MX2008007934A - Soft protease inhibitors and pro-soft forms thereof - Google Patents

Abstract

The invention provides compounds and methods for inhibiting proteases. One aspect of the invention features pro-soft inhibitors which react with an activating protease to release an active inhibitor moiety in proximity to a target protease. In certain instances, compounds inhibit proteasomes and/or post-proline cleaving enzymes (PPCE), such as dipeptidyl peptidase IV. The compounds of the invention provide a better therapeutic index, owing in part to reduced toxicity and/or improved specificity for the targeted protease.

Description

SOFT PROTEASE INHIBITORS AND PRO-SOFT FORMS OF THEMSELVES RELATED REQUESTS This application claims the priority benefit of United States Provisional Patent Application serial number 60 / 752,017, filed on December 19, 2005.

BACKGROUND OF THE INVENTION Proteases are enzymes that unfold proteins into specific peptide bonds. Proteases can be classified into four generic classes: serine, thiol or cysteinyl, acid or aspartyl, and metalloproteases (Cuypers et al., J., Biol. Chem. 1982, 257, 7086. Proteases are essential for a variety of activities biological, such as digestion, formation and dissolution of blood clots, reproduction, and immune reaction to external cells and organisms.However, aberrant proteolysis is associated with several diseases in humans and other mammals. It is often beneficial to break the function of one or more proteolytic enzymes in the course of a patient's treatment.The binding site for a peptide substrate P 1 7220SMX THXTO consists of a series of "subsites of specificity" across the surface of the enzyme. The term "specificity subsite" refers to a cavity or other site in the enzyme capable of interacting with a portion of a substrate for the enzyme. By discussing the interactions of peptides with proteases, for example, serine and cysteine proteinases, the present application uses the nomenclature of Schechter and Berger (Biochem Biophys, Res. Commun. 1967, 27, 157-162). The individual amino acid residues of a substrate or inhibitor Pl, P2, etc. are designated, and the corresponding subsites of the enzyme SI, S2, etc., are designated, starting with the carboxy terminal residue produced in the cleavage reaction. The cleavable bond of the substrate is the bond of the amide between the Pl-Pl 'of the substrate. Thus, for a Xaal-Xaa2 -Xaa3 -Xaa4 peptide that is split between the Xaa3 and Xaa residues, the Xaa3 residue refers to the Pl residue and binds to the SI subsite of the enzyme, Xaa2 is referred to as the P2 residue and binds to the subsitio S2, and so on. Dipeptidyl peptidase IV (DPIV or DPPIV) is a serine protease that cleaves the dipeptides at the N-terminus of a chain of peptides that preferably contain a proline residue in the penultimate position, for example, in the position Pl. The DPIV belongs to a group of peptidases associated with the cell membrane and, like most cell surface peptidases, it is an integral membrane protein of type II, which is anchored to the plasma membrane by its signal sequence. The DPIV is found in a variety of mammalian epithelia differentiated, endothelial and hematopoietic tissues and cells that include those of lymphoid origin that are found specifically on the surface of CD4 + T cells. The DPIV has been identified as the marker of differentiation of the leukocyte CD26 Proteasomes are cellular complexes that comprise proteases responsible for the majority of the production of muscle proteins in eukaryotic cells, which includes the proteolytic degradation of damaged, oxidized or misfolded proteins, as well as the process or degradation of important regulatory proteins required for various cellular functions, such as cell cycle progression. For example, the 26S proteasome is a multi-catalytic protease that comprises in its catalytic core the 20S proteasome, a complex of multiple subunits of approximately 700 kDa molecular weight. Although they function with an essential physiological role, the proteasome is also responsible for the improper or accelerated degradation of the protein that occurs as a result or cause of pathological conditions in which normal cellular processes they become sub-regu- lated. A notable example is cancer, in which the unregulated proteasome-mediated degradation of cell-cycle regulatory proteins, including cyclos, cyclin-dependent kinase inhibitors, and tumor suppressor genes, results in accelerated mitosis and unbridled, that promote the growth of cancer and its spread. (Goldberg et al. Chem. &; Biol. 1995, 2, 503-508; Coux et al. Ann. Rev. Biochem. , 1996, 65, 801-847, Deshaies, Trends Cell Biol. 1995, 5, 428-434). The inhibition of proteasome enzyme function promises to arrest or hinder the progress of the disease in disease states such as cancer or inflammation. Proteasome inhibitors, eg, lactacistma and its analogs, have been shown to block the development of the pre-epithelial and erythrocytic stages of parasites of Plasmodium species 1 of malaria. During both hepatic and epithelial stages, the parasite undergoes radical morphological changes and many rounds of replication, events that probably require proteasome activity. It has been found that lactacistm covalently modifies the catalytic N-terminal thromonomes of the active sites of the proteasomes, inhibiting the activity of all the proteasomes examined, which include those cells of mammals, protozoapos, and archaea. (Gantt et al., Antimicrob, Chemother Agents, 1998, 42, 2731-2738). The activation protein of the human fibroblast (FAP (x) is a cell surface molecule of 95,000 Mr originally identified with the monoclonal antibody (mAb) F19 (Rettig et al., Proc. Nati. Acad. Sci. 1988, 85, 3110-3114; Rettig et al. The Res of Cancer. 1993, 53, 3327-3335). The FAPa cDNA encodes a type of intact type II membrane protein with a large extracellular domain, trans-membrane segment, and short cytoplasmic tail (Scanlan et al., Proc. Nati Acad. Sci. USA 1994, 91, 5657 5661; WO 97/34927). FAPa shows 48% amino acid sequence identity for the CD26 T cell activation antigen, also known as dipeptidyl peptidase IV (DPP IV), a membrane binding protein with dipeptidyl peptidase activity (Scanlan et al. ). FAPa has the enzymatic activity and is a member of the senna protease family, with septa 624 which is critical for enzymatic function (WO 97/34927). The work using a membrane cover assay revealed that the FAPa dimers are capable of unfolding Ala-Pro-7-ammo-4-trifluoromethyl cumanna, Gly-Pro-7 -ammo-4-tpfluoromethyl cumapna, and di-peptides Lys- Pro-7-ammo-4-tpfluoromethyl cumapna (WO 97/34927).

FAPa is selectively expressed in reactive stromal fibroblasts of many histological types of human epithelial cancers, granulation tissue of scarred wounds and malignant cells of certain bones and soft tissue sarcomas. Normal adult tissues are generally devoid of perceptible AAP, but some fetal mesenchymal tissues express the molecule temporarily. In contrast, most common types of epithelial cancers, which include > 90% of breast carcinomas, non-small cell lung and colorectal carcinomas, contain reactive FAPa stromal fibroblasts (Scanlan et al.). These FAPa + fibroblasts accompany the newly formed tumor blood vessels, forming a distinct cellular compartment interposed between the capillary endothelium of the tumor and the basal aspect of clusters of malignant epithelial cells (Welt et al., J. Clin. Oncol., 1994, 12, 1193-1203). Although FAPa + stromal fibroblasts are found in both primary and metastatic carcinomas, benign and premalignant epithelial lesions tested (Welt et al) such as the fibroadenomas of sinus and colorectal adenomas, only rarely contain the FAPa + stromal cells. Based on the restricted distribution pattern of FAPa in normal tissues and its uniform expression in the stroma that supports many malignancies, clinical trials have begun with 131I-et? quetado F19 mAb in patients with metastatic colon carcinomas (Welt et al) BRIEF DESCRIPTION OF THE INVENTION One aspect of the present invention offers compounds that inhibit a protease . In certain cases, the compound is a soft inhibitor. The soft inhibitor is an inactive agent that is activated, i.e., unfolded by a "protease activation," to release a portion of the active inhibitor in the vicinity of an "objective protease." The identity of the target protease and protease protease may be the same or different. After activation of the pro-soft inhibitor, the active inhibitor portion undergoes self-deactivation by proto-desboronation. Another aspect of the present invention is that the irreversible proto-sputtering step produces harmless boric acid, which is expected to produce an improved safety profile (fewer side effects). The invention offers inhibitors for a broad series of proteases. For example, the inhibitor of the invention can inhibit post-proline unfolding enzymes (PPCE), such as dipeptidyl peptidase IV. In certain cases, the inhibitor of the invention inhibits the activity of the proteasome In other examples, the invention provides a soft inhibitor that is activated by a fibroblast activating protein to release a compound that inhibits prostate specific antigen (PSA). In other examples, the invention provides a soft inhibitor that is activated by a prostate specific antigen (PSA) to release a compound that inhibits proteasome activity. In a certain embodiment, the present invention provides pro-inhibitors that inhibit post-prolymal cleavage enzymes, such as dipeptidyl peptidase IV. Certain compounds of the invention have extended their duration. Accordingly, In certain embodiments, the inhibitor is selected, and the amount of inhibitor formulated, to provide a dosage that inhibits serum DPP IV levels by at least 50% for at least 4 hours after a single dose, and even more preferably for at least 8 hours or even 12 or 16 hours after a single dose. For example, In certain embodiments the dosage is selected in an effective amount to improve one or more aberrant indices associated with glucose metabolism disorders (e.g., glucose intolerance, insulin resistance, hyperglycemia, hyperinsulmia, and diabetes). I and II) for a period 24 hours Another aspect of the invention relates to a method of treating disorders and conditions by administering a protease inhibitor of the invention. In certain cases, the disorder is one that is mediated by DPP IV. In certain examples, the inhibitors in question can be used to over-regulate GIP and GLP-1 activities, for example, by increasing the half-life of those hormones or as part of a treatment for regulating glucose and / or metabolism levels. In certain examples, the inhibitors can be used to reduce insulin resistance, treat hyperglycemia, hyperinsulmia, obesity, hyperlipidemia, hyperlipoprotein-emia (such as chylomicrons, VLDL and LDL), and / or regulate body fat and more generally stores of lipids. In certain cases, inhibitors of the invention may be used to treat disorders of metabolism, such as those associated with diabetes, obesity and arteriosclerosis. While not wishing to link any particular theory, it is noted that compounds that inhibit DPP IV may be able to improve glucose tolerance through mechanisms involving the inhibition of DPP IV. In other embodiments, the invention offers a method for administering a pro-soft DPP IV inhibitor in an effective amount to improve aberrant rates associated with obesity. The fat cells release the leptin of the hormone, which travels in the bloodstream to the brain and, through the leptma receptors, there stimulates the production of GLP-1. GLP-1, in turn, produces the feeling of being full. The main theory is that the fat cells of most obese people probably produce a lot of leptma, but the leptoses may not be able to properly couple the leptma receptors in the brain, so that they do not stimulate the production of GLP-1. Therefore, there is a lot of research focused on using GLP-1 preparations as an appetite suppressant. The method in question provides a means to increase the half-life of both endogenous and ectopically aggregated GLP-1 in the treatment of disorders associated with obesity. DPP IV inhibitors have hypoglycemic and antidiabetic activities, and can be used in the treatment of disorders, disorders marked by aberrant glucose metabolism (including storage). In particular embodiments, the inhibitors of the invention are useful as nsulmotropic agents, or to enhance the msulinotropic effects of such molecules as GLP-1. In this regard, the invention also provides methods for the treatment and / or prophylaxis of a variety of disorders, including one or more of: hyperlipidemia, hyperglycemia, impaired glucose tolerance, insulin resistance and diabetic complications. Another aspect of the invention offers methods and pro-soft inhibitory compounds for altering the pharmacokinetics of a variety of different polypeptide hormones by inhibiting the proteolysis of one or more peptide hormones by DPP IV or some other proteolytic activity. For example, post-secretory metabolism is an important element in the global homeostasis of regulatory peptides, and the other enzymes involved in these processes may be convenient targets for pharmacological intervention by the method in question. In certain cases, the method in question can be used to increase the half-life of other proglucagon-derived peptides, such as glycemia (corresponding to PG 1-69), oxyntomodulm (PG 33-69), pancreatic polypeptides related to glycemia ( GRPP, PG 1-30), in which peptide 2 (IP-2, PG 111-122 amide), and the glucagon-like peptide-2 (GLP-2, PG 126-158) intervene. For example, GLP-2 has been identified as a factor responsible for inducing intestinal epithelial proliferation. See, for example, Drucker et al. Proc. Na ti. Acad. Sci. USA UU 1996, 93, 7911. DPP IV inhibitors that can also be used as part of a regimen to treat the injury, inflammation or intestinal tissue resection, for example, where growth improves and epithelial intestinal mucosal repair is desired, such as in the treatment of Crohn's disease or Inflammatory Bowel Disease (IBD). Another aspect of the invention relates to a method of treating growth hormone or somatotrophic deficient in children or to improve nutrition or alter the composition of the body (muscle vs. fat) in adults. DPP IV has been implicated in the metabolism and deactivation of the growth hormone releasing factor (GHRF). GHRF is a member of the family of homologous peptides that includes glucagon, secretma, vasoactive intestinal peptides (VIP), peptide histidine (PHI), pituitary adenylate cyclase that activates the peptide (PACAP), peptides Gastric inhibitors (GIP) and heloderma. Kubiak et al. PeptideRes. 1994, 7, 153. GHRF is secreted by the hypothalamus, and stimulates the release of growth hormone (GH) from the anterior pituitary. The method in question can also be used in veterinary practice, for example, to develop cattle with a high production of milk and a higher yield, and less fat. The DPP IV inhibitors of the invention can be used to alter the plasma half-life of the secretma, VIP, PHI, PACAP, GIP and / or helodermin. In certain cases, the inhibitors may also be used to alter the pharmacokinetics of Peptide YY and neuropeptides Y, both members of the pancreatic polypeptide family, because DPP IV has been involved in the processing of those peptides in a manner that alters the selectivity of the receiver. In other embodiments, DPP IV inhibitors can be used to stimulate hematopoiesis. In other embodiments, DPP IV inhibitors can be used to inhibit the growth or vascularization of transformed cells / tissues, for example, to inhibit cell proliferation, associated with tumor growth and metastasis, and to inhibit angiogenesis in a proliferative cell mass. abnormal. In other embodiments, DPP IV inhibitors can be used to reduce immunological responses, for example, as a immunosuppressant. In still other examples, DPP IV inhibitors can be used according to the present invention, to treat CNS diseases such as strokes, tumors, ischemia, Parkinson's disease, memory loss, hearing loss, vision loss, migraines, brain injury, spinal cord injury, Alzheimer's disease and amyotrophic lateral sclerosis (which has a CNS component). Additionally, DPP IV inhibitors they can be used to treat disorders that are more peripheral in nature, including multiple sclerosis and diabetic neuropathy. Another aspect of the present invention provides a method for stimulating hematopoietic cells in culture or live m. In certain embodiments, the DPP IV pro-mhibitors in question include a targeting portion that is a substrate for a protease that is expressed in the bone marrow. The DPP IV inhibitors of the invention can be used to restore or prevent a deficiency in the hematopoietic cell number in a subject. For example, such deficiencies may arise from genetic abnormalities, disease, stress, chemotherapy, and radiation treatments. Another aspect of the present invention offers compounds that inhibit proteasome function. In certain embodiments, the pro- soft inhibitors produce portions of the inhibitor that are potent and highly selective proteasome inhibitors and that can be employed to inhibit proteasome function. Inhibition of proteasome function has a variety of practical and prophylactic therapeutic applications. For example, embodiments of proteasome inhibitors may include targeting portions that are substrates for proteases that are expressed in tumors or other cells who are experiencing unwanted proliferation, or expressed in the tissue surrounding the tumor or other cells that proliferate in the target. In certain embodiments, the proteasome inhibitors of the present invention provide a method of reducing the rate of degradation of tumor suppressors. In other embodiments, the compounds of the present invention inhibit the growth of cancer cells. In still other embodiments, the compounds of the present invention can be formulated in the topical form for the treatment of skin disorders. Such proinhibitors are contemplated for possessing important practical application in the treatment of cell proliferative diseases such as cancer, restenosis, and psoriasis.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 describes an Ala-boroPro thioxamide. Figure 2 describes the pH-dependent behavior of Ala-boroPro Tioxamide and Ala_boroPro. Figure 3 describes a comparison of the IC50 value of Ala-boroPro Tioxa ida against DPP IV, DP8, and DP9. The IC50 values for the inhibition of Ala-boroPro thioxamide from DPP IV, DP8 and DP9 were measured in 50 mM sodium phosphate at pH 7.8 The inhibitor and the enzyme were incubated in various concentrations of inhibitor prior to the addition of the substrate Ala-Pro-paranitroanalido at a concentration equal to Km for each enzyme (20 μM for DPP IV and 100 μM for DP8 and DP9.) The reaction mixtures were incubated at 37 ° C for 30 mm and then the absorbance was read at 410 nm The data was normalized to the proportion of the non-inhibited reaction for each enzyme. Figure 4 depicts the K2 of Ala-boroPro thioxamide in an assay that measures the inhibition of DPP IV. The DPP IV purified from human placenta was incubated with the inhibitor in 50 mM HEPES, pH 8.0, 0.14 M NaCl at 23 ° C to allow complete binding. Chromogenic substrate Ala-Pro-paranitroanalide was added to the inhibitor of the complex enzyme 5 times the Km value and the reaction was monitored by measuring the absorbance at 410 nm for 2 min. The concentration of the enzyme is determined independently.

