alkynylene; R 220 is a substituent selected from 5- and 6-membered heterocyclo; lower cycloalkyl; lower cycloalkenyl; and aryl selected from phenyl, biphenyl, and naphthyl; and R 220 is optionally substituted at substitutable positions with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; R 221 is selected from lower alkyl and amino; R 222 is selected from hydrido, lower alkyl, phenyl, 5- and 6-membered heterocyclo, and lower cycloalkyl; or a pharmaceutically acceptable salt thereof.

[0255] Thiophene-substituted hydroxamic acid derivatives described in U.S. Pat. No. 6,515,014 (incorporated by reference) include: A 15 is thienyl [optionally substituted with substituents selected from acyl, halo, hydroxy, lower alkyl, lower haloalkyl, oxo, cyano, nitro, carboxyl, lower alkoxy, aminocarbonyl, lower alkoxycarbonyl, lower carboxyalkyl, lower cyanoalkyl, and lower hydroxyalkyl]; Y11 is selected from lower alkyl, lower alkenyl, and lower alkynyl; R 223 is a substituent selected from 5- and 6-membered heterocyclo; lower cycloalkyl; lower cycloalkenyl; and aryl selected from phenyl, biphenyl, and naphthyl; and R 223 is optionally substituted in substitutable positions with one or more substituents selected from lower alkyl, lower haloalkyl, cyano, carboxyl, lower alkoxycarbonyl, hydroxyl, lower hydroxyalkyl, lower haloalkoxy, amino, lower alkylamino, phenylamino, nitro, lower alkoxyalkyl, lower alkylsulfinyl, halo, lower alkoxy, and lower alkylthio; R 224 is selected from lower alkyl and amino; R 225 is selected from hydride and alkyl; It may have the above formula or a pharmaceutically acceptable salt thereof.

[0256] Compounds useful as Cox-2 selective inhibitors of the present invention include the pyrazolopyridine compounds described in U.S. Patent No. 6,498,166 (incorporated by reference). Such pyrazolopyridine compounds have the following formula: or a pharmaceutically acceptable salt, solvate, ester thereof, or a salt or solvate of such an ester: [ka] During the ceremony, R 226 and R 227 are independently selected from the group consisting of H; halogen; C1-C6 alkyl; C1-C6 alkoxy; and C1-C6 alkoxy substituted with one or more fluorine atoms; R 228 are halogens, CN, CONR 230 R 231 , CO2H, CO2C1-C6 alkyl, or NHSO2R 230 and R 229 is C1-C6 alkyl or NH2, R 225 and R 225 are independently selected from the group consisting of H; C1-C6 alkyl; phenyl; phenyl substituted with one or more atoms or groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 alkoxy substituted with one or more fluorine atoms.

[0257] Materials useful as Cox-2 selective inhibitors of the present invention include 4,5-diaryl-3(2H)-furanone derivatives, as described in U.S. Patent No. 6,492,416 (incorporated by reference). Such 4,5-diaryl-3(2H)-furanone derivatives have the following formula: or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, X 33 represents halo, hydrido, or alkyl; Y 12 represents alkylsulfonyl, aminosulfonyl, alkylsulfinyl, (N-acylamino)-sulfonyl, (N-alkylamino)sulfonyl, or alkylthio, Z 17 represents an oxygen or sulfur atom, R 233 and R 234 are independently selected from lower alkyl groups; R 232 represents a substituted or unsubstituted aromatic group having 5 to 10 atoms.

[0258] Cox-2 selective inhibitors that can be used in the present invention include the 2-phenyl-1,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbonyl-phenylselenyl derivatives described in U.S. Patent No. 6,492,416 (incorporated by reference), which 2-phenyl-1,2-benzisoselenazol-3(2H)-one derivatives and 2-phenylcarbonyl-phenylselenyl derivatives have one of the following formulae, salts thereof, or hydrates thereof: [ka] During the ceremony, R 235 is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, R 236 is an organic thiol group attached to the selenium atom by a hydrogen atom, a hydroxyl group, or a sulfur atom, or R 235 and R 236 are bonded to each other by a single bond, R 237 is a hydrogen atom, a halogen atom, an alkyl group having 1 to 3 carbon atoms, an alkoxy group having 1 to 3 carbon atoms, a trifluoromethyl group, or a nitro group, R 238 and R 239 are the same or different and each is a hydrogen atom, a halogen atom, an alkoxyl group having 1 to 4 carbon atoms, or a trifluoromethyl group, or R 238 and R 239 are bonded to each other to form a methylenedioxy group.

[0259] Pyrones, such as those disclosed in U.S. Patent No. 6,465,509 (incorporated by reference), are also useful as Cox-2 inhibitors in the present invention. These pyrone compounds have the following general formula: [ka] During the ceremony, X 34 teeth, (a) combination; (b)-(CH2) m - (m is 1 or 2), (c)-C(O)-, (d) -O-, (e)-S-, and (f)-N(R 244 )- selected from the group consisting of R 240 teeth, (a) C1 to C 10 Alkyl [optionally hydroxy, halo, C1-C 10 Alkoxy, C1-C 10 optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkylthio, and CN; (b) phenyl or naphthyl, and (c) Heteroaryl consisting of a 5-atom monocyclic aromatic ring containing one heteroatom that is S, O, or N and optionally containing 1, 2, or 3 additional N atoms, or a 6-atom monocyclic ring containing one heteroatom that is N and optionally containing 1, 2, or 3 additional N atoms. wherein each of the above groups (b) and (c) is optionally selected from the group consisting of halo, C1-C 10 Alkoxy, C1-C 10 Alkylthio, CN, C1-C 10 alkyl, optionally substituted with halo and N3, up to and including the above substituents; R 241 teeth, (a) C1-C6 alkyl [optionally substituted with halo up to that limit]; (b) NH2, and (c)NHC(O)C1~C 10 alkyl [optionally substituted up to the limit with halo] selected from the group consisting of R 242 and R 243are each independently selected from the group consisting of C1-C6 alkyl [optionally substituted with hydrogen, halo; and halo, up to and including the above]; R 244 is selected from the group consisting of C1-C6 alkyl [optionally substituted with hydrogen and halo, up to and including the limit].

[0260] Examples of pyrone compounds useful as Cox-2 selective inhibitors of the present invention include, but are not limited to, the following: 4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 3-(4-fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 3-(3-fluorophenyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 6-methyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-difluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-fluoromethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-pyran-2-one, 6-methyl-4-(4-methylsulfonyl)phenyl-3-phenylthio-pyran-2-one, 6-methyl-4-(4-methylsulfonyl)phenyl-3-phenoxy-pyran-2-one, 6-methyl-4-(4-methylsulfonyl)phenyl-3-pyridin-3-yl-pyran-2-one, 3-isopropylthio-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one, 4-(4-methylsulfonyl)phenyl)-3-phenylthio-6-trifluoromethyl-pyran-2-one, 3-isopropylthio-4-(4-methylsulfonyl)phenyl-6-trifluoromethyl-pyran-2-one, 4-(4-methylsulfonyl)phenyl-3-phenyl-6-(2,2,2-trifluoroethyl)-pyran-2-one, and 3-(3-Hydroxy-3-methylbutyl)-6-methyl-4-(4-methylsulfonyl)phenyl-pyran-2-one.

[0261] B-ring unsubstituted flavanoids, either organically synthesized or purified from plant sources, such as those described in U.S. Patent Publication No. 2003 / 0165588 (incorporated by reference), are useful as Cox-2 selective inhibitors of the present invention. Such B-ring unsubstituted flavanoids have the following general structure: [ka] During the ceremony, R 246 , R 247 , R 248 , R 249 , and R 250 -H, -OH, -SH, -OR, -SR, -NH2, -NHR 245 , -N(R 245 )2, -N(R 245 )3 + X 35- , carbon, oxygen, nitrogen, or sulfur; glycosides of a single sugar or a combination of sugars, said sugars including aldopentose, methyl aldopentose, aldohexose, ketohexose, and chemical derivatives thereof; R 245 is an alkyl group having 1 to 10 carbon atoms, and X 35 is selected from the group of pharmaceutically acceptable counter anions including hydroxyl, chloride, iodide, sulfate, phosphate, acetate, fluoride, and carbonate.