The Ratio vs. Inhibitor concentration was fixed in a simple equilibrium model to obtain the Kx value (Gutheil and Bachovchm, 1993 Biochemistry 32 (34) 8723-8731).

Figure 5 describes the results of an immunogenic oral glucose test using Ala-boroPro thioxamide. Following a nighttime fast, seven C57BL / 6 mice were given the drug or vehicle (0.25% methylcellulose), by an oral probe, two hours before an oral dose of 5 g / kg of glucose. The blood was taken from the vein of the tail and the glucose was simply measured with the meter of glucose of a free-style blood just before the drug, before glucose, and at 20, 40, 60 and 120 minutes after glucose. The AUC was calculated for the data from zero to 120 minutes. Figure 6 describes the plasma results of inhibition of DPP IV in rat plasma using Ala-boroPro thioxamide. Groups of four rats were each given a dose of Ala-Pro thioxamide. Blood samples were taken from the tail vein and plasma DPP IV was measured by the addition of 10 μL of plasma to 150 μL of 30 μM Ala-Pro paranitroanalide in 50 mM HEPES, pH 8, 0.14 M NaCl. The change in absorbance at 410 nm was recorded after 1 hour. The data was normalized for the average value of the pre-dose for each group. Figure 7 describes the deactivation of Ala-boroPro thioxamide at pH 7.8. The Ala-boroPro Thioxamide was pre-equilibrated to pH 2 and then the pH leapt to a pH 7.8 by the addition of 0.6 M sodium phosphate buffer. The XH NMR spectrum was recorded as a function of time at pH 7.8. The well-resolved resonances representing the active (pH 2) and inactive (pH 7.8) forms of the drug were integrated together and the integral as a function of time was set to a single exponential. The same procedure was followed for the deactivation of Ala-boroPro. The average life for reaction was 60 min for Ala-boroPro Tioxamida and 30 minutes for Ala-boroPro. Figure 8 describes the deactivation of Ala-boroPro thioxamide at pH 7.8. The Ala-boroPro and Ala-boroPro thioxamide were pre-equilibrated to pH 2 and then the pH leapt to a pH 7.8 by the addition of 0.5 M sodium phosphate solution. Inhibition of DPP IV was measured at several times after the pH jump and the IC0 values were plotted as a function of time. From the IC0 value, the mole fragment of the active inhibitor was calculated assuming that the pH 2 sample was 100% active. This value was set to a single exponential. The average life obtained from these adjustments was 47 minutes for Ala-boroPro Tioxamida and 24 minutes for Ala-boroPro. Figure 9 describes results of the 1H NMR analysis of Ala-boroPro thioxamide. Figure 10 describes the Ki measurements of Ala-boroPro thioxamide. Figure 11 describes a comparison of deactivation proportions for Ala-boroPro and Ala-boroPro thioxamide.

Figure 12 describes OGTT with Ala-boroPro thioxamide.

Figure 13 describes a comparison of Ala-boroPro and Ala-boroPro Thioxamide against DPPIV. Figure 14 depicts DPP IV activity in rat plasma in the presence of Ala-boroPro thioxamide.

Figure 15 describes Ala-boroPro Thioxamide, NVP LAF327, and MK0431. Figure 16 describes the results of Ala-boroPro thioxamide, NVP LAF327, and MK0431 in an assay measuring the inhibition of DPP IV in rat plasma. Figure 17 describes the results of Ala-boroPro Thioxamide, NVP LAF327, and MK0431 in an assay that measures the inhibition of glucose excursion. Figure 18 describes Kx and the IC 50 values for Ala-boroPro Thioxamide, NVP LAF327, and MK0431. Figure 19 describes the results of Ala-boroPro Thioxamide, NVP LAF327, and MK0431 in an assay measuring the DPP IV activity of rat plasma following a single oral dose (1 mg / kg). Figure 20 describes the results of Ala-boroPro thioxamide, NVP LAF327, and MK0431 in an assay measuring the inhibition of DPP IV in rat plasma. Figure 21 describes OGTT with Ala-boroPro Thioxamide and LAF327. Figure 22 describes the results of Ala-boroPro Tioxa ida in an immunogenic oral glucose test assay in normal mice. Figure 23 describes the results of NVP LAF327 in an oral glucose immunoglobulin test in normal mice Figure 24 describes the results of MK0431 in an oral glucose assay in normal mice. See Kim et al J. Med. Chem. 2005, 48, 141-51. Figure 25 describes the K of Thioxamide AbP and NVP LAF237. Figure 26 describes the Kx for MK0431. Figure 27 describes the binding / release of MK0431 with DPP IV. In proportion: Simultaneously the enzyme of the mixture, substrate and inhibitor. The response of the curve represents a slow link. Out of proportion: The enzyme is pre-incubated with the inhibitor at high concentration. Then, the mixture is diluted and the substrate is added. The curve reflects the slow release of the inhibitor following dilution. Figure 28 describes certain compounds of the invention. Figure 29 describes certain compounds of the invention. Figure 30 describes certain compounds of the invention. Figure 31 describes certain compounds of the invention. Figure 32 describes certain compounds of the invention.

DETAILED DESCRIPTION OF THE INVENTION Introduction The present invention provides protease inhibitors and methods of using protease inhibitors. The invention offers inhibitors for a broad series of proteases. For example, proteases can be an enzyme that cleaves to post-proline (PPCE), such as dipeptidyl peptidase IV. The invention also provides compounds that inhibit proteasome activity. In certain cases, the protease inhibitor is a soft inhibitor. A "soft" inhibitor is an inactive agent that is activated, i.e., cleaved by a "protease that is activated" to release a portion of the active inhibitor in proximity to a "target protease." The identity of the protease that is activated and the target protease can be the same or different. After activation of the pro-soft inhibitor, the active inhibitor portion undergoes self-deactivation by proto-desboronation. In certain cases, the invention offers inhibitors of boronic acid of a dipeptide of the Xaa-boroPro type, where Xaa refers to any natural or naturally occurring amino acid, which comprises a portion of Thioxamide, and boroPro refers to the proline analogue in the that the carboxylate at the C-terminus has been replaced by a boronyl group. Such compounds are potent inhibitors of dipeptidyl amino peptidase type IV (DPP IV). The boronic acid compounds of the dipeptide exist in an open chain under acidic conditions, but undergo proto-desboronation under basic and neutral conditions. The shape of the open chain is active as an inhibitor of the enzyme; the compound formed from the proto-sputtering reaction is substantially inactive as an inhibitor of the enzyme. The pro-inhibitors of the present invention do not re-undergo proto-desboronation and can be constructed such that they do not inhibit the selected target enzyme, or other enzymes to any significant extent, before being cleaved by the protease that is activated. One of the characteristics that makes the pro-soft inhibitor molecules of the present invention different from the typical prodrugs is that the inhibitor portion, after they generate in the active form near the target, experiences a deactivation with time, for example, it diffuses out of the target enzyme, reducing the possibility of deleterious side effects that may result from the inhibition of enzymes that occur in other parts of the patient. This combination of being released in an active form in the vicinity of the target enzyme together with this deactivation mechanism "programmed" makes the molecules of the invention more specific, effective, and safer (ie, have less effect) than the portion of the inhibitor used alone. Advantageous features for the compounds of the present invention include: better therapeutic indices, due in part to reduced toxicity and / or improved specificity for the targeted protease; better oral availability; increased average life; and / or increased duration of action (such as oral dosage formulations that are effective for more than 4 hours, and even more preferably for more than 8, 12, or 16 hours). In certain cases, a compound of the invention has a Ki for the inhibition of DPIV of about 50.0 nm or less, more preferably about 10.0 nm or less, and even more preferably about 1.0, 0.1, or even 0.01 NM or less. In fact, inhibitors with Ki values in the picomolar are contemplated and even contemplated in the femtomolar range. Another advantageous feature for the compounds of the present invention is that irreversible proto-sputtering liberates harmless boric acid. The LD50 of boric acid is approximately equal to that of common table salt. Accordingly, long-term chronic therapy with the compounds of the present invention is expected to yield a Improved safety profile (fewer side effects). The compounds of the present invention can be used as part of treatments for a variety of disorders / conditions, such as those that are mediated by DPIV. For example, the compounds can be used to sub-regulate GIP activities and GLP-1 activities, for example, by increasing the half-life of those hormones, as part of a treatment for regulating glucose and / or metabolism levels, for example, for reduce insulin resistance, treat hyperglycemia, hyperinsulinemia, obesity, hyperlipidemia, hyperlipoproteinemia (such as chylomicrons, VLDL and LDL), and to regulate body fat and more generally fat stores, and, more generally, for improvement of metabolic disorders, especially those associated with diabetes, obesity and / or arteriosclerosis. Certain compounds in question have extended their duration. Accordingly, In certain embodiments, the compound and the amount of the formulated compound are selected to provide a dosage that inhibits serum PPCE (e.g., DPIV) levels by at least 50% for at least 4 hours after a single dose, and even more preferably for at least 8 hours or even 12 or 16 hours after a single dose. For example, in certain modalities, the method involves the administration of a DPIV inhibitor, preferably at a predetermined time (s) for a period of 24 hours, in an amount effective to ameliorate one or more aberrant indices associated with disorders of glucose metabolism (eg, intolerance to glucose, insulin resistance, hyperglycemia, hyperinsulinemia, and Type I and II diabetes). In other embodiments, the method involves the administration of a DPIV inhibitor in an effective amount to improve the aberrant rates associated with obesity. Fat cells release leptin hormones, which travel in the bloodstream to the brain and, through the leptin receptors, stimulate the production of GLP-1. GLP-1, in turn, produces the feeling of being full. The main theory is that the fat cells of most obese people probably produce enough leptins, but leptins may not be able to properly attach to the leptin receptors in the brain, because they do not stimulate the production of GLP-1. . Therefore, there is a great agreement to use GLP-1 preparations as an appetite suppressant. The method in question provides a means to increase the half-life of both endogenous GLP-1 and ectopically aggregated in the treatment of disorders associated with obesity.

In a more general sense, the present invention provides methods and compositions for altering the pharmacokinetics of a variety of different polypeptide hormones by inhibiting the proteolysis of one or more peptide hormones by DPIV or some other proteolytic activities. The post-secretory metabolism is an important element in the global homeostasis of regulatory peptides, and other enzymes involved in these processes may be suitable targets for pharmacological intervention by the method in question. For example, the method in question can be used to increase the half-life of other proglucagon-derived peptides such as glicentma (corresponding to PG 1-69), oxmtomodulin.