[0262] Heterocyclo-alkylsulfonylpyrazoles, such as those described in European Patent Application No. EP 1312367, are useful as Cox-2 selective inhibitors of the present invention. Such heterocyclo-alkylsulfonylpyrazoles are shown in the formula: [ka] In the formula, the formula (R 255 )-A-(SO m R 254 ) ring is [ka] selected from the group consisting of m is 0, 1, or 2; X 35 is >CR 255 or >N, R 251 is H, NO2, CN, (C1-C6) alkyl, (C1-C6) alkyl-SO2-, (C6-C 10 )aryl-SO2-, H-(C=O)-, (C1-C6)alkyl-(C=O)-, (C1-C6)alkyl-)-(C=O)-, (C1-C9)heteroaryl-(C=O)-, (C1-C9)heterocyclyl-(C=O)-, H2N-(C=O)-, (C1-C6)alkyl-NH-(C=O)-, [(C1-C6)alkyl]2-N-(C=O)-, [(C6-C 10 )aryl]2-NH-(C=O)-, [(C1-C6} alkyl]-[((C6-C 10 a radical selected from the group consisting of (C1-C6)aryl-N]-(C=O)-, HO-NH-(C=O)-, and (C1-C6)alkyl-O-NH-(C=O)-; R 252 is H, -NO2, -CN, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, (C6-C 10 )aryl, (C1-C9)heteroaryl, (C1-C9)heterocyclyl, (C1-C6)alkyl-O-, (C3-C7)cycloalkyl-O-, (C6-C 10 )aryl-O-, (C1-C9)heteroaryl-O-, (C6-C9)heterocyclyl-O-, H-(C=O)-, (C1-C6)alkyl-(C=O)-, (C3-C7)cycloalkyl-(C=O)-, (C6-C 10)aryl-(C=O)-, (C1-C9)heteroaryl-(C=O)-, (C1-C9)heterocyclyl-(C=O)-, (C1-C6)alkyl-O-(C=O)-, (C3-C7)cycloalkyl-O-(C=O)-, (C6-C 10 )aryl-O—(C═O)—, (C1-C9)heteroaryl-O—(C═O)—, (C1-C9)heterocyclyl-O—(C═O)—, (C1-C6)alkyl-(C═O)—O—, (C3-C7)cycloalkyl-(C═O)—O—, (C6-C 10 )aryl-(C=O)-O-, (C1-C9)heteroaryl-(C=O)-O-, (C1-C9)heterocyclyl-(C=O)-O-, (C1-C6)alkyl-(C=O)-NH-, (C3-C7)cycloalkyl-(C=O)-NH-, (C6-C 10 Aryl-(C=O)-NH-, (C1-C9)heteroaryl-(C=O)-NH-, (C1-C9)heterocyclyl-(C=O)-NH-, (C1-C6)alkyl-O-(C=O)-NH-, (C1-C6)alkyl-NH, [(C1-C6)alkyl]2-N-, (C3-C7)cycloalkyl-NH-, [(C3-C7)cycloalkyl]2-N-, [(C6-C 10 )aryl]-NH-, [(C6-C 10 )aryl]2-N-, [(C1-C6)alkyl]-[((C6-C 10 )aryl)-N]-, [(C1-C9)heteroaryl]-NH-, [(C1-C9)heteroaryl]2-N-, [(C1-C9)heterocyclyl]-NH-, [(C1-C9)heterocyclyl]2-N-, H2N-(C=O)-, HO-NH-(C=O)-, (C1-C6)alkyl-O-NH-(C=O)-, [(C1-C6)alkyl]-NH-(C=O)-, [(C1-C6)alkyl]2-N-(C=O)-, [(C3-C7)cycloalkyl]-NH-(C=O)-, [(C3-C7)cycloalkyl]2-N-(C=O)-, [(C6-C 10 )aryl]-NH-(C=O)-, [(C6-C 10 Aryl]2-N-(C=O)-, [(C1-C6) alkyl]-[((C6-C 10a radical selected from the group consisting of: [(C1-C9)aryl]-N]-(C=O)-, [(C1-C9)heteroaryl]-NH-(C=O)-, [(C1-C9)heteroaryl]-N-(C=O)-, [(C1-C9)heterocyclyl]-NH-(C=O)-, (C1-C6)alkyl-S-, and (C1-C6)alkyl optionally substituted with one OH substituent or one to four fluoro substituents; R 253 is a saturated (3- to 4-membered)-heterocyclyl ring radical or a saturated, partially saturated, or aromatic (7- to 9-membered)-heterocyclyl ring radical, The saturated (3- to 4-membered)-heterocyclyl ring radical or the saturated, partially saturated, or aromatic (7- to 9-membered)-heterocyclyl ring radical optionally contains 1 to 4 ring heteroatoms independently selected from the group consisting of -N=, -NH-, -O-, and S-; The saturated (3- to 4-membered)-heterocyclyl ring radical or the saturated, partially saturated, or aromatic (7- to 9-membered)-heterocyclyl ring radical may optionally be selected from the group consisting of halo, -OH, -CN, -NO, (C2-C6)alkenyl, (C2-C6)alkynyl, (C3-C7)cycloalkyl, (C6-C 10 )aryl, (C2-C9)heterocyclyl, (C1-C6)alkyl-O-, H-(C=O)-, (C1-C6)alkyl-(C=O)-, HO-(C=O)-, (C1-C6)alkyl-O-(C=O)-, -NH2, (C1-C6)alkyl-NH-, [(C1-C6)alkyl]2-N-, (C3-C7)cycloalkyl-NH-, (C6-C 14 )aryl-NH-, [(C1-C6) alkyl]-[((C6-C 10 )aryl)-N]-, (C1-C9)heteroaryl-NH-, H2N-(C=O)-[(C1-C6)alkyl]-NH-(C=O)-, [(C1-C6)alkyl]2-N-(C=O)-, [(C6-C 10 )aryl]-NH-(C=O)-, [(C1-C6)alkyl]-[((C6-C 10)aryl)-N]-(C═O)-, (C1-C6)alkyl-O—NH—(C═O)-, (C1-C6)alkyl-(C═O)-HN-, (C1-C6)alkyl-(C═O)-[(C1-C6)alkyl-N]-, —SH, (C1-C6)alkyl-S—, (C1-C6)alkyl-(S═O)-, (C1-C6)alkyl-SO2-, and (C1-C6)alkyl optionally substituted with 1 to 4 fluoro moieties; The saturated (3- to 4-membered)-heterocyclyl ring radical or the saturated, partially saturated, or aromatic (7- to 9-membered)-heterocyclyl ring radical may optionally be (C3-C7)cycloalkyl, (C6-C 10 )aryl, (C2-C9)heterocyclyl, H-(C=O)-, (C1-C6)alkyl-(C=O)-, (C1-C6)alkyl-O-(C=O)-, H2N-(C=O)-, [(C1-C6)alkyl]-NH-(C=O)-, [(C1-C6)alkyl]2-N-(C=O)-, [(C6-C 10 )aryl]-NH-(C=O)-, [(C1-C6)alkyl]-[((C6-C 10 )aryl)-N]-(C=O)-, (C1-C6)alkyl-O-NH-(C=O)-, and (C1-C6)alkyl optionally substituted with 1 to 4 fluoro moieties; R 254 is a (C1-C6)alkyl radical optionally substituted with 1 to 4 fluoro substituents; R 255is H, halo, -OH, (C1-C6) alkyl-O-, (C2-C6) alkenyl, (C2-C6) alkynyl, (C3-C7) cycloalkyl, -CN, H-(C=O)-, (C1-C6) alkyl-(C=O)-, (C1-C6) alkyl-(C=O)-O-, HO-(C=O)-, (C1-C6) alkyl-O-(C=O)-, (C1-C6) alkyl-NH-, [(C1-C6) alkyl]2-N-, (C3-C7) cycloalkyl-NH-, (C6-C 10 )aryl-NH-, [(C1-C6) alkyl]-[((C6-C 10 )aryl)-N]-, (C1-C9)heteroaryl-NH-, H2N-(C=O)-, (C1-C6)alkyl-NH-(C=O)-, [(C1-C6)alkyl]2-N-(C=O)-, (C6-C 10 )aryl-(C=O)-, [(C1-C6) alkyl]-[((C6-C 10 )aryl)-N]-(C=O)-, (C1-C6)alkyl-O-NH-(C=O)-, (C1-C6)alkyl-S-, and (C1-C6)alkyl optionally substituted with 1 to 4 fluoro substituents.

[0263] 2-phenylpyran-4-one derivatives, such as those described in U.S. Patent No. 6,518,303 (incorporated by reference), are also useful as Cox-2 selective inhibitors of the present invention. Such 2-phenylpyran-4-one derivatives have the following general formula: [ka] During the ceremony, R 256 is alkyl or -NR 259 R 260 represents a group, and R 259 and R 260 each independently represents a hydrogen atom or an alkyl group, R 257represents an alkyl, C3-C7 cycloalkyl, naphthyl, tetrahydronaphthyl, or indanyl group, or a phenyl group [which may be unsubstituted or substituted with one or more halogen atoms, or alkyl, trifluoromethyl, hydroxy, alkoxy, methylthio, amino, mono- or dialkylamino, hydroxyalkyl, or hydroxycarbonyl groups]; R 258 is a methyl, hydroxymethyl, alkoxymethyl, C3-C7 cycloalkoxymethyl, benzyloxymethyl, hydroxycarbonyl, nitrile, trifluoromethyl, or difluoromethyl group, or CH2-R 261 represents a group, and R 261 represents an alkyl group, X 36 represents a single bond, an oxygen atom, a sulfur atom, or a methylene group.

[0264] Examples of 2-phenylpyran-4-one derivatives useful in the present invention include, but are not limited to, the following, or pharmaceutically acceptable salts thereof: 3-(4-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-bromophenyl)-2-(4-methylsulfonylphenyl)-6-methylpyran-4-one, 3-(2,4-difluorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(3,4-dichlorophenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(3-chloro-4-methylphenyl)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 2-(4-methanesulfonylphenyl)-6-methyl-3-phenoxypyran-4-one, 3-(4-fluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-fluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2-chlorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-bromophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 2-(4-methanesulfonylphenyl)-6-methyl-3-(4-methylphenoxy)pyran-4-one, 3-(2,4-difluorophenoxy)-2-(4-methanesulfonylphenyl)-6-methylpyran-4-one, 3-(2,5-difluorophenoxy)-2-(methanesulfonylphenyl)-6-methylpyran-4-one, 3-(4-chlorophenyl)-2-(4-methanesulfonylphenyl)-6-methoxymethylpyran-4-one, 3-(4-chlorophenyl)-6-difluoromethyl-2-(4-methanesulfonylphenyl)pyran-4-one.

[0265] Cox-2 selective inhibitors useful in the methods and compositions of the present invention include those disclosed in U.S. Pat. No. 6,472,416 (sulfonylphenylpyrazoles); U.S. Pat. No. 6,451,794 (2,3-diaryl-pyrazolo[1,5-b]pyridazines); U.S. Pat. Nos. 6,169,188, 6,020,343, and 5,981,576 ((methylsulfonyl)phenylfuranones); U.S. Pat. No. 6,222,048 (diaryl-2-(5H)-furanones); No. 6,057,319 (3,4-diaryl-2-hydroxy-2,5-dihydrofurans); U.S. Pat. No. 6,046,236 (carbocyclic sulfonamides); U.S. Pat. Nos. 6,002,014 and 5,945,539 (oxazole derivatives); and U.S. Pat. Nos. 6,359,182 and 6,538,116 (C-nitroso compounds), all of which are incorporated by reference.