(PG 33-69), pancreatic polypeptides related to glicentma (GRPP, PG 1-30), peptide-2-intervening (IP-2, PG lll-122am?), And peptide-two-2 type glucagon (GLP-2, PG 126 158). For example, GLP-2 has been identified as a factor responsible for inducing intestinal epithelial proliferation. See, for example, Drucker et al. Proc. Na ti Acad. Sci. USA UU 1996, 93, 7911. The method in question can be used as part of a regimen to treat injury, inflammation or resection of the intestinal tissue, for example, when improved growth and repair of epithelial intestinal epithelial epithelium is desired, such as in the treatment of Crohn's disease or Inflammatory Bowel Disease (IBD). DPIV has also been implicated in the metabolism and deactivation of the growth hormone releasing factor (GHRF). GHRF is a member of the homologous peptide family that includes glucagon, secretma, vasoactive intestinal peptide (VIP), peptide histidine (PHI), pituitary adenylate cyclase that activates peptides (PACAP), the gastric inhibitory peptide (GIP), and helodermuths (Kubiak et al., Peptide Res. 1994, 7, 153). GHRF is secreted by the hypothalamus, and stimulates the release of growth hormone (GH) from the anterior pituitary. Thus, the method in question can be used to improve clinical therapy for certain children with growth hormone deficiency, and in clinical therapy of adults to improve nutrition and alter body composition. (muscle vs. fat). The method in question can also be used in veterinary practice, for example, to develop cattle with milk production with superior yield, and with less fat. Likewise, the DPIV inhibitors of the invention can be used to alter the plasma half-life of secretma, VIP, PHI, PACAP, GIP, and / or heloderma. Additionally, the method in question can be used to altering the pharmacokinetics of peptide YY and neuropeptides Y, both members of the pancreatic polypeptide family, such as DPIV has been implicated in the processing of those peptides in a manner that alters receptor selectivity. In other embodiments, the compounds can be used to stimulate hematopoiesis. In other embodiments, the compounds can be used to inhibit the growth or vascularization of transformed cells / tissues, for example, to inhibit cell proliferation such as that associated with tumor growth and metastasis, and to inhibit angiogenesis in a mass of abnormal proliferative cells. In other embodiments, the compounds can be used to reduce the immunological responses, for example, as an immunosuppressant. In still other examples, the DPIV inhibitors according to the present invention can be used to treat CNS diseases such as strokes, tumors, ischemia, Parkinson's disease, memory loss, hearing loss, vision loss, migraines, brain injury, spinal cord injury, Alzheimer's disease, and amyotrophic lateral sclerosis (which has a component of the CNS). Additionally, DPIV inhibitors can be used to treat disorders that have a more peripheral nature, which includes sclerosis multiple and diabetic neuropathy. Another aspect of the present invention relates to the post-prolma subject pharmaceutical compositions that bind enzyme inhibitors, particularly inhibitors of DPIV, and their uses in treating and / or preventing disorders that can be improved by altering hormone homeostasis. peptide. In a certain embodiment, the compounds have hypoglycemic activities and antidiabetic activities, and can be used in the treatment of disorders marked by aberrant glucose metabolism (including storage). In particular embodiments, the compositions of the methods in question are useful as agents msulinotrópicos, or to enhance the msulinotrópicos effects of such molecules as GLP-1. In this regard, certain embodiments of the present compositions may be useful for the treatment and / or prophylaxis of a variety of disorders, including one or more of hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance, insulin resistance, and diabetic complications. In certain cases, the compounds of the method in question are small molecules, for example, with molecular weights of less than 7500 amu, preferably less than 5000 amu, and even more preferably less than 2000 or even less than 1000 amu. In certain modalities, the Compounds are orally active In certain cases, the compounds of the invention are used in combination with one or more pharmaceutical agents. A large number of pharmaceutical agents are known in the art and are treatable for use in the pharmaceutical compositions of the invention. The term "pharmaceutical agent" includes, without limitation, drugs; vitamins; mineral supplements; substances used for the treatment, prevention, diagnosis, cure or mitigation of a disease or diseases; or substances that affect the structure or function of the body; or in drugs that become biologically active or more active after they have been placed in a predetermined physiological environment. Non-limiting examples of broad categories of useful pharmaceutical agents include the following therapeutic categories: anabolic agents, antacids, anti-asthmatic agents, anti-cholelemic and anti-lipid agents, anti-coagulants, anti-convulsants, anti-diarrheals, anti-emetics , anti-mfective agents, anti-inflammatory agents, anti-manic agents, anti-nauseants, anti-neoplastic agents, anti-obesity agents, antipyretic agents and analgesic agents, anti-spasmodic agents, anti-thrombotic agents, anti -uricemic, anti-angmal agents, antihistammas, antiperspirants, appetite suppressants, biologics, brain dilators, coronary dilators, decongestants, diuretics, diagnostic agents, epmetropiatic agents, expectorants, gastrointestinal sedatives, hyperglycemic agents, hypnotics, hypoglycemic agents, ion exchange resins, laxatives, supplements minerals, mucolytic agents, neuromuscular drugs, peripheral vasodilators, psychotropics, sedatives, stimulants, thyroid and anti-thyroid agents, uterine relaxants, vitamins, and prodrugs. More specifically, non-limiting examples of useful pharmaceutical agents include the following therapeutic categories: analgesics, such as non-spheroidal anti-inflammatory drugs, opiate agonists and salicylates; antihistammas, such as Hx blockers and H blockers; anti-mfective agents, such as anthelmintics, antianaerobes, antibiotics, ammoglycoside antibiotics, antifungal antibiotics, cephalosporin antibiotics, macrolide antibiotics, miscellaneous beta-lactam antibiotics, penicillin antibiotics, qumolone antibiotics, sulfonamide antibiotics, tetracycline antibiotics , antimicobacterials, antimicrobial agents of antituberculosis, antiprotozoals, antiprotozoals antimalapa, antiviral agents, anti-retroviral agents, scabicides, and urinary anti-infective agents, antimalarial agents, such as alkylating agents, agents with mustard nitrogen alkyls, alkylation agents with nitrosourea, antimetabolites, purine analogues antimetabolites, antimetabolites analogous of pipmidma, antimicrobial antimicrobials, natural antimicrobial, natural antimicrobial, natural antimicrobial antimicrobial, and natural antimalarial vinca alkaloids, autonomic agents, such as anticholmergic, anticholinergic antimuscarinics, ergotamma alkaloids, parasimpatomimetics, parasimpatomimetics, cholinergic agonists, para-sympathomimetics of cholinesterase inhibitor , sympatholytics alpha blockers, sympatholytics beta blockers, sympatholytics, sympathomimetics, and sympathomimetics adrenergic agonists, cardiovascular agents, such as antiangmals, antiangma beta blockers, antiangma calcium channel blockers, nitrate antiangmals, antiarrhythmics, cardiac glycoside antiarrhythmics, class I antiarrhythmics, class II antiarrhythmics, class III antiarrhythmics, class IV antiarrhythmics, antihypertensive agents, alpha blocker antihypertensive, angiotensin converting enzyme inhibitor (ACE inhibitor) antihypertensive, antihypertensive beta blocker, calcium channel blocker antihypertensive, centrally acting adrenergic antihypertensives, diuretic antihypertensive agents, peripheral hypertensive antihypertensive agents, antilipemic, antilipemic bile acid sequestrant, antilipemic inhibitors of HMG-CoA reductase, motropos, motropos of cardiac glycoside, and thrombolytic agents; dermatological agents, such as antihistamines, anti-inflammatory agents, anti-inflammatory agents, corticosteroids, antipruritic / local anesthetics, topical anti-mfeccioses, antifungal topical antifungal agents, antiviral topical antimicrobial agents, and topical antimicrobials; electrolytic and renal agents, such as acidifying agents, alkalizing agents, diuretics, carbonic anhydrase inhibitor diuretics, loop diuretics, osmotic diuretics, potassium reserve diuretics, thiazide diuretics, electrolyte replacements, and upcosuric agents, enzymes, such as pancreatic enzymes and thrombolytic enzymes, gastrointestinal agents, such as antidiarrheals, antiemetics, gastrointestinal anti-inflammatory agents, salicylate of gastrointestinal anti-inflammatory agents, anti-ulcer anti-ulcer agents, anti-ulcer agents, acid pump inhibitors, gastric agents, anti-ulcer agents of gastric mucosa, anti-ulcer agents H2 blockers, colelitolytic agents, digestive agents, emetics, laxatives and softeners of fecal material, and pro-medical agents, general anesthetics, such as inhalation anesthetics, halogenated inhalation anesthetics, intravenous anesthetics, intravenous anesthetic barbiturates, intravenous anesthetics of benzodiazepine, and intravenous anesthetics opiate agonists; hematological agents, such as antianemia agents, hematopoietic antianemia agents, coagulation agents, anticoagulants, hemostatic coagulation agents, platelet inhibiting coagulation agents, clotting agents of the thrombolytic enzyme, and plasma volume expanders, hormones and modifiers of hormones, such as abortifacients, adrenal agents, adrenal agents, corticosteroids, androgens, anti-androgens, antidiabetic agents, antidiabetic agents of sulfonylurea, antihipoglycemic agents, oral contraceptives, progestin contraceptives, estrogens, fertility agents, oxytocics, parathyroid agents, pituitary hormones, progestins, antithyroid agents, thyroid hormones, and tocolytics; immunobiological agents, such as immunoglobulins, immunosuppressants, toxoids, and vaccines, local anesthetics, such as local amide anesthetics and local ester anesthetics, agents Musculoskeletal agents such as anti-gout anti-inflammatory agents, anti-inflammatory agents, anti-inflammatory agents, anti-inflammatory agents of gold compounds, anti-inflammatory agents immunosuppressants, non-spheroidal anti-inflammatory drugs (NSAIDs), salicylate anti-inflammatory agents, skeletal muscle relaxants, skeletal muscle relaxants neuromuscular blocker, and reverse muscle relaxant neuromuscular blocking relaxants, neurological agents, such as anticonvulsants, barbiturate anticonvulsants, benzodiazepine anticonvulsants, anti-migraine agents, anti-parkmsonian agents, anti-vertigo agents, opiate agonists, and opiate antagonists. opiate; ophthalmic agents, such as anti-glaucoma agents, beta-blocker anti-glaucoma agents, miotics anti-glaucoma agents, mydriatics, mid-adrenergic agonists, antimuscarinic mydriatics, ophthalmic anesthetics, ophthalmic anti-mfeccioses, anti-mfacic ammoglycoside ophthalmic, anti-mfective macrolide ophthalmic, anti-mfeccioso ophthalmic qumolona, sulfonamide ophthalmic anti-mfecciosos, tetracycline ophthalmic anti-mfectives, ophthalmic antimflammatory agents, ophthalmic corticosteroid anti-inflammatory agents, agents, and non-spheroid ophthalmic anti-inflammatory drugs (NSAIDs); psychotropic agents, such as antidepressants, heterocyclic antidepressants, monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs), antidepressants, cyclic antidepressants, antipsychotics, phenothiazine antipsychotics, anxiolytics, sedatives, and hypnotics, sedative and hypnotic barbiturates, benzodiazepine anxiolytics, sedatives, and hypnotics, and psychostimulatory respiratory agents, respiratory agents, such as antitussives, bronchodilators, adrenergic agonist bronchodilators, antimuscarinic bronchodilators, expectorants, mucolytic agents, respiratory anti-inflammatory agents, and anti-inflammatory agents respiratory corticosteroids; toxicology agents, such as antidotes, heavy metal antagonist / chelating agents, substance abuse agents, detergent substance abuse agents, and mineral substance abuse removal agents; and vitamins, such as vitamin A, vitamin B, vitamin C, vitamin D, vitamin E, and vitamin K. Preferred classes of useful pharmaceutical agents from the above categories include: (1) anti-inflammatory drug analgesics (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, and naproxen; (2) Analgesics of opiate agonist, such as codeine, fentanyl, hydromorphone and morphine, (3) salicylate analgesic, such as aspirin (ASA) (enteric coating ASA); (4) H1-blocking antihistamines (such as ciernastine and terfenadine; (5) H2-blocking antihistamines, such as cimetidma, famotidma, mzadma, and ranitidma; (6) anti-infective agents, such as mupirocma; antianaerobic drugs, such as chloramphenicol and clindamycin; (8) anti-infectious antifungal antibiotics, such as amphotericin b, clotrimazole, fluconazole, and ketoconazole; (9) anti-mfecciosos macrolide antibiotics, such as azithromycin and ephromicma; (10) antibiotics miscellaneous beta-lactam anti-mfecciosos, such as aztreonam and ímipenem, (11) antibiotics of penicillin anti-mfecciosos, such as nafcillma, oxacillma, penicillin G, and penicillin V; (12) antibiotics qumolona anti-mfecciosos, such as ciprofloxacin and norfloxacma; (13) antimicrobial tetracycline antibiotics, such as doxycycline, mmocyclic, and tetracycline, (14) antimicrobial anti-tuberculosis antimicrobial agents such as isoniazid (INH), and rifampic; (15) antipyretic anti-mfeccioses tozoapo, such as atovaquone and dapsone; (16) Anti-malarial antiprotozoa antimalarial drugs, such as chloroquine and pipmetamma; (17) anti-retroviral anti-mfecciosos, as ritonavir and zidovudma; (18) anti-viral antiviral agents, such as acyclovir, ganciclovir, alpha inferred, and pmantadma; (19) alkylated antmeoplastic agents, such as carboplatm and cisplatma; (20) altered mtrosourea antmeoplastic agents, such as carmustma (BCNU); (21) antimetabolite antimeoplastic agents, such as methotrexate; (22) Antimicrobial antimetabolite analogous agents of pipmidma, such as fluorouracil (5-FU) and gemcitabma; (23) hormonal antieoplastic drugs, such as goserelma, leuprolide, and tamoxifen, (24) natural antimicrobial agents, such as aldesleukin, mteleucma-2, docetaxel, etoposide (VP-16), alpha inferno, paclitaxel, and tretmom (ATRA); (25) natural antimicrobial antimicrobials, such as bleomicma, dactmomicma, daunorubicma, doxorubicma, and mitomicma; (26) natural antimalarials vinca alkaloids, such as vmblastma and vmcristma, (27) autonomic agents, such as nicotine; (28) anticholmergic autonomic agents, such as benzotropm and tphexyphenidyl; (29) anticholmergic antimuscarinic autonomic agents, such as atropine and oxybutynin; (30) autonomic alkaloid agents of ergotamma, such as bromocriptma, (31) parasimpatomimetics, cholinergic agonists, such as pilocarpma; (32) parasimpatomimetics inhibitor of cholinesterase, such as pyridostigm; (33) alpha blockers sympatholytics, such as prazosin; (34) sympatholytic beta blocker, such as atenolol; (35) sympathomimetic adrenergic agonists, such as albuterol and dobutamma; (36) cardiovascular agents, such as aspirin (ASA) (enteric coating ASA); (37) antiangials beta blocker, such as atenolol and propranolol; (38) antiangials calcium channel blocker, such as mfedipma and verapamil; (39) nitrate antiangials, such as iosorbide dinitrate (ISDN); (40) antiarrhythmics of cardiac glycosides, such as digoxma; (41) class I anti-arrhythmics, such as lidocama, mexiletma, fenitoma, procamamide, and quinidma, (42) class II antiarrhythmics, such as atenolol, metoprolol, propranolol, and timolol; (43) class III antiarrhythmics, such as amiodarone, (44) class IV antiarrhythmics, such as diltiazem and verapamil, (45) antihypertensive alpha blocker, such as prazosma; (46) antihypertensives of the enzyme inhibitor that converts to angiotensin (ACE inhibitor) such as captopril and enalapril; (47). beta blocker antihypertensive drugs, such as atenolol, metoprolol, nadolol, and propranolol, (48) calcium channel blocker antihypertensive agents, such as diltiazem and nifedipma, (49) adrenergic antihypertensive drugs that act in the center, such as clonidine and methyldopa , (50) diuretic antihypertensive agents, such as amiloride, furosemide, hydrochlorothiazide (HCTZ), and spironolactone; (51) antihypertensives of the peripheral vasodilator, such as hydralazm and mmoxidil; (52) antilipemic, such as gemfibrozil and probucol; (53) Antilipemic acid sequestrant of bile, such as cholestyramine; (54) Antilipemic inhibitor of HMG-CoA reductase, such as lovastatma and pravastatma; (55) motropos, such as amrinone, dobutamma, and dopamma; (56) motropos of cardiac glycosides, such as digoxma; (57) thrombolytic agents, such as alteplase (TPA), anistreplase, streptoqumase and uroqumase; (58) dermatological agents, such as colchicine, isotretmoin, methotrexate, mmoxidil, trethmoma (ATRA); (59) Dermatological corticosteroid anti-inflammatory agents, such as betamethasone and dexamethasone; (60) topical anti-fungal antifungal agents, such as amphotericin B, clotrimazole, miconazole, and nystatma; (61) antiviral topical antiseptics, such as acyclovir, (62) topical antimicrobials, such as fluorouracil (5-FU); (63) electrolytic and renal agents, such as lactulose; (64) loop diuretics, such as furosemide; (65) diuretics that reduce potassium such as triamterena, (66) thiazide diuretics, such as hydrochlorothiazide (HCTZ); (67) upcosuric agents, such as probenecid; (68) enzymes such as RNase and DNase, (69) thrombolytic enzymes such as alteplase, anistreplase, streptokinase and urokinase; (70) antiemetics, such as prochlorperazine, (71) salicylate gastrointestinal antiinflammatory agents, such as sulfasalazine; (72) anti-ulcer agents inhibiting the gastric acid pump, such as omeprazole, (73) H2-blocking anti-ulcer agents, such as cimetidine, famotidine, nizatidine, and ranitidine; (74) digestive, such as pancrelipase; (75) prokinetic agents, such as erythromycin; (76) intravenous opiate agonist anesthetics such as fentanyl, (77) hematopoietic antianemia agents, such as erythropoietin, filgrastim (G-CSF), and sargramostim (GM-CSF); (78) coagulation agents, such as antihemophilic factors 1-10 (AHF 1-10); (79) anticoagulants, such as warfarin; (80) coagulation agents of the thrombolytic enzyme such as alteplase, anistreplase, streptokinase and urokinase; (81) hormones and hormone modifiers, such as bromocriptine, (82) abortifacients, such as methotrexate (83) antidiabetic agents, such as insulin, (84) oral contraceptives, such as estrogen and progestin; (85) progestin contraceptives, such as levonorgestrel and norgestrel, (86) estrogens such as conjugated estrogens, diethylstilbestrol (DES), estrogen (estradiol, estrone, and estropipate); (87) fertility agents, such as clomiphene, gonadatropine human chorionic (HCG), and menotropic; (88) parathyroid agents such as calcitonin; (89) pituitary hormones, such as desmopressin, goserelma, oxytocma, and vasopresma (ADH); (90) progestins, such as medroxyprogesterone, noretmdrona, and progesterone; (91) thyroid hormones, such as levothyroxine, (92) immunobiological agents, such as inferred beta-Ib and inferred gamma-Ib; (93) the immunoglobulms, such as immune globulin IM, IMIG, IGIM and immune globulin IV, IVIG, IGIV, (94) local anesthetics of amide, such as lidocama, (95) local anesthetics of ester, such as benzocaine and procama, (96) corticosteroid anti-inflammatory agents musculoskeletal, such as beclomethasone, betamethasone, cortisone, dexamethasone, hydrocortisone, and prednisone, (97) musculoskeletal anti-inflammatory mmunosuppressants, such as azathioprma, cyclophosphamide, and methotrexate; (98) the non-spheroidal musculoskeletal anti-inflammatory drugs (NSAIDs), such as diclofenac, ibuprofen, ketoprofen, ketorlac, and naproxen; (99) skeletal muscle relaxants, such as baclofen, cyclobenzaprma, and diazepam; (100) reversible neuromuscular blocking skeletal muscle relaxants, such as pyridostigm; (101) neurological agents, such as nimodipma, pluzol, tacpna and ticlopidine; (102) anticonvulsants, such as carbamazepma, gabapentma, lamotrigine, phenytoin, and valproic acid; (103) barbiturate anticonvulsants, such as phenobarbital and primidone; (104) benzodiazepine anticonvulsants, such as clonazepam, diazepam, and lorazepam; (105) anti-parkinsonian agents, such as bromocriptine, levodopa, carbidopa, and pergolide; (106) anti-vertigo agents, such as meclizine, (107) opiate agonists, such as codeine, fentanyl, hydromorphone, methadone, and morphine, (108) opiate antagonists, such as naloxone,; (109). anti-glaucoma beta-blocking agents, such as timolol, (110) miotic anti-glaucoma agents, such as pilocarpine; (111) anti-infectives of aminoglycoside ophthalmic, such as gentamicin, neomycin and tobramycin; (112) quinolone ophthalmic anti-mfeccioses, such as ciprofloxacma, norfloxacin, and ofloxacin; (113) ophthalmic corticosteroid anti-inflammatory agents, such as dexamethasone and prednisolone, (114) nonsteroidal ophthalmic anti-inflammatory drugs (NSAIDs), such as diclofenac; (115) antipsychotics, such as clozapma, haloperidol, and risperidone; (116) benzodiazepine, sedative and hypnotic anxiolytics, such as clonazepam, diazepam, lorazepam, oxazepam, prazepam; (117) psychostimulants such as methylphenidate and pemoline; (118) antitussives such as codeine, (119) bronchodilators, such as theophylline; (120) bronchodilators adrenergic agonists, such as albuterol; (121) respiratory anti-inflammatory corticosteroid agents, such as dexamethasone; (122) antidotes, such as flumazenil and naloxone; (123) heavy metal antagonist / chelating agents, such as penicillamma; (124) agents that abuse dissuasive substances, such as disulfiram, naltrexone and nicotine; (125) agents that abuse withdrawal substances, such as bromocpptine; (126) minerals such as iron, calcium and magnesium; (127) vitamin B compounds, such as cyanocobalamma (vitamin B12) and macina (vitamin B3); (128) vitamin C compounds such as ascorbic acid; and (129) vitamin D compounds, such as calcitriol In addition to the above, the less common drugs may also be used: chlorhexidine; cypionate estradiol in oil; estradiol valerianate in oil; flurbiprofen, flurbiprofen sodium; ímemectma; levodopa; nafarelma and somatropma. In addition, the following drugs can also be used: recombinant beta-glucan; bovine immunoglobulin concentrate; bovine superoxide dismutase; the formulation comprising fluorouracil, epmefrma, and bovine collagen; recombinant hirudma (r-Hir), HIV-1 immunogen; anti-human CT antibody; human growth hormone (r-hGH); Recombinant human hemoglobin (r-Hb); Recombinant human mecasermame (r-IGF-1); inferred beta-la recombinant; lenograstim (G-CSF); olanzapma; recombinant thyroid stimulating hormone (r-TSH); and topotecan. Additionally, the following intravenous products may be used: sodium acyclovir; aldesleukin; atenolol; bleomicma sulfate, human calcitonin, calcitonma salmon; carboplatma; carmustma; dactmomicma, daunorubicma HCl; docetaxel; doxorubicma HCl; alpha epoetma; etoposide (VP-16); fluorouracil (5-FU); ganciclovir sodium; gentamicm sulfate; alpha inferred; leuprolide acetate; mepepdma of HCl; methadone HCl; sodium methotrexate; paclitaxel; ranitidma HCl; vmblastma sulfate; and zidovudma (AZT). In addition to the specific examples of useful pharmaceutical agents of the above categories include: (a) anti-neoplastic agents such as androgen inhibitors, antimetabolites, cytotoxic agents, and immunomodulators; (b) antiperspirants such as dextromethorphan, dextromethorphan hydrobromide, noscapma, carbetapentane citrate, and chlorphedianol hydrochloride; (c) antihistamines such as chlorpheramramide maleate, fenmdamma tartrate, piplamma maleate, doxilamma succinate, and feniltoloxamma citrate; (d) decongestants such as phenylephrine hydrochloride, phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, and ephedrine; (e) several alkaloids such as codeine phosphate, codeine sulfate and morphine; (f) mineral supplements such as potassium chloride, zinc chloride, calcium carbonate, magnesium oxide, and other alkali metals and alkaline metal salts; (g) ion exchange resins such as colestpramine; (h) anti-arrhythmics such as N-acetylprocamamide; (i) antipyretics and analgesics such as acetamofen, aspirin and buprofen; (j) appetite suppressants such as phenylpropanolamine hydrochloride or caffeine; (k) expectorants such as guaifenesma; (1) antacids such as aluminum hydroxide and magnesium hydroxide; (m) biologicals such as peptides, polypeptides, proteins and amino acids, hormones, methylferones or cytokines, and other bioactive peptide compounds such as metolems 1-18 which include mutants and analogs, RNase, DNase, hormones that release lutemization hormone (LHRH) ) and analogous, gonadotropin-releasing hormone (GnRH), which transforms growth factor-beta (TGF-beta), fibroblast growth factor (FGF), tumor necrosis factor alpha & beta (TNF-alpha &beta), nerve growth factor (NGF), growth hormone releasing factor (GHRF), epidermal growth factor (EGF), fibroblast growth factor homologous factor (FGFHF), hepatocyte growth factor (HGF), insulin growth factor (IGF), invasion that inhibits factor-2 (IIF-2), morphogenetic proteins 1-7 bone (BMP 1-7), somatostatma, timosm-alpha-1, gamma-globulm, superoxide dismutase (SOD), complement factors hGH, tPA, calcitonin, ANF, EPO and insulin; and (n) anti-infective agents such as antifungals, anti-virals, antiseptics and antibiotics. Alternatively, the pharmaceutical agent may be a radiosensitizer, such as metoclopromide, sensamide or neusensamide (manufactured by Oxigene); profiromycin (prepared by Vion); RSR13 (prepared by Allos); Thymitaq (elaborated by Agouron), etanidazole or lobenguana (elaborated by Nycomed); gadolinium texaphrine (manufactured by Pharmaciclics); BuDR / Broxme (developed by NeoPharm); IPdR (prepared by Sparta); CR2412 (prepared by Cell Therapeuti); LlX (elaborated by Terrapin); or similar. Preferably, the biologically active substance is selected from the group consisting of peptides, polypeptides, proteins, amino acids, polysaccharides, growth factors, hormones, anti-angiogenesis factors, interferons or cytokines, and pro-drugs. In a certain particular embodiment, the biologically active substance is a therapeutic or pro-drug, more preferably a drug selected from the group consisting of agents chemotherapeutics and other anti-neoplastic drugs such as paclitaxel, antibiotics, anti-virals, antifungals, anti-inflammatories and anticoagulants. The biologically active substances are used in amounts that are therapeutically effective. Although the effective amount of a biologically active substance will depend on the material to be used, amounts of the biologically active substance may be desirable from about 1% to about 65%. Smaller amounts may be used to achieve effective treatment levels for certain biologically active substances.