[0266] Examples of particular compounds useful as Cox-2 selective inhibitors include, but are not limited to, the following, or pharmaceutically acceptable salts or prodrugs thereof: a1) 8-acetyl-3-(4-fluorophenyl)-2-(4-methylsulfonyl)phenyl-imidazo(1,2-a)pyridine; a2) 5,5-dimethyl-4-(4-methylsulfonyl)phenyl-3-phenyl-2-(5H)-furanone; a3) 5-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole; a4) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-1-phenyl-3-(trifluoromethyl)pyrazole; a5) 4-(5-(4-chlorophenyl)-3-(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; a6) 4-(3,5-bis(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; a7) 4-(5-(4-chlorophenyl)-3-phenyl-1H-pyrazol-1-yl)benzenesulfonamide; a8) 4-(3,5-bis(4-methoxyphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; a9) 4-(5-(4-chlorophenyl)-3-(4-methylphenyl)-1H-pyrazol-1-yl)benzenesulfonamide; a10) 4-(5-(4-chlorophenyl)-3-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide; b1) 4-(5-(4-chlorophenyl)-3-(5-chloro-2-thienyl)-1H-pyrazol-1-yl)benzenesulfonamide; b2) 4-(4-chloro-3,5-diphenyl-1H-pyrazol-1-yl)benzenesulfonamide b3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b4) 4-[5-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b5) 4-[5-(4-fluorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b6) 4-[5-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b7) 4-[5-(4-chlorophenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b8) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b9) 4-[4-chloro-5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; b10) 4-[3-(difluoromethyl)-5-(4-methylphenyl)-1H-pyrazol-1-yl]benzenesulfonamide; cl) 4-[3-(difluoromethyl)-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide; c2) 4-[3-(difluoromethyl)-5-(4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide; c3) 4-[3-cyano-5-(4-fluorophenyl)-1H-pyrazol-1-yl]benzenesulfonamide; c4) 4-[3-(difluoromethyl)-5-(3-fluoro-4-methoxyphenyl)-1H-pyrazol-1-yl]benzenesulfonamide; c5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; c6) 4-[4-chloro-5-phenyl-1H-pyrazol-1-yl]benzenesulfonamide; c7) 4-[5-(4-chlorophenyl)-3-(hydroxymethyl)-1H-pyrazol-1-yl]benzenesulfonamide; c8) 4-[5-(4-(N,N-dimethylamino)phenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; c9) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; c10) 4-[6-(4fluorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide; d1) 6-(4-fluorophenyl)-7-[4-(methylsulfonyl)phenyl]spiro[3.4]oct-6-ene; d2) 5-(3-chloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d3) 4-[6-(3-chloro-4-methoxyphenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide; d4) 5-(3,5-dichloro-4-methoxyphenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d5) 5-(3-chloro-4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hept-5-ene; d6) 4-[6-(3,4-dichlorophenyl)spiro[2.4]hept-5-en-5-yl]benzenesulfonamide; d7) 2-(3-chloro-4-fluorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole; d8) 2-(2-chlorophenyl)-4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)thiazole; d9) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-methylthiazole; d10) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole; e1) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(2-thienyl)thiazole; e2) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-benzylaminothiazole; e3) 4-(4-fluorophenyl)-5-(4-methylsulfonylphenyl)-2-(1-propylamino)thiazole; e4) 2-[(3,5-dichlorophenoxy)methyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]thiazole; e5) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethylthiazole; e6) 1-methylsulfonyl-4-[1,1-dimethyl-4-(4-fluorophenyl)cyclopenta-2,4-dien-3-yl]benzene; e7) 4-[4-(4-fluorophenyl)-1,1-dimethylcyclopenta-2,4-dien-3-yl]benzenesulfonamide; e8) 5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]spiro[2.4]hepta-4,6-diene; e9) 4-[6-(4-fluorophenyl)spiro[2.4]hepta-4,6-dien-5-yl]benzenesulfonamide; e10) 6-(4-fluorophenyl)-2-methoxy-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile; f1) 2-bromo-6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-pyridine-3-carbonitrile; f2) 6-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyl-pyridine-3-carbonitrile; f3) 4-[2-(4-methylpyridin-2-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; f4) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; f5) 4-[2-(2-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; f6) 3-[1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine; f7) 2-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine; f8) 2-methyl-4-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine; f9) 2-methyl-6-[1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazol-2-yl]pyridine; f10) 4-[2-(6-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; g1) 2-(3,4-difluorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole; g2) 4-[2-(4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; g3) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-methyl-1H-imidazole; g4) 2-(4-chlorophenyl)-1-[4-(methylsulfonyl)phenyl]-4-phenyl-1H-imidazole; g5) 2-(4-chlorophenyl)-4-(4-fluorophenyl)-1-[4-(methylsulfonyl)phenyl]-1H-imidazole; g6) 2-(3-fluoro-4-methoxyphenyl)-1-[4-(methylsulfonyl)phenyl-4-(trifluoromethyl)-1H-imidazole; g7) 1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-1H-imidazole; g8) 2-(4-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole; g9) 4-[2-(3-chloro-4-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; g10) 2-(3-fluoro-5-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-(trifluoromethyl)-1H-imidazole; h1) 4-[2-(3-fluoro-5-methylphenyl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; h2) 2-(3-methylphenyl)-1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazole; h3) 4-[2-(3-methylphenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide; h4) 1-[4-(methylsulfonyl)phenyl]-2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazole; h5) 4-[2-(3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide; h6) 4-[2-phenyl-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide; h7) 4-[2-(4-methoxy-3-chlorophenyl)-4-trifluoromethyl-1H-imidazol-1-yl]benzenesulfonamide; h8) 1-allyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole; h9) 4-[1-ethyl-4-(4-fluorophenyl)-5-(trifluoromethyl)-1H-pyrazol-3-yl]benzenesulfonamide; i1) N-phenyl-[4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetamide; i2) ethyl [4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazol-1-yl]acetate; i3) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-1H-pyrazole; i4) 4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-1-(2-phenylethyl)-5-(trifluoromethyl)pyrazole; i5) 1-ethyl-4-(4-fluorophenyl)-3-[4-(methylsulfonyl)phenyl]-5-(trifluoromethyl)-1H-pyrazole; i6) 5-(4-fluorophenyl)-4-(4-methylsulfonylphenyl)-2-trifluoromethyl-1H-imidazole; i7) 4-[4-(methylsulfonyl)phenyl]-5-(2-thiophenyl)-2-(trifluoromethyl)-1H-imidazole; i8) 5-(4-fluorophenyl)-2-methoxy-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine; i9) 2-ethoxy-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine; i10) 5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-2-(2-propynyloxy)-6-(trifluoromethyl)pyridine; j1) 2-bromo-5-(4-fluorophenyl)-4-[4-(methylsulfonyl)phenyl]-6-(trifluoromethyl)pyridine; j2) 4-[2-(3-chloro-4-methoxyphenyl)-4,5-difluorophenyl]benzenesulfonamide; j3) 1-(4-fluorophenyl)-2-[4-(methylsulfonyl)phenyl]benzene; j4) 5-difluoromethyl-4-(4-methylsulfonylphenyl)-3-phenylisoxazole; j5) 4-[3-ethyl-5-phenylisoxazol-4-yl]benzenesulfonamide; j6) 4-[5-difluoromethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; j7) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; j8) 4-[5-methyl-3-phenyl-isoxazol-4-yl]benzenesulfonamide; j9) 1-[2-(4-fluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; j10) 1-[2-(4-fluoro-2-methylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; k1) 1-[2-(4-chlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; k2) 1-[2-(2,4-dichlorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; k3) 1-[2-(4-trifluoromethylphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; k4) 1-[2-(4-methylthiophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; k5) 1-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene; k6) 4-[2-(4-fluorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide; k7) 1-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]-4-(methylsulfonyl)benzene; k8) 4-[2-(4-chlorophenyl)-4,4-dimethylcyclopenten-1-yl]benzenesulfonamide; k9) 4-[2-(4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide; k10) 4-[2-(4-chlorophenyl)cyclopenten-1-yl]benzenesulfonamide; l1) 1-[2-(4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; l2) 1-[2-(2,3-difluorophenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; l3) 4-[2-(3-fluoro-4-methoxyphenyl)cyclopenten-1-yl]benzenesulfonamide; l4) 1-[2-(3-chloro-4-methoxyphenyl)cyclopenten-1-yl]-4-(methylsulfonyl)benzene; l5) 4-[2-(3-chloro-4-fluorophenyl)cyclopenten-1-yl]benzenesulfonamide; l6) 4-[2-(2-methylpyridin-5-yl)cyclopenten-1-yl]benzenesulfonamide; l7) ethyl 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]-2-benzyl-acetate; l8) 2-[4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazol-2-yl]acetic acid; l9) 2-(tert-butyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]oxazole; l10) 4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-2-phenyloxazole; m1) 4-(4-fluorophenyl)-2-methyl-5-[4-(methylsulfonyl)phenyl]oxazole; and m2) 4-[5-(3-fluoro-4-methoxyphenyl)-2-trifluoromethyl-4-oxazolyl]benzenesulfonamide; m3) 6-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m4) 6-chloro-7-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m5) 8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m6) 6-chloro-7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m7) 6-chloro-8-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m8) 2-trifluoromethyl-3H-naphthopyran-3-carboxylic acid; m9) 7-(1,1-dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; m10) 6-bromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n1) 8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n2) 6-trifluoromethoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n3) 5,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n4) 8-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n5) 7,8-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n6) 6,8-bis(dimethylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n7) 7-(1-methylethyl)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n8) 7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n9) 6-chloro-7-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; n10) 6-chloro-8-ethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o1) 6-chloro-7-phenyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o2) 6,7-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o3) 6,8-dichloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o4) 2-trifluoromethyl-3H-naphtho[2,1-b]pyran-3-carboxylic acid; o5) 6-chloro-8-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o6) 8-chloro-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o7) 8-chloro-6-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o8) 6-Bromo-8-chloro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; o9) 8-Bromo-6-fluoro-2-trifluoromethyl-2H-benzopyran-3-carboxylic acid; o10) 8-Bromo-6-methyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p1) 8-bromo-5-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p2) 6-chloro-8-fluoro-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p3) 6-bromo-8-methoxy-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p4) 6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p5) 6-[(dimethylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p6) 6-[(methylamino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p7) 6-[(4-morpholino)sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p8) 6-[(1,1-dimethylethyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p9) 6-[(2-methylpropyl)aminosulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; p10) 6-methylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q1) 8-chloro-6-[[(phenylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q2) 6-phenylacetyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q3) 6,8-dibromo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q4) 8-chloro-5,6-dimethyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q5) 6,8-dichloro-(S)-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q6) 6-benzylsulfonyl-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q7) 6-[[N-(2-furylmethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q8) 6-[[N-(2-phenylethyl)amino]sulfonyl]-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q9) 6-iodo-2-trifluoromethyl-2H-1-benzopyran-3-carboxylic acid; q10) 7-(1,1-dimethylethyl)-2-pentafluoroethyl-2H-1-benzopyran-3-carboxylic acid; r1) 5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methyl-sulfonyl-2(5H)-fluranone; r2) 6-chloro-2-trifluoromethyl-2H-1-benzothiopyran-3-carboxylic acid; r3) 4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; r4) 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; r5) 4-[5-(3-fluoro-4-methoxyphenyl)-3-(difluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide; r6) 3-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine; r7) 2-methyl-5-[1-[4-(methylsulfonyl)phenyl]-4-trifluoromethyl-1H-imidazol-2-yl]pyridine; r8) 4-[2-(5-methylpyridin-3-yl)-4-(trifluoromethyl)-1H-imidazol-1-yl]benzenesulfonamide; r9) 4-[5-methyl-3-phenylisoxazol-4-yl]benzenesulfonamide; r10) 4-[5-hydroxymethyl-3-phenylisoxazol-4-yl]benzenesulfonamide; s1) [2-trifluoromethyl-5-(3,4-difluorophenyl)-4-oxazolyl]benzenesulfonamide; s2) 4-[2-methyl-4-phenyl-5-oxazolyl]benzenesulfonamide; or s3) 4-[5-(3-fluoro-4-methoxyphenyl-2-trifluoromethyl)-4-oxazolyl]benzenesulfonamide.