Definitions The term "high affinity" as used herein means strong bond affinity between molecules with a constant KD dissociation of not more than 1 μM. In a preferred case, the KD is less than 100 nM, 10 nM, 1 nM, 100 pM, or even 10 pM or less. In a certain other mode, the two molecules can be linked covalently (KD is essentially 0). The term "boron-Ala" refers to the analogue of the alanine in which the carboxylate group (COOH) is replaced with a boronyl group (B (OH) 2). Similarly, the term "boro-Pro" refers to the proline analog in which the carboxylate group (COOH) is replaced with a boronyl group (B (OH) 2). More generally, the term "boro-Xaa", where Xaa is an amino acid residue, refers to the analogue of an amino acid in which the carboxylate group (COOH) is replaced with a boronyl group (B (OH) 2). The term "Ala-boroPro" refers to The term "Ala-boroPro thioxoamide" refers to.

The term "Pro-boroPro" refers to The term "thioxam" is used in association with chemical nomenclature refers to a compound wherein at least one amide group has been replaced by at least one thioxamide group. For example Pro (thioxam) refers to a proline residue wherein the amide group has been replaced by a thioxamide group. A "patient" or "subject" to be treated by the object method can be either a human or a non-human subject. The Non-human subjects include farm animals (e.g., cows, horses, pigs, sheep) and companion animals (e.g., cats, dogs). The term "ED50" means the dose of a drug that, in 50% of patients, will provide a clinically relevant improvement or change in a physiological measurement, such as glucose response, increase in hematocrit, decrease in tumor volume, etc. The term "IC50" means the dose of a drug that inhibits a biological activity by 50%, for example, the amount of compound required to inhibit at least 50% of DPIV (or other PPCE) m-activity. A compound is one that has a "msulinotrófica activity" if it is able to stimulate, or cause the stimulation of, the synthesis or expression of the hormone insulin. The term "interacting" as used herein is intended to include all interactions (eg, biochemical, chemical, or biophysical interactions) between molecules, such as protein-protein, protein-nucleic acid, nucleic acid-nucleic acid interactions. , small protein-mallet, small nucleic acid-mallet, or small-mallet evil. The term "LDb0" means the dose of a drug that is lethal in 50% of the subjects.

The term "prophylactic or therapeutic" treatment is recognized in the art and includes administration to the host of one or more of the subject compositions. If it is administered before the clinical manifestation of the unwanted condition (eg, disease or other unwanted condition of the host animal) then the treatment is prophylactic, (that is, it protects the host against the development of the unwanted condition) , whereas if it is administered after the manifestation of the unwanted condition, the treatment is therapeutic, (that is, it is intended to decrease, improve, or stabilize the existing undesired condition or side effects thereof). The term "prevent" is recognized in the art, and when used in relation to a condition, such as a local recurrence (eg, pain), a disease such as cancer, a complex syndrome such as heart failure or any other medical condition, is well understood in the art, and includes administration of a composition which reduces the frequency of, delays in the appearance of, or otherwise inhibits the symptoms of a medical condition in a subject relative to a subject who does not receive the composition. Thus, cancer prevention includes, for example , reduce the number of cancerous growths detectable in a population of patients receiving a prophylactic treatment relative to a control population untreated, and / or delaying the appearance of detectable cancerous growths in a treated population against an untreated control population, for example, by a statistically and / or clinically significant amount. Prevention of an infection includes, for example, reducing the number of diagnosis of the infection in a treated population against an untreated control population, and / or delaying the onset of symptoms of infection in a treated population against an untreated control population. . The prevention of pain includes, for example, reducing the magnitude of, or alternatively delaying, pain sensations experienced by subjects in a treated population against an untreated control population. The term "therapeutic index" refers to the therapeutic index of a drug defined as LD50 / ED50. A "therapeutically effective amount" of a compound, for example, such as a DPIV inhibitor of the present invention, with respect to the method being treated, refers to an amount of the compounds in a preparation which, when administered as part of a desired dosage regimen (to a mammal, preferably a human) alleviates a symptom, ameliorates a condition, or delays the onset of pathologies according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose, for example, in a reasonable benefit / risk ratio applicable to any medical treatment. A "simple oral dose formulation" is a dose that provides an amount of drug to produce a serum concentration at least as large as the EC50 for such a drug, but less than the LD50. Another measure for a simple oral dose formulation is that which provides an amount of drug necessary to produce a serum concentration at least as large as IC 50 for the drug, but less than LD 50. When measuring either, a single oral dose formulation is preferably a quantity of drug which produces a serum concentration at least 10% less than LD50, and even more preferably at least 50%, 75%, or even 90% less than LD0 drugs. An aliphatic chain comprises the class of alkyl, alkenyl and alkyl defined below. A straight aliphatic chain is limited to portions of unbranched carbon chain. As used herein, the term "aliphatic group" refers to a straight chain, branched chain, or cyclic aliphatic hydrocarbon group and includes saturated and unsaturated aliphatic groups, such as an alkyl group, an alkemyl group, or a group alquimlo. "Alkyl" refers to a portion of chain of Fully saturated cyclic or acyclic, branched or unbranched carbon having the number of specific carbon atoms, or up to 30 carbon atoms if the specification is not made. For example, alkyl of 1 to 8 carbon atoms refers to portions such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl, and those portions that are positional isomers of these portions. Alkyl of 10 to 30 atoms carbon includes decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl, eicosyl, heneicosyl, docosyl, tpcosyl and tetracosyl. In certain embodiments, a straight chain alkyl or branched chain has 30 or some carbon atoms. carbon in its column (eg, C; -C3O for straight chains, CJC-JO for branched chains), and more preferably 20 or some. Similarly, 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. Unless the carbon number is otherwise specified, "lower alkyl," as used herein, means an alkyl group, as defined above, but having from one to ten carbons, more preferably from one to six. carbon atoms in its column structure such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Similarly, "lower alkenyl" and "lower alkyl" have similar chain lengths. Throughout the application, preferred alkyl groups are lower alkyl. In certain embodiments, a substituent designated herein as alkyl is a lower alkyl. The term "alkylthio" refers to an alkyl group, as defined above, having a portion of sulfur bonded thereto. In certain embodiments, the "alkylthio" portion is represented by one of - (S) -alkyl, - (S) -alkenyl, - (S) -alkyl, and - (S) - (CH2) m-R1, wherein my R1 are defined below. Representative alkylthio groups include methylthio, ethylthio, and the like. "Alkenyl" refers to any portion of cyclic or acyclic, branched or unbranched chain that has the number of specific carbon atoms, or up to 26 carbon atoms if there is no limitation on the number of carbon atoms specified; and that has one or more double bonds in the portion. Alkenyl of 6 to 26 carbon atoms is exemplified by hexenyl, heptenyl, octenyl, nonemlo, decenyl, undecenyl, dodenyl, tridecenyl, tetradecenyl, pentadecenyl, hexadecenyl, heptadecemyl, octadecenyl, nonadecenyl, eicosenyl, heneicosoenyl, docosenyl, tpcosenyl, and tetracosenyl, in its various isomeric forms, where the unsaturated bonds can be located anywhere where the portion and can have either the (Z) or (E) configuration around the double bonds. "Alkyl" refers to hydrocarbyl portions of the alkenyl range, but having one or more triple bonds in the moiety. Analogous substitutions can be made to alkenyl and alkyloyl groups to produce, for example, moalkenyls, aminoalkyls, amidoalkenyls, amidoalkyms, aminoalkenyls, aminoalkyls, thioalkenyls, thioalkyls, carbonyl-substituted alkenyls, or alkyls. The terms "alkoxy" or "alkoxy" as used herein refers to an alkyl group, as defined below, having an oxygen moiety bonded thereto. Representative alkoxy groups include methoxy, ethoxy, propoxy, tert-butoxy, and the like. An "ether" is two hydrocarbons covalently bound by an oxygen. Accordingly, the substituent of an alkyl which makes such an alkyl an ether is or looks like an alkoxy, as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkyl, -O- (CH?) m-R1, where m and R are described below. The terms "amine" and "ammo" are recognized in the and refer both unsubstituted and substituted amines, for example, a portion that can be represented by the formula: wherein R3, R5 and Rs each independently represents a hydrogen, an alkyl, an alkene, - (CH) m-R1, or R3 and RJ taken together with the N atom to which a heterocycle having from 4 to 8 atoms in the ring structure; R1 represents an alkenyl, aryl, cycloalkyl, a cycloalkenyl, a heterocyclyl, or a polycyclyl; and m is zero or an integer in the range of 1 to 8. In certain embodiments, only one of R3 or Rl > it can be a carbonyl, for example, R3, R5, and nitrogen together do not form an iodide. In still more of certain embodiments, R3 and R5 (and optionally R6) each independently represents a hydrogen, an alkyl, an alkenyl, or - (CH2) m-R1. Thus, the term "alkylamine" as used herein means an amine group, as defined above, having a substituted or unsubstituted alkyl bonded thereto, that is, at least one of R3 and R 'is an alkyl group . In certain embodiments, an ammo group or an alkylamine is basic, which means that it has an acid conjugated with a pKa > 7.00, that is, the protonated forms of these functional groups that have pKa relative to water above about 7.00. The term "aplo" as used herein includes 5, 6, and 7 members substituted or unsubstituted single ring aromatic groups in which each ring atom is carbon (ie,, carbocyclic aryl) or where one or more atoms are heteroatoms (i.e., heteropole). The term "aryl" also includes polycyclic ring systems having two or more cyclic rings in which two or more carbons are cumun to two adjacent rings wherein at least one of the rings is aromatic, for example, the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkymls, aplos, heteroaryls, and / or heterocyclyls. Carbocyclic aryl groups include benzene, naphthalene, phenanthrene, phenol, aniline, and the like. Heteroaryl groups include substituted or unsubstituted 5 to 7 membered aromatic ring structures, more preferably 5 to 6 membered rings, whose ring structures include one to four heteroatoms. Heteroaryl groups include, for example, pyrrole, furan, thiophene, imidazole, oxazole, tlazole, tpazol, pyrazole, pyridine, pyrazma, pipdazm and pipmidma, and the like. The term "carbonyl" is recognized in the art and includes such portions as can be represented by the formula: wherein X is a bond or represents an oxygen or a sulfur, and R7 represents a hydrogen, an alkyl, an alkenyl, - (CH2) mR: or a pharmaceutically acceptable salt, R8 represents a hydrogen, an alkyl, an alkenyl or - (CH ^) m-R1, where m and R1 are as defined above. Where X is an oxygen and R7 or R8 is not hydrogen, the formula represents an "ester." Where X is an oxygen, and R7 is as defined above, the portion is referred to herein as a carboxyl group, and particularly when R7 is a hydrogen, the formula represents a "carboxylic acid". Where X is an oxygen, and R8 is a hydrogen, the formula represents a "format." In general, where the oxygen atom of the above formula is replaced by a sulfur, the formula represents a "thiocarbonyl" group. Where X is a sulfur and R 'or R8 is not hydrogen, the formula represents a "thioester" group. Where X is a sulfur and R7 is a hydrogen, the formula represents a group of "thiocarboxylic acid". Where X is a sulfur and R8 is a hydrogen, the formula represents a "thioformate" group. On the other hand, where X is a bond, and R7 is not hydrogen, the previous formula represents a "ketone" group. Where X is a bond, and R7 is a hydrogen, the above formula represents an "aldehyde" group. The terms "heterocyclyl" or "heterocyclic group" refer to ring structures of 3 to 10 members, more preferably rings of 3 to 7 members, whose ring structures include one to four heteroatoms. The heterocycles can also be polycycles. Heterocyclyl groups include, for example, thiophene, thiantrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxatm, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pipdma, pyrazma, pipmidma, pipdazm, mdolizma, isomol, indole, indazole, purine, qumolizma, ismolyme, qumolma, phthalazma, naphthyridma, qumoxalma, qumazolma, cmnolma, ptepdma, carbazole, carbolma, phenanthridine, acridma, pipmidma, fenantrolma, fenazma, fenarsazma, fenotiazma, furazan, fenoxazma, pyrrolidma, oxolane, thiolane, oxazole, piperidma, piperazma, morpholma, lactones, lactams such as azetidrones and pyrrolidmones, sultamas, sultones, and the like. The heterocyclic ring can be substituted at one or more positions with such substituents as described above, such as, for example, halogen, alkyl, aralkyl, alkenyl, alkyl, cycloalkyl, hydroxyl, ammo, nitro, sulfhydryl, imam, amido, phosphate, phophonate, phosphmate, carbonyl, carboxyl, silyl, sulfamoyl, sulfinyl, ether, alkylthio, sulfonyl, ketone, aldehyde, ester, a heterocyclyl, an aromatic or heteroaromatic portion, CF), -CN, and Similar. As used herein, the term "substituted" is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the admissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein above. The admissible substituents may be one or more and the same or different for suitable organic compounds. For purposes of this invention, heteroatoms such as nitrogen may have hydrogen substituents and / or any of the administrable substituents of organic compounds described herein that meet the valences of heteroatoms. This invention is not intended to be limited in any way by the admissible substituents of organic compounds. The term "hydrocarbyl" refers to a portion of monovalent hydrocarbon comprising chains of carbon or rings of up to 26 carbon atoms to whose hydrogen atoms are bonded. The term includes alkyl, cycloalkyl, alkenyl, alkynyl, and aryl groups, groups having a mixture of saturated and unsaturated bonds, carbocyclic rings, and include combinations of such groups. This may refer to straight chain, branched chain, cyclic structures, or combinations thereof. The term "hydrocarbylene" refers to a divalent hydrocarbyl portion. Representative examples include alkylene, phenylene, or cyclohexylene. Preferably, the hydrocarbylene chain is completely saturated and / or has a chain of 1 to 10 carbon atoms. As used herein, the term "nitro" means -N02; the term "halogen" designates -F, -Cl, -Br, or -I; the term "sulfhydryl" means -SH; the term "hydroxyl" means -OH; the term "sulfonyl" means -SO; -; the term "azido" means-N3; the term "cyano" means -CN; the term "isocyanate" means -NCO; the term "thiocyanate" means -SCN; the term "isothiocyanate" means -NCS; and the term "cyanate" means -OCN. It is understood that "substitution" or "substituted with" includes the implicit condition that such substitution is according to the permitted valency of the substituted atom and the substituent, and that the results of the substitution in a stable compound, for example, that are not subjected to spontaneous transformation such as by reconfiguration, cyclization, elimination, etc. The term "sulfamoyl" is recognized in the art and includes a portion that can be represented by the formula: in which R3 and R5 are as defined above. The term "sulfate" is recognized in the art and includes a portion that can be represented by the formula: in which R7 is as defined above. The term "sulfonamide" is recognized in the art and includes a portion that can be represented by the formula: in which R3 and R8 are as defined above. The term "sulfonate" is recognized in the art and includes a portion that can be represented by the formula: wherein R7 is a pair of electrons, hydrogen, alkyl, cycloalkyl, or aryl. The terms "sulfoxide" or "sulfinyl", as used herein, refers to a portion that can be represented by the formula: wherein R 12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl, or aryl. The term "thioxamide," as used herein, refers to a portion that can be represented by the formula: in which Rl is selected from the group consisting of hydrogen, alkyl, cycloalkyl, aralkyl, or aplo, preferably hydrogen or alkyl. However, compounds of "thioxamide derivatives" or "thioxamide analogs" refer to compounds in which one or more amide groups have been replaced by one or more corresponding thioxamide groups. Thioxamides are also referred to in the art as "thioamides." As used herein, the definition of each expression, for example, alkyl, m, n, etc., when this occurs more than once in any structure, is intended to be independent of its definition anywhere in the present the same structure. "Biohydrolyzable amide" refers to an amide portion that is released (eg, to form a hydroxyl and a carboxylic acid) or physiological conditions. Physiological conditions include the acidic and basic environment of the digestive tract (e.g., stomach, intestines, etc.), enzymatic release, metabolism, and other biological processes, and preferably refers to physiological conditions in a vertebrate, such as a mammal . "Biohydrolyzable ester" refers to an ester portion that is released (eg, to form a hydroxyl and a carboxylic acid) under physiological conditions. Physiological conditions include the acidic environment and basic digestive tract (eg, stomach, intestines, etc.), enzymatic release, metabolism, and other biological processes, and preferably refer to physiological conditions in a vertebrate, such as a mammal. "Biohydrolyzable imide" refers to an imide moiety that is released (eg, to form a hydroxyl and a carboxylic acid) under physiological conditions. The physiological conditions include the acidic and basic environment of the digestive tract (e.g., stomach, intestines, etc.), enzymatic release, metabolism, and other biological processes, and preferably refer to physiological conditions in a vertebrate, such as a mammal. . The terms "amino acid residue" and "peptide residue" mean an amino acid or peptide molecule without the -OH of its carboxyl group. In general, the abbreviations used herein to designate amino acids and protecting groups are based on recommendations of the Commission on IUPAC-IUB chemical bionomenclature (see Biochemistry 1972, 11, 1726-1732). For example, Met, Lie, Leu, Ala, and Gly represent "residues" of metionma, ísoleucma, leucma, alanma, and glycine, respectively. The residue means a portion derived from the corresponding α-ammo acid by eliminating the OH portion of the group carboxyl and the H portion of the a-amino group. The term "amino acid side chain" is that part of an amino acid exclusive of the -CH (NH2) COOH portion, as defined by K. D. Kopple, Peptides and Amino Acids; Benjamin: New York, 1966; pp. 2 and 33; examples of such side chains of the common amino acids are -CH2CH2SCH3 (the side chain of methionine), -CH2 (CH3) -CH2CH3 (the side chain of teucus), -CH2CH (CH3) 2 (the side chain of leucma) or H - (the glycine side chain). For the most part, the amino acids used in the application of this invention are those naturally occurring amino acids found in proteins, or the anabolic or catabolic products that naturally occur from such amino acids that contain amino and carboxyl groups. Particularly suitable amino acid side chains include side chains selected from those of the following amino acids: glycine, alanine, valma, cistern, leucma, ísoleucma, sepna, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagma, lysine, arginine, proline , histidma, phenylalanma, tyrosma, and tryptophan, and those amino acids and amino acid analogs that have been identified as constituents of cell walls of peptidylglycan bacteria. The term amino acid residue also includes analogs, derivatives and congeners of any specific amino acid referred to herein, as well as C-terminal or N-terminal protected amino acid derivatives (eg, modified with an N-terminal or C-terminal protecting group) For example, the present invention contemplates use of amino acid analogs wherein a side chain is elongated or shortened, while providing a carboxyl, ammo or other reactive precursor functional group for cyclization, as well as amino acid analogs having variant side chains with appropriate functional groups) For example, The subject compound can include an amino acid analogue such as, for example, cyanoalanma, canavanine, djencholic acid, norleucma, 3 -phosphoserine, homosepna, dihydroxy-phenylalanine, 5-h? drox? tr? tofano, 1-met? lh? st? dma, 3-methylhistidma, diammopimélico acid, ornitma, or diammobutírico acid Other metabolites or amino acid precursors that occur naturally that t The side chains which are suitable herein will be recognized by those skilled in the art and are included within the scope of the present invention. The stereoisomers (D) and (L) of such amino acids are also included when the structure of the amino acid supports stereoisomers The configuration of the amino acids and amino acid residues in the present is they designate by the appropriate symbols (D), (L) or (DL), on the other hand when the configuration is not designated, the amino acid or residue may have the configuration (D), (L), or (DL). It will be noted that the structure of some of the compounds of this invention include asymmetric carbon atoms. It is to be understood accordingly that the isomers derived from such asymmetry are included within the scope of this invention. Such isomers can be obtained in substantially pure form by classical separation techniques and by spherically controlled synthesis. For the purpose of this application, unless expressly stated otherwise, a so-called amino acid will be interpreted as including both the stereoisomers (D) and (L). The phrase "protecting group" as used herein means substituents that protect the reactive functional group from undesirable chemical reactions. Examples of such protecting groups include esters of carboxylic acids and boronic acids, ethers of alcohols, and acetals and ketals of aldehydes and ketones. For example, the phrase "Terminal N protecting group" or "amino protecting group" as used herein refers to various amino protecting groups that can be employed to protect the N-terminus of an amino acid or peptide against undesirable reactions during synthetic Examples of suitable groups include acyl protecting groups such as, to illustrate, formyl, dansyl, acetyl, benzoyl, tpfluoroacetyl, succinyl, and methoxysuccinyl; aromatic urethane protecting groups such as, for example, benzyloxycarbonyl (Cbz); and urethane-aliphatic protecting groups such as t-butoxycarbonyl (Boc) or 9-Fluoren-lmetox-carbonyl (Fmoc). As noted above, certain compounds of the present invention can exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans isomers, R- and S-enantiomers, diastereomers, isomers (D), isomers (L), racemic mixtures thereof, and other mixtures thereof, as illustrated herein. of the scope of the invention. Additional asymmetric carbon atoms may be present in a substituent such as an alkyl group. All of such isomers, as well as mixtures thereof, are intended to be included in this invention. In certain embodiments where a particular enantiomer is preferred, a compound of the present invention is enriched to have > 60%, > 70%, > 80%, > 90%, > 95%, or even greater than 98% or 99% of the preferred enantiomer, as opposed to a racemate where the two enantiomers each occur to the degree of 50%. If, for example, a particular enantiomer of a The compound of the present invention is desired, this can be prepared by asymmetric synthesis or by derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary group is liberated to provide the desired pure enantiomer. Alternatively, where the molecule contains a basic functional group, such as amino, or an acidic functional group, such as carboxyl, diastereomeric salts are formed with an appropriate optically active acid or base, followed by resolution of the diastereomers thus formed by fractional crystallization or chromatographic media well known in the art, and subsequent recovery of the pure enantiomer. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 67th ed., 1986-87, covered therein. A compound is one that has a "msulinotrophic activity" is capable of stimulating, or causing the stimulation of, the synthesis or expression of the hormone insulin The term "ammo terminal protective group" as used herein, refers to groups terminal ammo protectants that are typically employed in organic synthesis, especially peptide synthesis. Any of the known categories of protective groups can be employ, including acyl protecting groups, such as acetyl, and benzoyl; aromatic urethane protecting groups, such as benzyloxycarbonyl; and aliphatic urethane protecting groups, such as tert-butoxycarbonyl. See, for example, Gross and Mienhoffer, Eds., The Ppetides, Academic Press: New York, 1981;, Vol. 3, 3-88; and Green, T. W.; Wuts, P. G. M., Protective Groups in Organic Synthesis, 2nd ed., Wiley: New York, 1991. Preferred protecting groups include aryl-, aralkyl-, heteroaryl- and heteroarylalkyl-carbonyl and sulfonyl moieties. The term "amino acid analog" refers to a compound structurally similar to an naturally occurring amino acid wherein either the C-terminal carboxy group, the N-terminal amino group or the terminal chain functional group has been chemically modified. For example, aspartic acid (beta-methyl ester) is an analogous amino acid of aspartic acid; N-ethylglycine is an amino acid analogue of glycine; or alanine carboxamide is an amino acid analogous to alanine. The terms "gastrointestinal inflammation," "inflammatory bowel disease," and "inflammation of the gastrointestinal tract" are used interchangeably herein to mean inflammation of any portion of the gastrointestinal tract, from the esophagus to sigmoid flexion or the termination of the colon in the straight. The Inflammation can be acute, but, generally, the composition of this invention is used to treat chronic conditions. A "simple oral dose formulation" is a dose that provides an amount of drug to produce a serum concentration at least as large as the EC50 for such a drug, but less than the LD50. Another measure for a simple oral dose formulation is that which provides an amount of drug necessary to produce a serum concentration at least as large as IC50 for such a drug, but less than LD50. When measuring either, a single oral dose formulation is preferably an amount of drug that produces a serum concentration at least 10% less than LD50, and even more preferably at least 50%, 75%, or even 90% less than LD50. . The phrase "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that are, within the scope of current medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, consistent with a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a material pharmaceutically acceptable, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material, involved in carrying out or transporting the inhibitors of the present invention from one organ, or portion of the body, to another organ , or portion of the body. Each carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not harmful to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as carboxymethyl sodium cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa buffer and waxes in suppository; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl acetate and ethyl laurate; (13) agar; (14) damping agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) RingeRs solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. The term "pharmaceutically acceptable salts" in these instances refers to the relatively non-toxic, inorganic and organic base addition salts of the compounds of the present invention. The term "pharmaceutically functional derivative" refers to any pharmaceutically acceptable derivative of an inhibitor of the present invention, for example, an ester or an amide, which upon administration to a mammal is capable of providing (directly or indirectly) the inhibitor. Such derivatives are recognized by those skilled in the art, without undue experimentation. However, reference is made to the teaching of Burger's Medicinal Chemistry and Drug Discovery, 5th ed., Vol. 1. As used herein, the term "physiological conditions" refers to temperature, pH, ionic strength, viscosity, and biochemical parameters. similar ones that are compatible with a viable organism, and / or that typically exist intracellularly in a viable mammalian cell.