[0267] Cox-2 inhibitors useful in the methods and compositions of the present invention can be supplied by any source, so long as the Cox-2 inhibitor is pharmaceutically acceptable. Cox-2 inhibitors useful in the compositions and methods of the present invention can also be synthesized, for example, as described in Example 1. Some Cox-2 inhibitors suitable for use with the compositions and methods of the present invention can be synthesized, for example, by the method described in U.S. Pat. No. 5,466,823 to Talley et al. (incorporated by reference). Cox-2 inhibitors can also be isolated and purified from natural sources. Cox-2 inhibitors should be of the quality and purity customary in the industry for use in pharmaceutical products.

[0268] Preferred Cox-2 selective inhibitory compounds include celecoxib, parecoxib, deracoxib, valdecoxib, etoricoxib, meloxicam, rofecoxib, lumiracoxib, RS57067, T-614, BMS-347070 (Bristol Meyers Squibb, described in U.S. Pat. No. 6,180,651, incorporated by reference), JTE-522 (Japan Tobacco), S-2474 (Shionogi), SVT-2016, CT-3 (Atlantic Pharmaceutical), ABT-963 (Abbott), SC-58125 (GD Searle), nimesulide, flosulide, NS-398 (Taisho Pharmaceutical), L-745337 (Merck), RWJ-63556, L-784512 (Merck), dalbuferon (Pfizer), CS-502 (Sankyo), LAS-34475 (Almirall Prodesfarma), LAS-34555 (Almirall Prodesfarma), S-33516 (Servier), SD-8381 (Pharmacia, described in U.S. Pat. No. 6,0340,256, which is incorporated by reference), MK-966 (Merck), L-783003 (Merck), T-614 (Toyama Chemical Co., Ltd.), D-1376 (Chiroscience), L-748731 (Merck), CGP-28238 (Novartis), BF-389 (Biofor / Scherer), GR-253035 (Glaxo Wellcome), prodrugs of any of these, and mixtures thereof.

[0269] More preferably, the Cox-2 selective inhibitor is selected from the group consisting of celecoxib, parecoxib, deracoxib, valdecoxib, lumiracoxib, etoricoxib, rofecoxib, any prodrug thereof, and mixtures thereof.

[0270] Even more preferably, the Cox-2 selective inhibitor is celecoxib.

[0271] Various classes of Cox-2 inhibitors useful in the present invention can be prepared as follows: Pyrazoles can be prepared by the methods described in WO 95 / 15316. Pyrazoles can also be prepared by the methods described in WO 95 / 15315. Pyrazoles can also be prepared by the methods described in WO 96 / 03385 (all of which are incorporated by reference).

[0272] Thiophene analogs useful in the present invention can be prepared by the methods described in WO 95 / 00501 (incorporated by reference). The preparation of thiophene analogs is also described in WO 94 / 15932 (incorporated by reference).

[0273] The oxazoles useful in the present invention can be prepared by the methods described in WO 95 / 00501 (incorporated by reference). The preparation of oxazoles is also described in WO 94 / 27980 (incorporated by reference).

[0274] Isoxazoles useful in the present invention can be prepared by the methods described in WO 96 / 25405 (incorporated by reference).

[0275] Imidazoles useful in the present invention can be prepared by the methods described in WO 96 / 03388 (incorporated by reference). The preparation of imidazoles is also described in WO 96 / 03387 (incorporated by reference).

[0276] Cyclopentene Cox-2 inhibitors useful in the present invention can be prepared by the methods described in U.S. Patent No. 5,344,991 (incorporated by reference). The preparation of cyclopentene Cox-2 inhibitors is also described in WO 95 / 00501 (incorporated by reference).

[0277] Terphenyl compounds useful in the present invention can be prepared by the methods described in WO 96 / 1693 (incorporated by reference).

[0278] Thiazole compounds useful in the present invention can be prepared by the methods described in WO 96 / 03392 (incorporated by reference).

[0279] The pyridine compounds useful in the present invention can be prepared by the methods described in WO 96 / 03392 (incorporated by reference). The preparation of pyridine compounds is also described in WO 96 / 24585 (incorporated by reference).

[0280] The benzopyranopyrazolyl compounds useful in the present invention can be prepared by the methods described in WO 96 / 09304 (incorporated by reference).

[0281] The chromene compounds useful in the present invention can be prepared by the methods described in WO 98 / 47890. The preparation of chromene compounds is also described in WO 00 / 23433. The chromene compounds can also be prepared by the methods described in U.S. Patent No. 6,077,850. The preparation of chromene compounds is also described in U.S. Patent No. 6,034,256 (which are incorporated by reference in their entirety).

[0282] The arylpyridazinones useful in the present invention can be prepared by the methods described in WO 00 / 24719. The preparation of arylpyridazinones is also described in WO 99 / 10332. Arylpyridazinones can also be prepared by the methods described in WO 99 / 10331 (which are incorporated by reference in their entirety).

[0283] 5-Alkyl-2-arylaminophenylacetic acids and derivatives useful in the present invention can be prepared by the methods described in WO 99 / 11605 (incorporated by reference).

[0284] Diarylmethylidene furan derivative Cox-2 selective inhibitors useful in the present invention can be prepared by the methods described in US Pat. No. 6,180,651 (incorporated by reference).

[0285] Celecoxib for use in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 5,466,823 (incorporated by reference).

[0286] Valdecoxib for use in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 5,633,272 (incorporated by reference).

[0287] Parecoxib for use in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 5,932,598 (incorporated by reference).

[0288] Rofecoxib for use in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 5,474,995 (incorporated by reference).

[0289] Deracoxib for use in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 5,521,207 (incorporated by reference).

[0290] Etoricoxib for use in the compositions and methods of the present invention can be prepared by the methods described in WO 98 / 03484 (incorporated by reference).

[0291] Meloxicam for use in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 4,233,299 (incorporated by reference).

[0292] The compound 4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide used in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 5,994,381 (incorporated by reference).

[0293] The compound 2-(3,4-difluorophenyl)-4-(3-hydroxy-3-methylbutoxy)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone used in the compositions and methods of the present invention can be prepared by the methods described in WO 00 / 24719 (incorporated by reference).

[0294] The compound 2-(3,5-difluorophenyl)-3-[4-(methylsulfonyl)phenyl]-2-cyclopenten-1-one used in the compositions and methods of the present invention can be prepared by the methods described in European Patent Application Publication No. 0863134 (incorporated by reference).

[0295] The compound 2-[(2-chloro-6-fluorophenyl)amino]-5-methylbenzeneacetic acid used in the compositions and methods of the present invention can be prepared by the methods described in WO 99 / 11605 (incorporated by reference).

[0296] The compound N-[2-(cyclohexyloxy)-4-nitrophenyl]methanesulfonamide used in the compositions and methods of the present invention can be prepared by the methods described in US Pat. No. 4,885,367 (incorporated by reference).

[0297] The compound (3Z)-3-[(4-chlorophenyl)[4-(methylsulfonyl)phenyl]methylene]dihydro-2(3H)-furanone used in the compositions and methods of the present invention can be prepared by the methods described in U.S. Pat. No. 6,180,651 (incorporated by reference).

[0298] Cytosolic phospholipase A2 (cPLA2) inhibitors In one embodiment, the PEG2 antagonist may be, by way of example only, arachidonyl trifluoromethyl ketone, [ka] are inhibitors of cytosolic phospholipase A2 (cPLA2), such as

[0299] C. Further Combinations—Representative Checkpoint Inhibitors In certain embodiments, the combination therapy comprising a combination of a PGE2 antagonist and an I-DASH inhibitor may be further supplemented by treatment with one or more additional agents, such as other cancer immunotherapeutics (i.e., other checkpoint inhibitors), chemotherapeutics, adjuvants, and / or agents that render tumor cells more susceptible to chemical or immunological killing.

[0300] For example, the therapy may further include administering an inhibitor of an immune checkpoint molecule, or an activator of a costimulatory molecule, or a combination thereof. Exemplary inhibitors of immune checkpoint molecules include inhibitors of one or more of PD-1, CTLA-4, TIM-3, LAG-3, CEACAM, VISTA, BTLA, TIGIT, LAIR1, CD160, 2B4, NLRP1, NRLP3, STING, or TGFRβ. Exemplary activators of costimulatory molecules include agonists of one or more of OX40, CD2, CD27, CDS, ICAM-1, LFA-1 (CD11a / CD18), ICOS (CD278), 4-1BB (CD137), GITR, CD30, CD40, BAFFR, HVEM, CD7, LIGHT, NKG2C, SLAMF7, NKp80, CD160, B7-H3, or CD83 ligand. Exemplary immune checkpoint inhibitors and exemplary costimulatory molecule activators can be found in WO 2016 / 054555, which is incorporated herein by reference.

[0301] Antibody: The antibody can be selected from any antibody, for example, any recombinantly produced or naturally occurring antibody known in the art, particularly antibodies suitable for therapeutic purposes. As used herein, the term "antibody" is used in its broadest sense and specifically encompasses monoclonal and polyclonal antibodies (including antagonists, and blocking or neutralizing antibodies), as well as antibody species with polyepitopic specificity. According to the present invention, "antibody" typically includes naturally occurring antibodies, antibodies produced by immunization in a host organism, antibodies isolated and identified from naturally occurring antibodies or antibodies produced by immunization in a host organism, antibodies recombinantly produced by molecular biology methods known in the art, as well as any antibody known to those skilled in the art (e.g., IgM, IgD, IgG, IgA, and IgE antibodies), including chimeric antibodies, human antibodies, humanized antibodies, bispecific antibodies, intrabodies (i.e., antibodies expressed intracellularly and optionally localized to a specific cellular compartment), and fragments and variants of the aforementioned antibodies. Generally, antibodies consist of a light chain and a heavy chain, each of which has a variable region and a constant region. The light chain consists of an N-terminal variable region, VL, and a C-terminal constant region, CL. On the other hand, the heavy chain of an IgG antibody, for example, consists of an N-terminal variable region, VH, and three constant regions, CH1, CH2, and CH3. Single-chain antibodies can also be used in accordance with the present invention. The antibody preferably comprises a full-length antibody, i.e., one composed of a full-length heavy chain and a full-length light chain as described above. However, antibody derivatives, such as antibody fragments, variants, or adducts, can also be used in accordance with the present invention as inhibitors of PD-1, CTLA-4, or other immune checkpoint pathways. The antibody fragment can be selected from the Fab, Fab', F(ab')2, Fc, Facb, pFc', Fd, and Fv fragments of the (full-length) antibodies described above. Antibody fragments are generally known in the art. For example, a Fab ("fragment, antigen-binding") fragment consists of one constant region and one variable region from each of the heavy and light chains. The two variable regions bind to an epitope on a specific antigen. The two chains are linked via disulfide bonds. An scFv ("single-chain variable fragment") fragment, for example, typically consists of the variable regions of a light chain and a heavy chain.The domains are linked by artificial bonds (typically polypeptide bonds, such as peptides consisting of 15-25 glycine, proline and / or serine residues).