The term "prodrug" as used herein encompasses compounds which, under physiological conditions, are they become therapeutically active agents. A common method for making a prodrug is one that includes selected portions that are hydrolyzed under physiological conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal. The term "shelf life" typically refers to the period of time for which the performance characteristics of an inhibitor remain pointed. As used herein, the term "T90" refers to the amount of time it takes for a preparation of the target inhibitor to degrade to the point that it has 90% of the activity of the starting sample, for example, a decrease of 10% Similarly, the term "T50" refers to the amount of time it takes for a preparation of the target inhibitor to degrade to the point that it has 50% of the activity of the start sample, eg, a 50% decrease. The shelf life, reported as T90 or T50, for a given pharmaceutical preparation of an inhibitor is the measure for preparation as it is packaged for use by a health care provider or patient. As used herein, the term "substantially soluble" refers to inhibitors that can be dissolved in an inhaled helix mixture to form a substantially clear to dark solution that does not It will separate in layers or form a precipitate when left unstirred for a minimum of 24 hours at room temperature. By "transdermal patch" is meant a system capable of releasing a drug to a patient by means of the skin, or any suitable external surface, including mucosal membranes, such as those found within the mouth. Such delivery systems generally comprise a flexible support, an adhesive and a matrix that preserves the drug, the backing that protects the adhesive and the matrix, and the adhesive that completely protects the skin of the patient. In contact with the skin, the matrix that retains the drug releases the inhibitor to the skin, the drug is then passed through the skin in the patient's system. The term "quaternizing agent" refers to a chemical compound that converts a nitrogen atom with less than four substituents to a nitrogen atom positively charged with four substituents. Examples of "quaternizing agents" include lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl sulphates such as dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl chlorides, lauryl, mipstyl and stearate, bromides and iodides, aralkyl halides such as benzyl and phenethyl bromides, and others . The term "therapeutic index" refers to the therapeutic index of a drug defined as LD50 / ED5o. A "therapeutically effective amount" of a compound, for example, such as a dipeptidyl peptidase inhibitor of the present invention, with respect to the method being treated, refers to an amount of the compounds in a preparation which, when administered as part of a desired dose regimen (to a mammal, preferably a human) brings relief from a symptom, improves a condition, or delays the onset of pathologies according to clinically acceptable standards for the disorder or condition to be treated or the cosmetic purpose , for example, in a reasonable benefit / risk ratio applicable to any medical treatment.

A "therapeutically effective daily dose" of a compound, for example, such as an inhibitor of the present invention, with respect to the method to be treated, refers to an amount of the compounds in a preparation which, when administered as part of a desired daily dose regimen (to a mammal, preferably a human) that brings relief from a symptom, improves a condition, or delays the onset of pathologies according to clinically acceptable standards for the disorder or condition to be treated or the purpose cosmetic, for example, in a reasonable benefit / risk ratio applicable to any medical treatment.

It is understood that all generic structures recited where, with respect to appropriate combinations of substituents, are intended to cover those modalities that allow for valence and stability.

Modalities and emplares (i). Compounds Useful compounds will be described below using various formulas. In each case, the variables in the formula are specifically defined for each individual formula. A definition of a variable for a formula will not be used to vary a definition provided by another formula, although a variable that has been defined for a formula can be interpreted by anology with a definition in other parts of a similar formula.

Modality A A representative class of compounds for use in the method of the present invention are represented by the formula I: (I) wherein A represents a 4-8 membered heterocycle including N and carbon Ca; Z represents C or N; W represents a functional group that reacts with an active site residue of the target protease, such as, for example, -CN, -CH = NR5, R? represents an amino acid residue thermally linked to C or an analogous amino acid, or a peptide thermically bonded to C or analogous peptide, or S R ° -; wherein the bond between Ri and N is a thioxamide linkage; R? is absent or represents one or more substitutions to ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkyl, carbonyl (such as a carboxyl, ester, formate, or ketone), thiocarbomyl (such as a thioester, thioacetate, or thioformate), ammo, acylammon, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, lower alkyl- (CH2) m-0-, lower alkenyl- (CH?) m-0-, - (CH2) n-0- (CH2) m-R7, - (CH2) m-SH, lower alkyl - (CH7) m-S-, lower alkenyl - (CH2) m-S-, or - (CH2) n-S- (CH2) m-R7, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate,, or C ____ = C R8; when Z is N, R3 is absent; when Z is C, R3 represents hydrogen or a halogen lower alkyl, lower alkenyl, lower alkynyl carbonyl, thiocarbonyl, amino, acylamino, amido, nitro sulfate, sulfonate, a sulfonamido, - (CH2) m-R7, - (CH2) m -OH lower alkyl- (CH2) m-0-, lower alkenyl- (CH2) m-0- - (CH2) n-0- (CH?) M-R7, - (CH2) m-SH, lower alkyl- (CH2) mS-lower alkenyl - (CH2) mS-, or - (CH2) nS- (CH2) m-R7, azido cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, R? represents H, alkyl, alkenyl, alkynyl, C (X,) (X?) X3, - (CH2) m-R7, - (CH2) n-OH, - (CH2) n-0-alkyl? , (CH?) N-0-alkenyl, - (CH2) n-0-alkynyl, - (CH2) n-0- (CH2) m-R7, - (CH2) n-SH, - (CH2) nS- alkyl, - (CH2) nS-alkenyl, - (CH2) nS-alkynyl, - (CH2) nS- (CH2) m -R7, -C (O) C (O) NH2, or C (0) C (0 ) 0R '-,; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkynyl, aryl, - (CH2) m-R7, - (CH2) m-0H, - (CH2) m- O-alkyl, - (CH2) m-0-alkenyl, - (CH2) m-0-alkyl, - (CH2) m-0- (CH2) m-R7, - (CH2) m-SH , - (CH2) mS-alkylene, - (CH2) mS-alkenyl, - (CH2) mS-alkylene, - (CH2) mS- (CH2) m-R7, O O O I I II I I • (CH2) n - C - O - R7 (CH2) n - C - (CH2) alkyl n - C - alkepyl O O II. || "(CH2) n-C-alkynyl (CH2) n-C- (CH2) m-R7 R / represents, each occurring, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R '/ represents, each occurring, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aplo, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and Y: and Y can be independently or together OH, or a group capable of hydrolyzing to a hydroxyl group, including cyclic derivatives where Y and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure ( such as pmacol or the like), R50 represents 0 or S; R5i represents N3, SH2, NH2, N02 or ORd; R? represents hydrogen, a lower alkyl, amine, ORd, or a pharmaceutically acceptable salt, or R5? and R52 taken together with the phosphorus atom to which a heterocyclic ring having from 5 to 8 atoms in the ring structure is linked; X-i represents a halogen; X? and X3 each represents a hydrogen or a halogen m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. In certain embodiments, ring A is a ring of 5, 6, or 7 members, for example, represented by and more preferably a 5 or 6 member ring. The ring can, optionally, also be replaced. In certain modalities, W represents In certain modalities, Ri is wherein R35 is a small hydrophobic group, eg, a lower alkyl or a halogen and R38 is hydrogen, or, R36 and RJ8 together form a 4-7 member heterocycle including N and carbon Ca, as defined by Upstairs; and R-io represents an amino acid residue thermally linked to C or analogous amino acid, or a peptide thermally bonded to C or analogous peptide, or an ammo protecting group. In certain embodiments, R 2 is absent, or represents a small hydrophobic group such as a lower alkyl or a halogen. In certain embodiments, R3 is a hydrogen, or a small hydrophobic group such as a lower alkyl or a halogen. In certain embodiments, R5 is a hydrogen, or a halogenated lower alkyl. In certain embodiments, Xi is a fluorine, and X2 and X3, if the halogens, are fluorine. Also considered as equivalents are any of the compounds that can be hydrolytically converted into any of the aforementioned compounds including boronic acid esters and halides, and carbonyl equivalents including acetals, hemiacetals, ketals, and hemiketals, and cyclic dipeptide analogues. Longer peptide sequences are needed to the inhibition of certain proteases and improve the specificity of the inhibition in some cases. In certain embodiments, the subject method uses, as a DPIV inhibitor, a boronic acid analogous to an amino acid or amino acid derivative, such as a thioxamide-modified amino acid. For example, the present invention contemplates the use of boron-prolyl derivatives in the subject method. Exemplary boronic acid derivative inhibitors of the present invention are represented by formula II: (II) wherein R-, represents an amino acid residue thermally linked to C or analogous amino acid, or a peptide thermally bonded to C or analogous peptide, or ; wherein the bond between Ri and N is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkyl, aryl, - (CH2) m-R7, - (CH2) m-OH, - (CH) mO-alkyl, - (CH7) m-0-alkenyl , - (CH2) m-0-alkyl, - (CH2) m- 0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-alkyl, - (CH2) mS-alkenyl, - (CH2) mS-alkynyl, - (CH2) mS- (CH2 ) m-R7, / RK O "D, Rs N I H, _I2? O W (Cldm-N ^ - (CH3) n-C-N _ (CH2) n-NH2-C-NH2 _ (CH2) n-C-0-R7 R R - (H2) R represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and R9 each independently represent hydrogen, alkyl, alkenyl, - (CH2) m-R7, -C (= 0) -alkyl, -C (= 0) -alkenyl, -C (= 0) -alkynyl, -C (= 0) - (CH2) m-R7, or R8 and R9 are taken together with the N atom to which they are linked complete to a heterocyclic ring having from 4 to 8 atoms in the ring structure; R and Ri2 each independently represents hydrogen, an alkyl, or a pharmaceutically acceptable salt, or Rn and R12 are taken together with the 0-BO atoms to which they are bonded complete to a heterocyclic ring having from 5 to 8 atoms in the structure From the ring; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. In other embodiments, the compounds include proline analogue aldehydes or prolyl derivatives, such as thioxamide derivatives. The compounds derived from Exemplary aldehydes of the present invention are represented by formula III: (III) where RT represents a residue of amino acid terminally bound to C or analogous amino acid, or to bound peptide terminally to C or analogous peptide, or; wherein the bond between Ri and N is a thioxamide bond; R5 represents hydrogen, a halogen, alkyl, alkenyl, alkynyl, aryl, - (CH2) m-R7, - (CH2) m-OH, - (CH2) mO-alkyl, - (CH2) m-0-alkenyl, - (CH2) m-0-alkynyl, - (CH2) m-0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-alky ?, - (CH2) mS-alkenyl, - (CH2) mS-alkynyl, - (CH2) mS- (CH2) m-R7, R? 0, Rs Cl l. m- N /? - (CH?) N- 8C-N Rs _ (CH2) n-NH? -C-Ni H? _ (CH2) n- flC- O O O - (Cl l?) N- alkyl, - (Cl l2) n-C-alkenyl, - (C H?) J-alkynyl, 0 - (CH?) P-í- (CH?) N- R7 R7 represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R8 and Rg each independently represent hydrogen, alkyl, alkenyl, - (CH2) m-R7, -C (= 0) -alkyl, -C (= 0) -alkenyl, -C (= 0) -alkyl, -C (= 0) - (CH2 ) m-R7, or R8 and Rg are taken together with the N atom to which they are linked complete to a heterocyclic ring having from 4 to 8 atoms in the ring structure; and m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. In still further embodiments, the compounds include a halo-methyl ketone analog of an amino acid or amino acid derivative, such as a thioxamide-modified amino acid. Exemplary compounds of this class include compounds represented by formula IV: (IV) where R-! represents an amino acid residue thermally linked to C or analogous amino acid, or a peptide thermally bonded to C or analogous peptide, or S Rb-, wherein the bond between R and N is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkynyl, aryl, - (CH2) m-R7, - (CH) m-OH, - (CH2) m- O-alkyl, - (CH2) m-0-alkenyl, - (CH2) m-0- alkynyl, - (CH2) m- 0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-alky ?, - (CH2) mS-alkenyl, - (CH2) mS-alkynyl, - (CH2) mS- (CH2) m-R7, - (Cl l >) "? - N R7 O O - (Cl l, n-C1-alkyl, - (CH2) n-C-alkenyl, - (CH2)) nn-- CC-alkynyl, or - (CH 2) n- - (CH?) N-i-R7 R / represents an aryl, a cycloalkyl, a cycloalkenyl, or a heterocycle; R¡¡ and Rg each independently represents hydrogen, alkyl, alkenyl, - (CH2) m-R7, -C (= 0) -alkyl, - C (= 0) -alkenyl, -C (= 0) -alkynyl, -C (= 0) - (CH2) m-R7, or R8 and Rg are taken together with the N atom to which link complete to a heterocyclic ring that has 4 up to 8 atoms in the ring structure; X:, X and X each represent a hydrogen or a halogen; Y m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8.

In certain embodiments, the compounds are peptides or peptidomimetics including a polyl group or analogue of the same in the position of specificity Pl, and a non-polar amino acid at the specificity position P2, by example, a non-polar amino acid such as alanine, leucine, isoleucine, valine, proline, phenylalanine, tryptophan or methionine, or an analogue thereof, such as an analogous thioxamide. For example, the compound may include a dipeptide sequence Ala-Pro or Pro-Pro or equivalent thereof, and be represented in formulas V and VI: (VI) In certain embodiments, ring A is a ring 5, 6 or 7 members, for example, represented by In certain embodiments, R32 is a small hydrophobic group, for example, a lower alkyl or a halogen. 5 In certain modalities, R30 represents a waste of amino acid thermically bonded to C or analogous amino acid, or a peptide thermally bonded to C or analogous peptide, or an ammo protecting group wherein optionally where the bond between R30 and the N to which it is bonded is applied is a thioxamide bond. In certain modalities, R30 is H. In certain modalities, R2 is absent, or is it a halogen, azido, cyano, isocyanate, thiocyanate, ©? isothiocyanate, cyanate, N = C,, 8 or small hydrophobic group such as a lower alkyl. In certain embodiments, Z is C and R3 is a hydrogen, or a small hydrophobic group such as a lower alkyl or a halogen. Another representative class of compounds for use in the subject method includes (D) -Ala- (L) -Ala peptide and peptide mimics, for example, preserving the diastereomer orientation, in which one or more amide groups are replaced by one or more groups thioxamide. Such compounds include compounds represented by formula VII: (VII) wherein W represents a functional group that reacts with an active site residue of the target protease, such as -CN, -CH = NR5, Ri represents an amino acid residue terminally linked to C or analogous amino acid, or a peptide terminally linked to C or analogous peptide, or an amino protecting group, or where optionally the link between R is applied? and the N to which it is linked is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkynyl, aryl, - (CH2) m-R7, - (CH2) m-0H, - (CH2) mO-alkyl, - (CH2) m-0-alkenyl, - (CH2) m-0-alkynyl, - (CH2) m-0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-alkyl, - (CH2) mS-alkenyl, - ( CH2) mS-alkynyl, - (CH2) mS- (CH2) m-R7, / Rs M Rs NH? O - (CH.) M- N? - (CH2) "- C-N _ (CH2) n_NH2_c_NH, _ (CH2) _r_c_o_R. R R9 Cl l. > ) n-C-alkyl, - (CH?) "- C-alkenyl, - (CH2)" - C-alkylene, or - (CH2) n-C- (CH?) n- R7 / Rβ NH2 (CH2) m- N, _ - (CH2) n - C-N? II R9 (CH2) n-NH2-C-NH2 R9 0 0 0 I 1 'II II' 11 11 - (CH2) n - C -0 - R7 (CH2) n - C - (CH2) alkyl n - C - alkenyl O O - (CH2) n-C-alkynyl (CH2) n-C- (CH2) n R / represents, each occurring, a substituted or unsubstituted aryl aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R '/ represents, each occurring, hydrogen, or either a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R6i and Re2 / independently, represents small hydrophobic groups; YT and Y2 can independently or together be OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Yi and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like), R50 represent O or S; Ri ,! represent N3, SH2, NH2, N02 or ORd; Rl) 2 represent hydrogen, a lower alkyl, an amine, OR '/, or a pharmaceutically acceptable salt, or R5X and R,) 2 are taken together with the phosphorus atom to which link complete to a heterocyclic ring having from 5 to 8 atoms in the ring structure; Xi represents a halogen; X? and X3 each represents a hydrogen or a halogen m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. In certain modalities, R1 is Where R3S is a small hydrophobic group, eg, a lower alkyl or a halogen and R38 is hydrogen, or, R3G and R38 together form a 4-7 membered heterocycle including N and carbon C, as defined by A previously; and R40 represents an amino acid residue thermally linked to C or analogous amino acid, or a peptide thermally linked to C or analogous peptide, or an ammo protecting group. In certain embodiments, Z is C and R3 is a hydrogen, or a small hydrophobic group such as a lower alkyl or a halogen. In certain embodiments, R5 is a hydrogen, or a halogenated lower alkyl.

In certain modalities, Xi is a fluorine, and X2 and X3, are halogens, are fluorine. In certain embodiments, Rs_ and Re2, independently, represent lower alkyls, such as methyl, ethyl, propyl, isopropyl, tert-butyl or the like.

Modality B Another representative class of compounds for use in the method of the present invention are represented by the formula VIII: (VIII) wherein Ri represents hydrogen, halogen or lower alkyl, lower alkenyl, or lower alkynyl, preferably lower alkyl such as methyl, ethyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc.; R 2 represents a branched lower alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, preferably a bulky hydrophobic group, such as cyclohexyl, t- butyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc.; R3 represents hydrogen or an amino protecting group, preferably hydrogen; R4 represents hydrogen, an amino acid residue thermally bonded to C or an analogous amino acid, a peptide thermally bonded to C or an analogous peptide, an ammo protecting group, or O S O II II II R6-C-. Ré-C-, R6-S- O preferably hydrogen, wherein optionally where the bond between R and the N to which it is bonded is applied is a thioxamide bond; . R6 represents hydrogen, a halogen, alkyl, alkenyl, alkyl, aryl, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m- 0 -alkyl, - (CH?) M- 0-alkenyl, - (CH) m-0-alkyl, - (CH2) m- 0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-alkyl , - (CH2) mS-alkenyl, - (CH2) mS-alkylene, - (CH2) mS- (CH2) m-R7; R / represents, each occurring, a substituted or unsubstituted aplo, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; Ri: and R ?? each independently represents hydrogen, an alkyl, or a pharmaceutically salt acceptable, or Ru and R12 are taken together with the O-B-0 atoms to which they are bonded complete to a heterocyclic ring having from 5 to 8 atoms in the ring structure; and m is zero or an integer in the range of 1 to 8. In other embodiments, the target compounds include analogs of alamine aldehyde or alanyl derivatives, such as modified thioxamide derivatives. Exemplary compounds of the present invention are represented by formula IX: : ?? ) wherein R-i represent hydrogen, halogen or lower alkyl, lower alkenyl, or lower alkyl, preferably lower alkyl such as methyl, ethyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc .; R represent a branched lower alkyl, aralkyl, aplo, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, preferably a bulky hydrophobic group, such as cyclohexyl, t-butyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc .; R3 represent hydrogen or an ammo protecting group, preferably hydrogen; R4 represents hydrogen, an amino acid residue thermally bonded to C or analogous amino acid, a peptide thermally bonded to C or analogous peptide, an ammo protecting group, o or s or II II II Ro-C-, R6-C-, R6-S- O preferably hydrogen, wherein optionally where the bond between R and the N to which it is bonded is applied is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkyl, aryl, - (CH2) m-R7, - (CH) m-OH, - (CH2) m-0-alkyl, - (CH?) M- 0-alkenyl, - (CH2) m-0-alkyl, - (CH2) m-0- (CH2) mR ,, - (CH2) m-SH, - (CH2) mS-alkylene, - (CH2) mS-alkenyl, - (CH2) mS-alkanol, - (CH2) mS- (CH2) m-R7; R7 represents, each occurring, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; m is zero or an integer in the range of 1 to 8. In still further embodiments, the compounds are halo-methyl ketones analogous to an amino acid or amino acid modified with thioxamide. Exemplary inhibitors of this class include compounds represented by the formula X: (X) wherein RT represents hydrogen, halogen or lower alkyl, lower alkenyl, or lower alkynyl, preferably lower alkyl such as methyl, ethyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc.; R? represents a branched lower alkyl, aralkyl, aryl, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, preferably a bulky hydrophobic group, such as cyclohexyl, t-butyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc.; R3 represents hydrogen or an amino protecting group, preferably hydrogen; R represents hydrogen, an amino acid residue terminally linked to C or amino acid analogues, a peptide thermically to C or analogous peptide, an amino protecting group, or preferably hydrogen, where optionally where the bond between R 4 and the N to which it is bonded is applied is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkylo, aplo, - (CH2) m-R7, - (CH2) m-OH, - (CH2) mO-alkyl, - (CH2) m-0-alkenyl , - (CH2) m-0-alkyl, - (CH2) m-0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-alkyl, - (CH2) mS-alkenyl, - (CH2) mS-alkanol, - (CH2) mS- (CH2) m-R7; R7 represents, each occurring, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; X-i, X? and X3 each represents a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8. In certain embodiments, the compound is a peptide or peptidomimetic including an alanyl or analog group thereof, such as an analogous thioxamide, at the position of specificity Pl, and an amino acid which occurs not naturally in the specificity position P2, or an analogue thereof, such as an analog of thioxamide. For example, the compound may include a dipeptide sequence Cyclohexylglycine-Ala or t-butylglycine-Ala or equivalent thereof, and be represented in formula XI: (xi) R: represents hydrogen, halogen or lower alkyl, lower alkenyl, or lower alkyl, preferably lower alkyl such as methyl, ethyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc.; R 2 represents a branched lower alkyl, aralkyl, aplo, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, preferably a bulky hydrophobic group, such as cyclohexyl, t-butyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy , alkoxy, etc; R3 represents hydrogen or an ammo protecting group, preferably hydrogen; R represents hydrogen, an amino acid residue thermally bonded to C or amino acid analogs, a peptide thermally bonded to C or analogous peptide, a group ammo protector, or or s or II II II R6-C-, Re-C-, R6-S- O preferably hydrogen, where optionally where the bond between R 4 and the N to which it is bonded is applied is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkyl, aplo, - (CH2) m-R7, - (CH2) m-OH, - (CH2) mO-alkyl, - (CH) m-0-alkenyl , - (CH2) m-0-alkyl, - (CH2) m- 0- (CH,) mR ,, - (CH2) ra-SH, - (CH2) mS-alk? L ?, - (CH2 ) mS-alkenyl, - (CH2) mS-alkylene, - (CH2) mS- (CH2) m-R7; R7 represents, each occurring, a substituted or unsubstituted aplo, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; W represents a functional group that reacts with an active site residue of the target protease, such as -CN, -CH = NR53, preferably B S ^ O Y ^ R 53 Y: and Y2 are, independently, OH, or a group capable of being hydrolyzed, for example, under physiological conditions to a hydroxyl group, such as alkoxy, aryloxy, etc., including cyclic derivatives where Yx and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like); R50 represent O or S; R1 represents N3, SH, NH2, N02 or OR'7; Rb2 represents hydrogen, a lower alkyl, an amine, ORd, or a pharmaceutically acceptable salt, or R5? and R.,? they are taken together with the phosphorus atom to which they are linked complete to a heterocyclic ring having from 5 to 8 atoms in the ring structure; R53 represents hydrogen, an alkyl, an alkenyl, an alkynyl, -C (X:) (X2) -X3, - (CH2) m-R7, - (CH2) n-OH, - (CH2) n-0-alkyl , - (CH2) n-0-alkenyl, - (CH2) n-0-alkynyl, - (CH2) n-0- (CH2) m-R7, - (CH2) n-SH, - (CH2) nS- alkyl, - (CH 2) n S-alkenyl, - (CH 2) n S-alkynyl, - (CH 2) n S- (CH 2) m-R 7, -C (O) C (O) NH 2, C (O) C (O ) OR '7, preferably a hydrogen, or a halogenated lower alkyl; Xi represents a halogen, preferably a fluorine; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. Another representative class of compounds for use in the object method include peptide and peptide mimetics of (L) -Ala- (L) -cyclohexylglycine or thioxamide thereof, for example, preserve the spherical arrangement of the portions. Such inhibitors include compounds represented by formula XII: (XII) wherein R- represents hydrogen, halogen or lower alkyl, lower alkenyl, or lower alkyl, preferably lower alkyl such as methyl, ethyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy, alkoxy, etc .; R 2 represents a branched lower alkyl, aralkyl, aplo, heteroaralkyl, heteroaryl, cycloalkyl, or cycloalkylalkyl, preferably a bulky hydrophobic group, such as cyclohexyl, t-butyl, etc., optionally substituted by one or more small substituents such as halogen, hydroxy , alkoxy, etc.; R3 represents hydrogen or an amino protecting group, preferably hydrogen; R4 represents hydrogen, an amino acid residue thermally bonded to C or analogous amino acid, a peptide thermically bonded to C or analogous peptide, an ammo protecting group, or preferably hydrogen, wherein optionally where the bond between R 4 and the N to which it is bonded is applied is a thioxamide bond; R6 represents hydrogen, a halogen, alkyl, alkenyl, alkyl, aryl, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m- O-alkyl, - (CH2) m-0-alken - (CH2) m-0-alkyl, - (CH2) m-0- (CH,) mR ,, - (CH2) m-SH, - (CH2) mS-alk? l ?, - (CH2) mS-alkenyl, - (CH) mS-alkylene, - (CH2) mS- (CH2) m-R7; R, represents, each which is presented, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; W represents a functional group that reacts with an active site residue of the target protease, such as -CN, -CH = NR53, 9 I I n O ^ .Y, I I o o - S I I -Xl _ Pü-_Xv1 - B - P-R52 O Y R 51 53 preferably YT and Y2 are, independently, OH, or a capable group of being hydrolyzed, for example, under physiological conditions to a hydroxyl group, such as alkoxy, aryloxy, etc., including cyclic derivatives where Yx and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like); R0 represents O or S; Rsi represents N3, SH, NH2, N02 or OR'7; R represents hydrogen, a lower alkyl, amine, OR '/, or a pharmaceutically acceptable salt, or R5 and R52 are taken together with the phosphorus atom to which they are linked complete to a heterocyclic ring having from 5 to 8 atoms in the ring structure; Rb represents hydrogen, alkyl, alkenyl, alkyl, -C (X) (X2) -X3, - (CH2) m-R7, - (CH2) n-OH, - (CH2) n-0-alkyl, - (CH ) n-0-alkenyl, - (CH2) n-0-alkyl, - (CH2) n-0- (CH,) "- R ,, - (CH2) n-SH, - (CH2) nS-alkylene, - (CH2) nS-alkenyl, - (CH,) nS-alkyl, - (CH2) nS- (CH2) m-R7, -C (O) C (O) NH2 , C (O) C (O) OR '7, preferably a hydrogen, or a halogenated lower alkyl; XT represents a halogen, preferably a fluorine; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8.

Modality C A representative class of compounds for use in the method of the present invention are represented by formula XIII: A-G (XIII) or a pharmaceutically acceptable salt thereof, wherein A represents a peptidyl moiety that is a substrate for a protease activation; A and G are linked covalently by a bond that is divided by protease activation; G represents an inhibitor of a target protease which, when divided from A by the activation of serine protease, is characterized by one or both of the following: it is subjected to proto-desboronación and / or inhibit the target protease with a Ki of lOOnM or less; and the compound of Formula XIII comprising one or more thioxamide groups. In certain embodiments, the protease activation may be a serine protease, a cysteine protease or a metalloprotease. Similarly, the target protease may be a serine protease, a cysteine protease or a metalloprotease. In certain embodiments, the target protease and activation are serine proteases.

In certain embodiments, the protease activation is a protease divided into post-prolyl, such as selected from the group consisting of DPP IV, DPP II, prolyl oligopeptidase (PO), Fibroblast Activation Protein (FAP), and prolyl carboxypeptidase. In certain embodiments, the divided post-prolyl protease is an endopeptidase, and A includes an ammo terminal block. In other embodiments, the protease activation is selected from the group consisting of thromboma (Factor X), matriptase, falcipam, prostate specific antigen (PSA), and thus homologous proteases. In certain embodiments, the target protease is a post-prolyl divided protease, such as selected from the group consisting of DPP IV, DPP II, prolyl oligopeptidase (PO), Fibroblast Activation Protein (FAP), and prolyl carboxypeptidase. In certain embodiments, G is a dipeptidyl moiety, for example, derivatives of naturally occurring amino acids or analogs thereof. In certain embodiments, G represents an inhibitor of a target protease which, when splitting A by septa protease activation, inhibits the target protease with a Ki of lOOnM or less, and In certain embodiments, 10, 1 or 0.1 nM or less. In certain embodiments, the half-life time (T: / 2) in serum of inhibitor G is less than 24 hours, and even more preferably less than 10 hours, 1 hour or even 10 min. In certain embodiments, the direction of portion A represents a peptide thermally bonded to C or analogous peptide, for example, 2-10 amino acid residues, more preferably 2-4 residues, which is a substrate for activation of the enzyme. In certain embodiments, A is a dipeptidyl or tppepidyl portion. In certain embodiments, A is derived from naturally occurring amino acids or analogs thereof, and In certain embodiments, at least one residue of A is an analogous amino acid that occurs not naturally. In certain embodiments, such as when the direction of portion A is a DPP IV substrate, the amino terminus of the analogous peptide or peptide is blocked with an amino terminal protecting group, preferably a lower alkyl such as a methyl group. certain embodiments, the portion of the inhibitor G is a portion of dipeptidyl and a functional electrophilic group that can form a covalent adduct with a residue at the active site of a protease by replacing the carboxyl terminus of the dipeptidyl portion. For example, the portion of the inhibitor G can be represented in the formula XIV: Xaa, -Xaa2- (XIV) wherein Xaa: is an amino acid occurring naturally or analogous thereto, wherein Xaai contains a thioxamide group; Xaa2 is an amino acid that occurs naturally or analogously thereof; W represents a functional group that reacts with an active site residue of the target protease to form a covalent adduct, such as, for example, -CN, -CH = NR5, Rb represents H, alkyl, alkenyl, alkynyl, C (X (X2) X, - (CH2) m -R6, - (CH2) n-0H, - (CH2) n-0-alkyl, (CH,) n-0-alkenyl, - (CH2) n-0-alkynyl, - (CH2) n-0- (CH2) m -R6, - (CH,) n-SH, - (CH2) nS- alkyl, - (CH2) nS-alkenyl, - (CH2) n-S-alkynyl, - (CH2) nS- (CH2) m-Re, -C (O) C (O) NH2, or C (0) C (0) OR7; R6 represents a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R; independently represents each presented hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; and Yi and Y can independently or together be -OH, or a group capable of being hydrolyzed to a hydroxyl group, including cyclic derivatives where Yi and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like), R0 represents 0 or S; R ^ represents N3, SH2, NH2, N02 or -OR7; Rb2 represents hydrogen, a lower alkyl, an amine, -OR;, or a pharmaceutically acceptable salt, or R51 and R.) 2 are taken together with the phosphorus atom to which they are linked complete to a heterocyclic ring having from 5 to 8 atoms in the ring structure X-i represents a halogen; X? and X3 each represents a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. The pro-soft inhibitors of the present invention do not subject themselves to proto-desboronation and can be constructed such that they do not inhibit the selected target enzyme, or other enzymes for any significant extension, before being divided by the activation of the protease. That is, the pro-soft inhibitors themselves become inactive, but produce a portion of active G inhibitor in the body when the direction of the A portion is removed from the pro-soft inhibitor. One of the characteristics that makes the pro-soft inhibitor molecules of the present invention different from the typical prodrugs is that the inhibitor portion, then generated in the active form near the target, is subjected to inactivation over time, for example , as it diffuses through the target enzyme, thereby reducing the possibility of side effects of deterioration that may result from the inhibition of enzymes that occur in other parts of the patient. This combination of releasing in an active form in the vicinity of the target enzyme together with this "programmed" deactivation mechanisms makes the molecules of the invention more specific, effective, and safe (that is, having fewer side effects) than the portion of the inhibitor used in itself. In certain embodiments, the portion of the inhibitor G is a portion of dipeptidyl, for example, derived from naturally occurring amino acids or analogous amino acids that comprise a thioamide moiety. In certain embodiments, the portion of the G inhibitor is an inhibitor of a target protease which, when split from the pro-soft inhibitor by protease activation, inhibits the target protease with a Ki of lOOnM (10"7M) or less, and even more preferably, a Ki less than or equal to 25nM, lOnM (10 8M), InM (10 ~ 9M), or 0.1 nM (10 ~ 10M) .In certain embodiments, Ki of less than 10_11M and even 10 12M have been measured or estimated for the inhibited portions subjected.