[0302] Polyclonal antibody: A polyclonal antibody typically refers to a mixture of antibodies directed against a particular antigen or immunogen or protein epitope, produced by immunizing a host organism such as a mammal, including, for example, goats, cows, pigs, dogs, cats, donkeys, monkeys, apes, and rodents (such as mice, hamsters, and rabbits). Polyclonal antibodies are generally not identical and therefore typically recognize different epitopes or regions from the same antigen. Thus, in such cases, a mixture (composition) of different antibodies is typically used, each antibody directed against a particular antigen or immunogen or protein epitope, particularly, by way of example only, antibodies against PD-1, PD-L1, PD-L2, CTLA-4, or other immune checkpoint proteins.

[0303] Monoclonal antibody: The term "monoclonal antibody" typically refers to an antibody obtained from a population of substantially identical antibodies, i.e., each antibody in the population is identical except for minor naturally occurring mutations. Monoclonal antibodies are highly specific, being directed against a single antigenic site. Furthermore, in contrast to conventional (polyclonal) antibody preparations, which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen. For example, the monoclonal antibodies defined above can be produced by the hybridoma method first described by Kohler and Milstein, Nature, 256:495 (1975), or may be produced by recombinant DNA methods, e.g., as described in U.S. Pat. No. 4,816,567 (incorporated by reference). "Monoclonal antibodies" may also be isolated from phage libraries generated using the techniques described, e.g., in McCafferty et al., Nature, 348:552-554 (1990). According to Kohler and Milstein, an immunogen (antigen) of interest is injected into a host, such as a mouse, and B cell lymphocytes produced in response to the immunogen are harvested after a period of time. The B cells are mixed with myeloma cells obtained from the mouse and introduced into a culture medium that allows the B cells to fuse with the myeloma cells, creating hybridomas. These fused cells (hybridomas) are then placed into individual wells of a microtiter plate and grown to produce monoclonal antibodies. The monoclonal antibodies are tested to determine which are suitable for detecting the antigen of interest. After selection, the monoclonal antibodies can be expanded in cell culture or by injecting the hybridomas into mice. For the present invention, and by way of example only, monoclonal antibodies against PD-1, PD-L1, PD-L2, CTLA-4, or other immune checkpoint proteins are particularly preferred.

[0304] Chimeric antibodies: Chimeric antibodies may be used as PD-1, CTLA-4 or immune checkpoint pathway inhibitors according to the present invention, and are preferably antibodies in which the constant regions of the above-mentioned antibodies have been replaced with sequences of antibodies from other organisms, preferably human sequences.

[0305] Humanized antibodies: Humanized (non-human) antibodies may be used as PD-1, CTLA-4 or immune checkpoint pathway inhibitors according to the present invention; these humanized antibodies are antibodies in which the constant and variable regions (excluding the hypervariable regions) of the antibody have been replaced with human sequences.

[0306] Human antibodies: Human antibodies can be isolated from human tissue or from immunized non-human host organisms transgenic for the human IgG locus. Additionally, human antibodies can be provided using phage display.

[0307] Bispecific antibodies: In the context of the present invention, bispecific antibodies preferably bind to two different F domains to recruit effector molecules, such as, for example, toxins, drugs, cytokines, etc., to target effector cells, such as CTLs, NK cells, macrophages, granulocytes, etc. ab Bispecific antibodies are antibodies that act as adapters between effectors and their corresponding targets through their F domains (see Kontermann RE, Acta Pharmacol. Sin, 2005, 26(1): 1-9). The bispecific antibodies described herein generally comprise two different F domains. abThe regions are configured to recognize, for example, two different antigens, immunogens, epitopes, drugs, cells (or receptors on cells), or other molecules (or structures) as described above. As used herein, a bispecific antibody means that the antigen-binding regions of the antibody are specific for two different epitopes. Thus, different antigens, immunogens, epitopes, etc. are brought into close proximity, optionally allowing direct interaction between the two components. For example, different cells, such as effector cells and target cells, can be connected via bispecific antibodies. The present invention encompasses, but is not limited to, antibodies or fragments thereof that bind to a soluble antigen on the one hand and to an antigen or receptor, such as PD-1 or its ligands PD-L1 and PD-L2 on the cell surface of tumor cells, etc., on the other hand. Intrabodies (or intrabodies): Intrabodies can be antibodies as described above. These antibodies are intrabodies, and thus can be encoded by nucleic acids used to express the encoded antibodies. Thus, nucleic acids encoding antibodies, preferably antibodies as described above, particularly antibodies against members of the PD-1 pathway (e.g., PD-1, PD-L1, or PD-L2), can be used as PD-1 pathway inhibitors of the present invention.

[0308] PD-1 antagonist The PD-1 gene is a 55 kDa type I transmembrane protein that is part of the Ig gene superfamily (Agata et al. (1996) Int Immunol 8:765-72). PD-1 contains a membrane-proximal immunoreceptor tyrosine-based inhibitory motif (ITIM) and a membrane-distal tyrosine-based switch motif (ITSM) (Thomas, ML (1995) J Exp Med 181:1953-6; Vivier, E and Daeron, M (1997) Immunol Today 18:286-91). Two ligands for PD-1, PD-L1 and PD-L2, have been identified that have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J Exp Med 192: 1027-34; Latchman et al. (2001) Nat Immunol 2:261-8; Carter et al. (2002) Eur J Immunol 32:634-43). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1 but not other CD28 family members. PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9). The interaction between PD-1 and PD-L1 results in a reduction in tumor-infiltrating lymphocytes, a decrease in T cell receptor-mediated proliferation, and immune evasion by cancerous cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100). Immunosuppression can be abrogated by inhibiting the local interaction of PD-1 with PD-L1, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170: 1257-66).

[0309] As used herein, the terms "programmed death 1," "programmed cell death 1," "protein PD-1," "PD-1," "PD1," "PDCD1," "hPD-1," and "hPD-I" are used interchangeably and encompass variants, isoforms, species homologs of human PD-1, and analogs that share at least one epitope with human PD-1. The complete human PD-1 sequence can be found in Genbank Accession No. U64863.

[0310] As used herein, the terms "programmed cell death 1 ligand 1," "PD-L1," "PDL1," "PDCD1L1," "PDCD1LG1," "CD274," "B7 homolog 1," "B7-H1," "B7-H," and "B7H1" are used interchangeably and include variants, isoforms, species homologs, and analogs of human PDL-1 that share at least one epitope with human PDL-1. The complete human PD-L1 amino acid sequence—isoform a precursor—can be found in Genbank accession number NP_054862.1. The complete human PD-L1 amino acid sequence—isoform b precursor—can be found in Genbank accession number NP_001254635.1.

[0311] The term "PD-1 axis binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners, so as to eliminate T cell dysfunction resulting from signaling in the PD-1 signaling axis and thereby restore or enhance T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

[0312] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-1 with one or more of its binding partners (e.g., PD-L1, PD-L2, etc.). In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to its binding partners. In particular aspects, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes mediated by signaling through PD-1, such that dysfunction of dysfunctional T cells is alleviated (e.g., effector responses to antigen recognition are enhanced). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a particular aspect, the PD-1 binding antagonist is MDX-1106, as described herein. In another particular aspect, the PD-1 binding antagonist is Merck 3745, as described herein. In another particular aspect, the PD-1 binding antagonist is CT-011, as described herein.

[0313] A "PD-L1 binding antagonist" is a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1, B7-1). In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In particular aspects, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L1 with one or more of its binding partners (e.g., PD-1, B7-1). In one embodiment, the PD-L1 binding antagonist reduces negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes that are mediated by signaling through PD-L1, such that the dysfunction of the dysfunctional T cells is reduced (e.g., the effector response to antigen recognition is enhanced). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In a specific aspect, the anti-PD-L1 antibody is YW243.55.S70, as described herein. In another specific aspect, the anti-PD-L1 antibody is MDX-1105, as described herein. In another specific aspect, the anti-PD-L1 antibody is MPDL3280A, as described herein.

[0314] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or interferes with signal transduction resulting from the interaction of PD-L2 with one or more of its binding partners (e.g., PD-1). In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to its binding partner. In a particular aspect, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or interfere with signal transduction resulting from the interaction of PD-L2 with one or more of its binding partners (e.g., PD-1). In one embodiment, the PD-L2 binding antagonist reduces the negative costimulatory signal mediated by or through cell surface proteins expressed on T lymphocytes that is mediated by signaling through PD-L2, such that the dysfunction of the dysfunctional T cell is reduced (e.g., the effector response to antigen recognition is enhanced). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0315] PD-1 pathway: All members of the PD-1 pathway are proteins involved in PD-1 signal transduction. On the one hand, these proteins may be proteins that induce PD-1 signal transduction upstream of PD-1, such as PD-1 ligands PD-L1 and PD-L2, and PD-1, a signaling receptor. On the other hand, these proteins may be signaling proteins downstream of the PD-1 receptor. In the context of the present invention, particularly preferred members of the PD-1 pathway are PD-1, PD-L1, and PD-L2.

[0316] PD-1 pathway inhibitor: In the context of the present invention, a PD-1 pathway inhibitor is preferably defined as a compound capable of impairing PD-1 pathway signaling, preferably signaling mediated by the PD-1 receptor. Accordingly, a PD-1 pathway inhibitor may be any inhibitor of any member of the PD-1 pathway capable of antagonizing PD-1 pathway signaling. In this regard, the inhibitor may be an antagonist antibody as defined herein that targets any member of the PD-1 pathway, preferably against the PD-1 receptor, PD-L1, or PD-L2. This antagonist antibody may be encoded by a nucleic acid. Such an encoded antibody is also referred to as an "intrabody" as defined herein. Alternatively, a PD-1 pathway inhibitor may be a fragment of a PD-1 receptor or a PD1 receptor that blocks the activity of a PD-1 ligand. B7-1 or a fragment thereof may similarly act as a PD-1 inhibitory ligand. Furthermore, the PD-1 pathway inhibitor may be a small interfering RNA (siRNA) or an antisense RNA against a member of the PD-1 pathway (preferably PD-1, PD-L1, or PD-L2). Additionally, the PD-1 pathway inhibitor may be a protein (or a nucleic acid sequence encoding the same) that contains an amino acid sequence capable of binding to PD-1 and preventing PD-1 signaling, for example, by inhibiting the interaction of PD-1 with B7-H1 or B7-DL. Furthermore, the PD-1 pathway inhibitor may be a small molecule inhibitor capable of inhibiting PD-1 pathway signaling, such as a PD-1-binding peptide or a small organic molecule.

[0317] In certain embodiments, PD-1 antagonists of the present invention include substances that bind to a ligand of PD-1 and interfere with, reduce, or inhibit the binding of one or more ligands to the PD-1 receptor, or that bind directly to the PD-1 receptor without participating in signaling through the PD-1 receptor. In one embodiment, the PD-1 antagonist binds directly to PD-1 and blocks PD-1 inhibitory signaling. In another embodiment, the PD-1 antagonist binds to one or more ligands of PD-1 (e.g., PD-L1 and PD-L2) and reduces or inhibits the ligand(s) from causing inhibitory signaling through PD-1. In one embodiment, the PD-1 antagonist binds directly to PD-L1 and inhibits or prevents PD-L1 from binding to PD-1, thereby blocking PD-1 inhibitory signaling.

[0318] PD-1 antagonists used in the methods and compositions of the present invention encompass PD-1-binding scaffold proteins, including, but not limited to, PD-1 ligands, antibodies, and multivalent drugs. In one specific embodiment, the antagonist is a fusion protein such as AMP-224. In another embodiment, the antagonist is an anti-PD-1 antibody ("PD-1 antibody"). Anti-human PD-1 antibodies (or VH and / or VL domains derived therefrom) suitable for use in the present invention can be generated using methods well known in the art. Alternatively, art-recognized anti-PD-1 antibodies may be used. For example, antibodies MK-3475 or CT-011 can be used. In addition, monoclonal antibodies 5C4, 17D8, 2D3, 4H1, 4A11, 7D3, and 5F4, described in WO 2006 / 12116 (the teachings of which are incorporated by reference), can be used. Antibodies that compete with any of these art-recognized antibodies for binding to PD-1 can also be used.

[0319] In another embodiment, the PD-1 antagonist is an anti-PD-L1 antibody. Anti-human PD-L1 antibodies (or VH and / or VL domains derived therefrom) suitable for use in the present invention can be generated using methods known in the art. Alternatively, art-recognized anti-PD-L1 antibodies can be used. For example, MEDI4736 (also known as anti-B7-H1) or MPDL3280A (also known as RG7446) can be used. In addition, monoclonal antibodies 12A4, 3G10, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4, described in WO 2007 / 005874 and U.S. Patent No. 7,943,743 (the teachings of which are incorporated by reference), can be used. Antibodies that compete with any of these art-recognized antibodies for binding to PD-L1 can also be used.

[0320] An example of an anti-PD-Ll antibody is 12A4 (WO 2007 / 005874 and U.S. Patent No. 7,943,743). In one embodiment, the antibody comprises the heavy and light chain CDRs or VRs of 12A4. Thus, in one embodiment, the antibody comprises the CDRl, CDR2, and CDR3 domains of the VH region of 12A4 having the sequence set forth in SEQ ID NO: 1, and the CDRl, CDR2, and CDR3 domains of the VL region of 12A4 having the sequence set forth in SEQ ID NO: 3. In another embodiment, the antibody comprises the CDRl, CDR2, and CDR3 domains of the heavy chain having the sequences set forth in SEQ ID NOs: 5, 6, and 7, respectively, and the CDRl, CDR2, and CDR3 domains of the light chain having the sequences set forth in SEQ ID NOs: 8, 9, and 10, respectively. In another embodiment, the antibody comprises the VH and / or VL regions having the amino acid sequences set forth in SEQ ID NO: 1 and / or SEQ ID NO: 3, respectively. In another aspect, the antibody comprises a heavy chain variable (VH) region and / or a light chain variable (VL) region encoded by the nucleic acid sequences set forth in SEQ ID NO:2 and / or SEQ ID NO:4, respectively. In another embodiment, the antibody competes for binding to and / or binds to the same epitope on PD-L1 as the above antibodies. In another embodiment, the antibody has at least about 90% variable region amino acid sequence identity to the above antibodies (e.g., at least about 90%, 95%, or 99% variable region identity to SEQ ID NO:1 or SEQ ID NO:3).

[0321] Anti-PD-1 antibody or anti-PD-L1 antibody is 10 -7 M or less, 5x10 -8 M or less, 10 -8 M or less, 5x10 -9 M, 10 -9 Medium, 5x10 -10 M or 10 -10 They can bind to PD-1 or PD-L1, respectively, with a KD of ≤M.

[0322] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody selected from nivolumab, pembrolizumab, or pidilizumab. A preferred PD-1 inhibitor is nivolumab.

[0323] In some embodiments, the anti-PD-1 antibody is nivolumab. Other names for nivolumab include MDX-1106, MDX-1106-04, ONO-4538, or BMS-936558. In some embodiments, the anti-PD-1 antibody is nivolumab (CAS Registry Number: 946414-94-4). Nivolumab is a fully human IgG4 monoclonal antibody that specifically blocks PD1. Nivolumab (clone 5C4) and other human monoclonal antibodies that specifically bind to PD1 are disclosed in U.S. Pat. No. 8,008,449 (incorporated by reference) and WO 2006 / 121168 (incorporated by reference). In other embodiments, the anti-PD-1 antibody is pembrolizumab. Pembrolizumab (trade name KEYTRUDA, formerly known as lambrolizumab, Merck 3745, MK-3475, or SCH-900475) is a humanized IgG4 monoclonal antibody that binds to PD1. Pembrolizumab is disclosed, for example, in Hamid, O. et al. (2013) New England Journal of Medicine 369 (2): 134-44, WO 2009 / 114335 (incorporated by reference), and U.S. Pat. No. 8,354,509 (incorporated by reference).

[0324] In some embodiments, the anti-PD-1 antibody is pidilizumab. Pidilizumab (CT-011; Cure Tech) is a humanized IgG1k monoclonal antibody that binds to PD1. Pidilizumab and other humanized anti-PD-1 monoclonal antibodies are disclosed in WO 2009 / 101611. Other anti-PD1 antibodies are disclosed in U.S. Patent No. 8,609,089, U.S. Patent Application Publication No. 2010028330, and / or U.S. Patent Application Publication No. 20120114649. Other anti-PD1 antibodies include AMP514 (Amplimmune).

[0325] In some embodiments, the PD-1 inhibitor is an immunoadhesin (e.g., an immunoadhesin comprising an extracellular or PD-1-binding portion of PD-L1 or PD-L2 fused to a constant region (e.g., an Fc region of an immunoglobulin sequence). In some embodiments, the PD-1 inhibitor is AMP-224. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the anti-PD-L1 inhibitor is YW243.55.S70, MPDL3280A, MEDI-4736, MSB-0010718C, or MDX-1105.

[0326] In one embodiment, the PD-L1 inhibitor is MDX-1105. MDX-1105, also known as BMS-936559, is an anti-PD-L1 antibody described in WO 2007 / 005874. In one embodiment, the PD-L1 inhibitor is YW243.55.S70. The YW243.55.S70 antibody is an anti-PD-L1 antibody described in WO 2010 / 077634 (incorporated by reference) (the heavy and light chain variable region sequences are set forth in SEQ ID NOs: 20 and 21, respectively).

[0327] In one embodiment, the PD-L1 inhibitor is MDPL3280A (Genentech / Roche). MDPL3280A is a human Fc-optimized IgG1 monoclonal antibody that binds to PD-L1. MDPL3280A and other human monoclonal antibodies against PD-L1 are disclosed in U.S. Patent No. 7,943,743 (incorporated by reference) and U.S. Patent Application Publication No. 2012 / 0039906 (incorporated by reference). In another embodiment, the PD-L2 inhibitor is AMP-224. AMP-224 is a PD-L2Fc fusion soluble receptor that blocks the interaction between PD-1 and B7-H1 (B7-DCIg; Amplimmune; disclosed, for example, in WO 2010 / 027827 and WO 2011 / 066342 (both of which are incorporated by reference)).

[0328] In one embodiment, the PD-1 pathway inhibitor is a small molecule antagonist of PD-1 pathway signaling. Such small molecule antagonists include substances that bind to one or more of PD-1, PD-1L, and / or PD-1L2 and inhibit the interaction of PD-1 with PD-1L1 and / or PD-1L2.

[0329] Exemplary small molecule antagonists of PD-1 pathway signaling can be found, inter alia, in U.S. Patent Application Publication Nos. 2014 / 0294898 and 2014 / 0199334, and WO 2013 / 132317 and WO 2012 / 168944, each of which is incorporated herein by reference.

[0330] By way of example only, the combination therapy of the present invention can be practiced with a small molecule antagonist selected from the group consisting of: [ka]

[0331] In other embodiments, the small molecule antagonist is represented by the following general formula: or a retro analogue thereof, or a pharmaceutically acceptable stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R1 is the free or amidated C-terminus of Ser; L is -NH(CH2) n NH- or -NH(CH2CH2O) n is a linker selected from NH-; R4 is hydrogen, amino (C1-C 20 ) alkyl, —NHCOCH3 or —NHCONH2.

[0332] In yet another embodiment, the small molecule antagonist is represented by the following general formula: or a retro analog thereof, or a pharmaceutically acceptable stereoisomer thereof, or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R1 is either the N-terminus of Ser or substituted with either the hydroxyl or amino group of Ser (C1-C 20 ) is acyl; L is -NH(CH2) n NH-, -NH(CH2) n CH(NH2)CO-, -OOC(CH2) m COO-, -NH(CH2) n CO-, -NH(CH2CH2O) n NH-, -NH(CH2CH2O) n CO- or -CO(CH2CH2O) n CO-; R2 is the free C-terminus, the amidated C-terminus, or the N-terminus of Am2; or Y-R5; Y is -OOC(CH2) m COO-, -CO(CH2) n NH-, -CO(CH2CH2O) n NH- or -COCH2(OCH2CH2) n is an optional linker selected from NH-; R5 is an albumin binding moiety (such as maleimidopropionic acid); R3 is OH or NH2; R4 is a substituent on the phenyl group of Phe, and can be hydrogen, amino (C1-C 20 ) alkyl, -NHCOCH3 or -NHCONH2; n is an integer having a value selected from 2 to 10, inclusive; m is an integer having a value selected from 0 to 8, inclusive; and One of the peptide bonds (-CONH-) of Ser-Asn, Asn-Thr, or Thr-Ser is [ka] may be replaced by a modified peptide bond of where Q is hydrogen, -CO(C1-C 20 ) alkyl or -COO(C1-C 20 ) alkyl groups; and one or more or all of the amino acids may be in the D configuration.

[0333] For example, the small molecule antagonist is selected from the group consisting of: [ka] [ka] [ka] [ka] [ka] [ka] [ka]

[0334] CTLA4 antagonist In certain embodiments, the combinations described herein also include a CTLA-4 inhibitor. Exemplary anti-CTLA-4 antibodies include tremelimumab (an IgG2 monoclonal antibody available from Pfizer, formerly known as ticilimumab, CP-675,206) and ipilimumab (a CTLA-4 antibody, also known as MDX-010, CAS No. 477202-00-9).

[0335] Information regarding tremelimumab (or an antigen-binding fragment thereof) for use in the methods described herein can be found in U.S. Patent No. 6,682,736 (incorporated by reference) (referred to therein as 11.2.1), the disclosure of which is incorporated herein by reference in its entirety. Tremelimumab (also known as CP-675,206, CP-675, CP-675206, and ticilimumab) is a human IgG2 monoclonal antibody that is highly selective for CTLA-4 and blocks the binding of CTLA-4 to CD80 (B7.1) and CD86 (B7.2). The antibody has been shown to result in immune activation in vitro, and some patients treated with tremelimumab have shown tumor regression.

[0336] Tremelimumab for use in the methods described herein comprises a heavy chain and a light chain, or a heavy chain variable region and a light chain variable region. In certain embodiments, tremelimumab or an antigen-binding fragment thereof for use in the methods described herein comprises a light chain variable region comprising the amino acid sequence described above and a heavy chain variable region comprising the amino acid sequence described above. In certain embodiments, tremelimumab or an antigen-binding fragment thereof for use in the methods described herein comprises a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences described above, and the light chain variable region comprises the Kabat-defined CDR1, CDR2, and CDR3 sequences described above. Those skilled in the art can easily identify CDRs according to Chothia definition, Abm definition, or other definitions known to those skilled in the art. In certain embodiments, tremelimumab for use in the methods described herein comprises the variable heavy and variable light chain CDR sequences of an antibody disclosed in U.S. Patent No. 6,682,736 (incorporated herein by reference in its entirety).

[0337] The present invention also contemplates utilizing small molecule inhibitors of CTLA-4, such as those described in Huxley et al. 2004 Cell Chemical Biology 11:1651-1658, including compounds of the formula: [ka]

[0338] Other small molecule CTLA-4 antagonists include: [ka] Examples include:

[0339] In one embodiment, the combination comprises an immuno-DASH inhibitor, an anti-PD-1 antibody molecule (such as those described herein), and an anti-CTLA-4 antibody (e.g., ipilimumab). Exemplary doses that can be used include a dose of about 1-10 mg / kg, e.g., 3 mg / kg, of the anti-PD-1 antibody molecule, and a dose of about 3 mg / kg of the anti-CTLA-4 antibody (e.g., ipilimumab).

[0340] Other exemplary anti-CTLA-4 antibodies are disclosed, for example, in US Pat. No. 5,811,097.

[0341] D. Further Combination Chemotherapy Agents Exemplary classes of chemotherapeutic agents with which the PD-1 antagonist / immuno-DASH inhibitor combination therapy of the present invention can be used in further combination therapy include: DNA-alkylating agents (such as cyclophosphamide, ifosfamide, cisplatin, carboplatin, dacarbazine, etc.), antimetabolites (such as 5-fluorouracil, capecitabine, 6-mercaptopurine, methotrexate, gemcitabine, cytarabine, fludarabine, etc.), mitotic inhibitors (such as paclitaxel, docetaxel, vinblastine, vincristine, etc.), anticancer antibiotics (such as daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, etc.), topoisomerase I and / or II inhibitors (such as topotecan, irinotecan, etoposide, teniposide, etc.), and hormone therapy agents (such as tamoxifen, flutamide, etc.).

[0342] In some embodiments, the chemotherapeutic agent is vemurafenib, GDC-0879, PLX-4720, 5-fluorouracil, aldesleukin, aminopterin, asparaginase, bleomycin sulfate, capecitabine, carboplatin, chlorambucil, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin hydrochloride, decitabine, docetaxel, doxorubicin, doxorubicin hydrochloride, epirubicin hydrochloride, etoposide, etoposide phosphate, floxuridine, fludarabine, fluorouracil, gemcitabine, gemcitabine hydrochloride, hydroxyurea, idarubicin hydrochloride, ifosfamide, interferon, interferon-α2a, interferon-α2 b, interferon-alpha n3, interferon-alpha 1b, interleukin, iproplatin, irinotecan, lobaplatin, mechlorethamine hydrochloride, melphalan, mercaptopurine, methotrexate, methotrexate sodium, mitomycin, mitoxantrone, nedaplatin, olmiplatin, oxaliplatin, paclitaxel, pemetrexed, pegaspargase, pentostatin, prednisone, porfimer sodium, procarbazine hydrochloride, raltitrexed, satraplatin, taxol, taxotere, teniposide, thioguanine, topotecan hydrochloride, triplatin tetranitrate (BBR3464), tetraplatin, vinblastine sulfate, vincristine sulfate, and vinorelbine tartrate.

[0343] Recent evidence indicates that certain anticancer drugs, such as anthracyclines, induce an immunogenic type of apoptosis that stimulates phagocytosis of apoptotic cells by dendritic cells (DCs) and activation of cytotoxic CD8+ T cells via cross-priming. In some embodiments, the chemotherapeutic agent is a substance that induces immunogenic cell death (e.g., antigenic apoptosis) of tumor cells. For example, the effect of the chemotherapeutic agent may include increasing cell surface expression of calreticulin and / or heat shock protein 70 (HSP70). Exemplary chemotherapeutic agents of this type include anthracyclines, such as doxorubicin.

[0344] In a preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with an antitumor platinum complex, including but not limited to cisplatin, oxaliplatin, carboplatin, triplatin tetranitrate (BBR3464), satraplatin, tetraplatin, olmiplatin, iproplatin, nedaplatin, and lobaplatin, in the treatment of cancer, more particularly in the treatment of cancer selected from lung cancer, sarcoma, melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, brain tumor, and lymphoma. Particularly preferred is the combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with cisplatin, oxaliplatin, carboplatin, triplatin tetranitrate, satraplatin, tetraplatin, olmiplatin, iproplatin, nedaplatin and lobaplatin, and even more preferred is the combination with cisplatin and oxaliplatin in the treatment of cancer, more particularly in the treatment of a cancer selected from lung cancer, sarcoma, malignant melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer and brain cancer. In another preferred embodiment, the present invention relates to the use of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof in combination with an antimetabolite, including but not limited to 5-fluorouracil, gemcitabine, cytarabine, capecitabine, decitabine, floxuridine, fludarabine, aminopterin, methotrexate, pemetrexed, raltitrexed, ladribine, clofarabine, mercaptopurine, pentostatin, and thioguanine, in the treatment of cancer, more particularly, cancer selected from lung cancer, sarcoma, malignant melanoma, bladder cancer, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, esophageal cancer, brain tumor, anal cancer, leukemia, and lymphoma.Particularly preferred is a combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with 5-fluorouracil, gemcitabine, cytarabine, capecitabine, decitabine, floxuridine, fludarabine, aminopterin, methotrexate, pemetrexed, raltitrexed, ladribine, clofarabine, mercaptopurine, pentostatin, and thioguanine, and even more preferred is a combination with 5-fluorouracil, gemcitabine, cytarabine, and methotrexate, in the treatment of cancer, more specifically, a cancer selected from lung cancer, sarcoma, malignant melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, brain tumor, leukemia, and lymphoma.

[0345] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a mitotic inhibitor, including but not limited to paclitaxel, docetaxel, vinblastine, vincristine, vindesine, and vinorelbine, in the treatment of cancer, more particularly, a cancer selected from lung cancer, sarcoma, prostate cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, brain tumor, leukemia, and lymphoma. Particularly preferred is the combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with paclitaxel, docetaxel, vinblastine, vincristine, vindesine, and vinorelbine, and even more preferred is the combination with paclitaxel, docetaxel, vincristine, and vinorelbine, in the treatment of cancer, more particularly, in the treatment of a cancer selected from lung cancer, sarcoma, prostate cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, and brain tumors.

[0346] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with an anti-cancer antibiotic, including but not limited to daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pixantrone, valrubicin, mitomycin C, bleomycin, actinomycin A, and mithramycin, in the treatment of cancer, more specifically, a cancer selected from lung cancer, sarcoma, melanoma, bladder cancer, prostate cancer, pancreatic cancer, thyroid cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, neuroblastoma, brain cancer, anal cancer, testicular cancer, leukemia, multiple myeloma, and lymphoma. Particularly preferred is a combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, pixantrone, valrubicin, mitomycin C, bleomycin, actinomycin D, and mithramycin, and even more preferred is a combination with daunorubicin, doxorubicin, mitomycin C, and actinomycin D, in the treatment of cancer, more specifically, a cancer selected from lung cancer, sarcoma, malignant melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, brain tumor, leukemia, and lymphoma.

[0347] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a topoisomerase I and / or II inhibitor in the treatment of cancer, more particularly in the treatment of a cancer selected from lung cancer, sarcoma, melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, neuroblastoma, brain cancer, cervical cancer, testicular cancer, leukemia, and lymphoma. This group of chemotherapy includes, but is not limited to, topotecan, SN-38, irinotecan, camptothecin, rubitecan, etoposide, amsacrine, and teniposide. Particularly preferred is the combination of PM00104 or a pharmaceutically acceptable salt thereof with topotecan, SN-38, irinotecan, camptothecin, rubitecan, etoposide, amsacrine, and teniposide, and even more preferred with topotecan, irinotecan, and etoposide, in the treatment of cancer, more particularly, a cancer selected from lung cancer, sarcoma, malignant melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, and brain tumors.

[0348] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a proteasome inhibitor in the treatment of cancer, more specifically, in the treatment of cancer selected from lung cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, colorectal cancer, brain tumors, multiple myeloma, and lymphoma. This chemotherapy group includes, but is not limited to, bortezomib, disulfiram, epigallocatechin gallate, and salinosporamide A. Particularly preferred is the combination of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof with bortezomib, disulfiram, epigallocatechin gallate, and salinosporamide A, and even more preferred is the combination with bortezomib, in the treatment of cancer, more specifically, in the treatment of cancer selected from lung cancer, prostate cancer, pancreatic cancer, gastric cancer, liver cancer, colorectal cancer, and brain tumors.

[0349] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a histone deacetylase inhibitor, including but not limited to romidepsin, panobinostat, vorinostat, mocetinostat, belinstat, entinostat, resminostat, PCI-24781, AR-42, CUDC-101, and valproic acid, in the treatment of cancer, more particularly, a cancer selected from lung cancer, sarcoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, colorectal cancer, renal cancer, brain tumor, and lymphoma. Particularly preferred is a combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with romidepsin, panobinostat, vorinostat, mocetinostat, belinostat, entinostat, resminostat, PCI-24781, AR-42, CUDC-101, or valproic acid, and even more preferred is a combination with vorinostat, in the treatment of cancer, more specifically, in the treatment of a cancer selected from lung cancer, sarcoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, colorectal cancer, renal cancer, and brain tumor.

[0350] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a nitrogen mustard alkylating agent, including but not limited to melphalan, ifosfamide, chlorambucil, cyclophosphamide, mechlorethamine, uramustine, estramustine, and bendamustine, in the treatment of cancer, more particularly, a cancer selected from lung cancer, sarcoma, bladder cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, leukemia, multiple myeloma, and lymphoma. Particularly preferred is the combination of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof with melphalan, ifosfamide, chlorambucil, cyclophosphamide, mechlorethamine, uramustine, estramustine, and bendamustine, and even more preferred is the combination with cyclophosphamide, in the treatment of cancer, more particularly, in the treatment of cancer selected from lung cancer, sarcoma, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, and kidney cancer. In another preferred embodiment, the present invention relates to the combination of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof with a nitrosourea alkylating agent in the treatment of cancer, more particularly, in the treatment of cancer selected from lung cancer, ovarian cancer, breast cancer, brain tumor, multiple myeloma, and lymphoma. This group of chemotherapy includes, but is not limited to, lomustine, semustine, carmustine, fotemustine, and streptozotocin. Particularly preferred is the combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with lomustine, semustine, carmustine, fotemustine, and streptozotocin, and even more preferred is the combination with carmustine, in the treatment of cancer, more particularly in the treatment of a cancer selected from lung cancer, ovarian cancer, and breast cancer.

[0351] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a non-classical alkylating agent in the treatment of cancer, more specifically, in the treatment of cancer selected from lung cancer, sarcoma, melanoma, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, colorectal cancer, kidney cancer, brain tumor, leukemia, and lymphoma. This chemotherapy group includes, but is not limited to, procarbazine, dacarbazine, temozolomide, and altretamine. Particularly preferred is the combination of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof with procarbazine, dacarbazine, temozolomide, and altretamine, and even more preferred is the combination with dacarbazine and temozolomide, in the treatment of cancer selected from lung cancer, sarcoma, melanoma, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, colorectal cancer, kidney cancer, and brain tumor. In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with an estrogen antagonist in the treatment of cancer, more particularly in the treatment of breast cancer. This group of chemotherapy includes, but is not limited to, toremifene, fulvestrant, tamoxifen, and nafoxidine. Particularly preferred is the combination of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof with toremifene, fulvestrant, tamoxifen, and nafoxidine, and even more preferably with tamoxifen, in the treatment of breast cancer.

[0352] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with an androgen antagonist in the treatment of cancer, more particularly in the treatment of prostate cancer. This chemotherapy group includes, but is not limited to, bicalutamide, flutamide, MDV3100, and nilutamide. Particularly preferred is the combination of an immuno-DASH inhibitor or a pharmaceutically acceptable salt thereof with bicalutamide, flutamide, MDV3100, and nilutamide, and even more preferred is the combination with flutamide, in the treatment of prostate cancer.

[0353] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with an mTOR inhibitor in the treatment of cancer, more particularly in the treatment of cancer selected from lung cancer, sarcoma, melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, colorectal cancer, renal cancer, and brain tumors, including, but not limited to, sirolimus, temsirolimus, everolimus, ridaforolimus, KU-0063794, and WYE-354. Particularly preferred is a combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with sirolimus, temsirolimus, everolimus, ridaforolimus, KU-0063794, and WYE-354, and even more preferred is a combination with temsirolimus, in the treatment of a cancer selected from lung cancer, sarcoma, malignant melanoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, breast cancer, colorectal cancer, and brain tumors.

[0354] In another preferred embodiment, the present invention relates to the combination of a PD-1 antagonist / immuno-DASH inhibitor with a tyrosine kinase inhibitor in the treatment of cancer, more particularly in the treatment of cancer selected from lung cancer, sarcoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, and brain tumors, including but not limited to erlotinib, sorafenib, axitinib, bosutinib, cediranib, crizotinib, dasatinib, gefitinib, imatinib, canertinib, lapatinib, lestaurtinib, neratinib, nilotinib, semaxanib, sunitinib, vatalanib, and vandetanib. Particularly preferred is a combination of an immunoDASH inhibitor or a pharmaceutically acceptable salt thereof with erlotinib, sorafenib, axitinib, bosutinib, cediranib, crizotinib, dasatinib, gefitinib, imatinib, canertinib, lapatinib, lestaurtinib, neratinib, nilotinib, semaxanib, sunitinib, vatalanib, and vandetanib, and even more preferred is a combination with erlotinib, in the treatment of cancer, more particularly, in the treatment of a cancer selected from lung cancer, sarcoma, prostate cancer, pancreatic cancer, gastric cancer, ovarian cancer, liver cancer, breast cancer, colorectal cancer, kidney cancer, and brain tumors.

[0355] Another embodiment of the present invention relates to any one of the aforementioned methods, further comprising administering to said patient a MAP kinase pathway inhibitor or a WNT pathway inhibitor.

[0356] In some embodiments, the MAP kinase pathway inhibitor is selected from the group consisting of a BRAF inhibitor, a MEK inhibitor, a PI3K inhibitor, and a c-KIT inhibitor.

[0357] In some embodiments, the BRAF inhibitor is selected from the group consisting of GDC-0879, PLX-4720, sorafenib tosylate, dabrafenib, and ...

Claims

1. A compound having a structure represented by formula Ib: 【Chemistry 1】 [In the formula, W is -CN, -CH=NR ４ , 【Chemistry 2】 represents; X is O or S; X １ represents a halo; Y １ and Y ２ are independently OH or together with the boron atom to which they are attached form a 5-8 membered ring which can be hydrolyzed to a boronic acid; R １ represents, independently at each occurrence, a lower alkyl; R ２ Each occurrence of is selected from hydrogen, lower alkyl, lower alkynyl, -(CH ２ ) ｍ -R ３ , —C(═O)-alkyl, —C(═O)-alkenyl, —C(═O)-alkynyl, or —C(═O)-(CH ２ ) ｍ -R ３ represents; R ３ represents at each occurrence hydrogen, or substituted or unsubstituted lower alkyl, lower alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R ４ is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, -(CH ２ ) ｍ -R ３ , -(CH ２ ) ｎ -OH, -(CH ２ ) ｎ -O-lower alkyl, -(CH ２ ) ｎ -O-alkenyl, -(CH ２ ) ｎ -O-alkynyl, -(CH ２ ) ｎ -SH, -(CH ２ ) ｎ -S-lower alkyl, -(CH ２ ) ｎ -S-lower alkenyl, -(CH ２ ) ｎ -S-lower alkynyl, -(CH ２ ) ｎ -S-(CH ２ ) ｍ -R ３ , -C(O)C(O)NH ２ or -C(O)C(O)OR ８ represents; R ５ represents O or S; R ６ is N ３ , S.H., N.H. ２ , NO ２ OR ８ represents; R ７ is hydrogen, lower alkyl, amine, or OR ８ or R ５ and R ６ together with the phosphorus atom to which they are attached complete a heterocycle having 5 to 8 atoms in the ring structure; R ８ represents hydrogen or a substituted or unsubstituted alkyl, alkenyl, aryl, heteroaryl, aralkyl, heteroaralkyl, cycloalkyl, cycloalkenyl, or heterocyclyl; R ９ and R １０ are each independently absent or represent one, two or three substituents on the ring to which they are each attached, each of which is independently selected from halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, amino, acylamino, amido, cyano, isocyano, thiocyanato, isothiocyanato, cyanato, nitro, azido, sulfate, sulfonate, sulfonamido, lower alkyl-C(O)OH, -O-(lower alkyl)-C(O)OH, -guanidinyl; -(CH ２ ) ｍ -OH, -(CH ２ ) ｍ -O-lower alkyl, -(CH ２ ) ｍ -O-lower alkenyl, -(CH ２ ) ｎ -O-(CH ２ ) ｍ -R ３ , -(CH ２ ) ｍ -SH, -(CH ２ ) ｍ -S-lower alkyl, -(CH ２ ) ｍ -S-lower alkenyl, -(CH ２ ) ｎ -S-(CH ２ ) ｍ -R ３ may be; p is 1, 2 or 3; n is 0, 1, 2 or 3; m is 0, 1, 2 or 3.

2. 2. The compound of claim 1, which is a compound having a structure represented by Formula Ic, or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】

3. R ９ is absent or independently at each occurrence lower alkyl, -OH, -NH ２ , -N ３ 3. The compound according to claim 1 or 2, which is -(lower alkyl)-C(O)OH, -O-lower alkyl, -O-(lower alkyl)-C(O)OH, or -guanidinyl.

4. Each R １ The compound according to any one of claims 1 to 3, wherein is methyl.

5. Each R ２ The compound according to any one of claims 1 to 4, wherein is lower alkyl.

6. Each R ２ The compound according to any one of claims 1 to 4, wherein is methyl.

7. Each R ２ The compound according to any one of claims 1 to 4, wherein is hydrogen.

8. R １０ is absent or is —OH, —NH ２ , -CN or -N ３ A compound according to any one of claims 1 to 7, which exhibits a single substitution by:

9. R １０ The compound of claim 8, wherein is not present.

10. W is -B(OH) ２ or -CN.

11. W is -B(OH) ２ 11. The compound of claim 10,

12. The compound according to any one of claims 1 to 11, wherein X is O.

13. 【Chemical 4】 2. The compound of claim 1,

14. 【Chemical 5】 2. The compound of claim 1,

15. 【Chemical 6】 A compound having the structure:

16. 【Chemical 7】 A compound having the structure:

17. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a pharma- ceutically acceptable excipient.

18. 18. The pharmaceutical composition of claim 17, further comprising a PGE2 antagonist.

19. A pharmaceutical composition for treating cancer, comprising a compound according to any one of claims 1 to 16.

20. 20. The pharmaceutical composition of claim 19, further comprising a PGE2 antagonist.

21. 20. The pharmaceutical composition of claim 19, co-administered with a PGE2 antagonist.

22. 20. Use of a compound according to any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, in the manufacture of a medicament for treating cancer.

23. 23. The use according to claim 22, wherein the medicament further comprises a PGE2 antagonist.

24. 23. The use according to claim 22, wherein the medicament is co-administered with a PGE2 antagonist.

Images