In certain embodiments, the therapeutic index for the soft inhibitor is at least 2 times greater than the therapeutic index for the inhibitor portion alone, and even more preferably 5, 10, 50 or even 100 times higher. For many of the target pro-soft inhibitors, another improvement over the inhibitor's own portion is increased in stability in pharmaceutical preparations, such as in solution, oils or solid formulations. Such stability can be expressed in terms of useful life. In certain embodiments, the target pro-soft inhibitors have a T90 of at least 7 days, and even more preferably of at least 20, 50, 100 or even 200 days. In certain embodiments, the subject pro-soft inhibitor has a T, or at least 20 days, and even more preferably at least 50, 100, 200 or even 400 days. In certain modalities, the pro-soft inhibitor fastened has a T90 as a solid, simple oral dosage formulation of at least 20, 50, 100 or even 200 days. In certain embodiments, the supported soft pro-inhibitor has a T90 as a liquid, simple dosage suspension of at least 20, 50, 100 or even 200 days. The preferred pharmaceutical preparations of the target pro-active inhibitors are substantially free of pyrogen. For example, In certain embodiments, the endotoxin concentration of the submitted preparation, as an assay by means of the gel conglomerate method (as a limiting test with comparison to the maximum permitted FDA limit, as set forth in Appendix E of the guide) of endotoxm), is less than 10 EU / mL or single dose formulation / EU, and even more preferably less than 5.1, or even 0.1 EU / mL or single dosage formulation / EU. In certain embodiments, a simple administration of the pro-soft inhibitor, such as bolus injection, oral dosage or inhaled dosage, can produce a sustained m-effect, such as to provide a therapeutically effective amount (concentration> FD50) of the inhibitor G for a period of at least 4 hours, and even more preferably at least 8, 12 or even 16 hours.

In certain embodiments, the portion of inhibitor released G, and particularly the inactive compound, has a half-life (e.g., relative to decomposition into low molecular weight fragments) in serum or other biologically relevant fluid of greater than 10 hours, and even more preferably a half-life greater than 24, 48 or 120 hours. Formulations of the present invention include those specially formulated for oral, buccal, parental, transdermal, inhalation, m-nasal, transmucosal, implant, or rectal administration. In certain embodiments, the target inhibitors are orally available, and may be provided in the form of solid dosage formulations suitable for oral administration to a human patient. In certain embodiments, the target inhibitors are transdermally active, and may be provided in the form of a topical cream or suspension or a transdermal patch. Another aspect of the invention provides a pharmaceutical package including one or more of the objective pro-soft inhibitors, and instructions (white and / or pictorial) that describe the administration of the formulation to a patient. For illustration only, exemplary packages are properly dosed and include instructions for one or more of: treatment or prophylaxis of metabolic disorders, gastrointestinal disorders, viral disorders, inflammatory disorders, diabetes, obesity, hyperlipidemia, dermatological or mucosal membrane disorders, psoriasis, intestinal distension, constipation, autoimmune disorders, encephalomyelitis, mid-disorders by complement, glomerulonephritis, lipodystrophy; tissue damage, psychosomatic, depressive, and neuropsychiatric disorders, HIV infection, allergies, inflammation, arthritis, transplant rejection, high blood pressure, congestive heart failure, tumors, and stress-induced abortions. Preferably, the package includes one or more soft inhibitors provided as a simple oral dosage formulation. Where the pro-soft inhibitor includes one or more chiral centers, In certain embodiments, the pro-soft inhibitor is provided as at least 75% of the eutomer (relative to the diastomer) of such a pro-soft inhibitor, and even more preferably at least 85, 90, 95 or even 99% mol. Generally, the eutomer with the 1-enantiomer (with respect to the Ca carbon) of an amino acid or amino acid analogue. In certain embodiments, the pro-soft inhibitor is an amount of tetrapeptidyl represented in the formula XV: Xaa-i '-Xaa2' -Xaa? -Xaa2-W:? V) where Xaa! ', Xaa2', and Xaa2 each independently represents an amino acid occurring naturally or analogous thereof; Xaai is an amino acid occurring naturally or analogous thereto, wherein Xaax contains a thioxamide group; W represents a functional group that reacts with an active site residue of the target protease to form a covalent adduct, such as, for example, -CN, CH = NR5, R5 independently for each occurrence of H, alkyl, alkenyl, alkynyl, -C (X?) (X2) X3, - (CH2) m-R6, (CH,) n-OH, - (CH2) n-0-alkyl, - (CH2) nO-alkenyl, - (CH2) nO-alkynyl, - (CH2) n-0- (CH2) m-R6, - (CH2) n-SH, - (CH2) nS-alkyl, - (CH2) nS-alkenyl, - (CH2) nS-alkynyl, - (CH2) nS- (CH2) m -R6, -C (0) C (0) NH2, or -C (O) C (0) 0R7; R6 independently represents for each one a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R, independently represents each hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; Yi and Y can be independently or together being OH, or a group capable of hydrolyzing a hydroxyl group, including cyclic derivatives where Yi and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure (such as pinacol or the like), R50 represents O u S; Rbl represents N3, SH2, NH2, N02 or -0R7; R52 represents hydrogen, a lower alkyl, an amine, -OR ,, or a pharmaceutically acceptable salt, or R51 and R ") 2 are taken together with the phosphorus atom to which they are linked they complete a heterocyclic ring having from 5 to 8 atoms in the ring structure Xi represents a halogen; X2 and X each represent a hydrogen or a halogen, m is zero or an integer in the range from 1 to 8; and n is an integer in the range from 1 to 8. In certain embodiments, Xaal 'includes an ammo terminal protective group. In certain embodiments, Xaal 'is an analogous amino acid having a tetrasubstituted Cβ carbon, for example, a carbon having four substituents none of which is a hydrogen. For example, Xaal 'may be an analogous amino acid represented in the formula: wherein • R8 and R9 each independently represents a lower alkyl or a halogen; Ri0 represents a lower alkyl, an aplo, a hydroxyl group or - (CH2) m -COOH; Z represents a hydrogen or an amino terminal protecting group, and m = 0, 1 or 2. In certain embodiments, R8 and R9 each independently represents a lower alkyl, more preferably methyl, ethyl or propyl, and even more preferably a methyl. In certain embodiments, R10 represents a lower alkyl, more preferably methyl, ethyl or propyl, and even more preferably a methyl. In other certain embodiments, Rio represents an aryl, such as phenyl or hydroxyphenyl (preferably para-hydroxy). In still other certain modalities, Rio represents a hydroxyl group. In certain embodiments, Rio represents - (CH2) m -COOH, where m = 0, 1 or 2, and preferably where m is 0 or 1. In certain embodiments, W is -B (Y?) (Y2). In certain embodiments, R 2 is absent or represents halogen or lower alkyl. In certain embodiments, R 4 represents hydrogen or lower alkyl. In certain embodiments, R 5 represents H or alkyl. In certain modalities, Y3 and Y2 are OH. In certain embodiments, W is -B (OH) 2. In general, inhibitors pro-soft objects can be divided into two distinct types in the bases of whether they are activated by the same or by a different enzyme as the target enzyme of the inhibitory portion. The first type should be referred to as the Type 1 or Target-Activated Smart Protease Inhibitors (TASPI), the second type 2 or Target-Directed Smart Protease Inhibitors (TDSPI). Both modalities of the pro- soft inhibitors for the specific release of the active compound to the enzyme target and are provided for the attenuation of inhibitor activity as the inhibitory portions diffuse out of the target enzyme. The TDSPIs of the present invention offer the additional prospects for tissues or specific cellular inhibition of the target enzymes. In other words, the TDSPIs offer the prospect of inhibiting a given enzyme in one type of cell or tissue in another. For example, each cell of the body contains a proteasome protease complex. Inhibition of proteasome function have a number of practical and prophylactic therapeutic applications. However, this is difficult to provide the inhibition of proteasome activity in a cell or tissue type selected manner. In certain embodiments of the current invention, the TDSPIs can be constructed to release a portion of the proteasome inhibitor in a selective manner by using a soft inhibitor having a targeting portion for a protease that is expressed on or adjacent to the target cells. understood of the cell or tissue. To illustrate, it can be activated by the FAP or prostate-specific antigen (PSA) and the resulting inhibitor portion G is a proteasome inhibitor. In certain modalities of the TDSPIs, the portion directed to A is not an efficient substrate for the protease objective. For example, as a substrate, the targeted portion A preferably has a folded number as a substrate for the target protease of less than 1 / second, and even more preferably less than 0.1 / second, 0.001 / second or even 0.0001 / second. In certain embodiments of the target pro-soft inhibitors, the targeted portion is a substrate for an active protease selected from among the serine proteases, cysteine proteases and metalloproteases. Similarly, the inhibitory moiety can be a dipeptidyl inhibitor for a target protease selected from serine proteases, cysteine proteases and metalloproteases. Similarly, the inhibitory moiety may be a dipeptidyl inhibitor for a target protease selected from the serine proteases, cysteine proteases and meteoroproteases. In certain embodiments, the target protease is a serine protease. The pro-wave inhibitors of the present invention can be designated for working with activated and target serine proteases including, but not limited to, dipeptidyl peptidase-11 (DPP-XI), dipeptidyl peptidase IV (DPP IV), dipeptidyl peptidase (DPP VIII), dipeptidyl peptidase 9 (DPP IX), aminopeptidase P, activated fibroblast alpha protein (seprase), prolyl tripeptidyl peptidase, prolyl oligopeptidase (endoproteinase Pro-C), attractant (soluble dipeptidyl-ammopeptidase), acylamoacyl-peptidase (N-acylpeptide hydrolase; fMet ammopeptidase) and lysosomal Pro-X carboxypeptidase (angiotensmase C, prolyl carboxypeptidase). The pro-soft inhibitors of the present invention can be designated to work with the target or activated metalloproteases including Pro-X membrane carboxypeptidase (carboxypeptidase P), angiotensin-converted enzyme (Peptidyl-dipeptidase A multipeptidase), collagenase I (mterticial collagenase; matrix of metalloprotemase 1; MMP-1; Mcol-A), ADAM 10 (alpha-secretase, dismtegrma metalloprotemase associated with myeloma), nepplisma (atriopeptidase; CALLA; CD10; endopeptidase 24.1 1; encephalmase), macrophage elastase (metalloelastase; matrix of metalloprotemase 12; MMP-12], Matrilism (matrix of metalloprotemass 7; MMP-7), and neurolysin (endopeptidase 24.16; microsomal endopeptidase; mitocondpal oligopeptidase) In certain embodiments, activated protease is a protease of post-prolyl cleavage , as selected from the group consisting of DPP IV, DPP II, Prolyl oligopeptidase (PO), activated fibroblast protein (FAP), and prolyl carboxypeptidase. In certain embodiments where the post-prolyl cleavage protease is an endopeptidase, the amino terminal of A is blocks with an amino terminal protecting group, preferably a lower alkyl such as a methyl group. In certain modalities, the objective compound is represented by formula XVI: (XVI) wherein A represents a heterocycle of 4-8 members including carbon N and Cot; W represents a functional group which is reacted with a residue of the active site of the target protease to form a covalent adduct, for example, R3 represents a peptide or analogous peptide terminally linked to C which is a substrate for a active enzyme, R 2 is absent or represents one or more substitutions on ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkyl, carbonyl (such as a carboxyl, ester, formate, or ketone) , thiocarbonyl (such as thioester, thioacetate, or thioformate), amino, acylamm, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) ra- 0-lower alkyl, - (CH2) m-0-lower alkenyl, - (CH2) n-0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS-lower alkyl, - (CH2) mS-alkenyl lo, or - (CH2) nS- (CH2) mR /, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, ® T r = r R -N = C C C Re R3 represents a hydrogen or a substituent which does not conjugate the electron pair of the nitrogen to which it binds, such as a lower alkyl; R4 represents hydrogen, halogen, lower alkyl, lower alkenyl, lower alkyl, aplo, or aralkyl, Rb represents H, alkyl, alkenyl, alkyl, C (X?) (X2) X3, - (CH2) m-R6, - (CH2) n-OH, - (CH2) nO-alkyl, (CH2) n-0-alkenyl, - (CH2) n-0-alkyl, - (CH2) nO- (CH2) m-R6 , - (CH2) n-SH, - (CH2) nS-alkyl, - (CH2) nS-alkenyl, (CH2) n-S-alkynyl, - (CH2) n-S- (CH2) m -R6, -C (O) C (O) NH2, or -C (0) C (0) OR7; R6 independently represents for each one a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R7 independently represents each hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R8 represents hydrogen, -CH3, or - (CH2) n-CH3; Y: and Y2 can independently or together be OH, or a group capable of hydrolyzing a hydroxyl group, including cyclic derivatives where Yx and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure ( such as pinacol or the like); Rb0 represents O u S; R53 represents N3, SH2, NH2, N02 or -0R7; RS represents hydrogen, a lower alkyl, an amine, -0R7, or a pharmaceutically acceptable salt, or R5? and R.)? they are taken together with the phosphorus atom to which they are bound they complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; Xi represents a halogen; X; and X3 each represents a hydrogen or a halogen; m is zero or an integer in the range from 1 to 8; and n is an integer in the range from 1 to 8. In certain embodiments, R2 is absent or represents a small hydrophobic group. In certain embodiments, A represents a 5-membered heterocycle including carbon N and Ca. In certain modalities, W is -B (Y?) (Y2). In certain embodiments, R 2 is absent or represents halogen or lower alkyl. In certain embodiments, R 4 represents hydrogen or lower alkyl. In certain embodiments, R 5 represents H or alkyl. In certain modalities, Yx and Y2 are OH. In certain embodiments, W is -B (OH) 2. In certain embodiments, W is -B (OH) 2, and A represents a 5-membered heterocycle including carbon N and C. In certain embodiments, W is -B (OH) 2, A represents a 5-membered heterocycle including carbon N and Ca, and R2 is absent or represents halogen or lower alkyl. In certain embodiments, W is -B (OH) 2, A represents a 5-membered heterocycle including carbon N and Ca, R2 is absent or represents halogen or lower alkyl, and R 4 represents hydrogen or lower alkyl. In other embodiments, W is -B (OH) 2, A represents a 5-membered heterocycle including carbon N and Ca, R4 represents hydrogen or lower alkyl, and R2 is azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, ® T -NE zC In certain modalities, Rx is one of the following In certain embodiments, W is -B (OH) 2, A represents a 5-membered heterocycle including carbon N and Ca, R2 is absent or represents halogen or lower alkyl, and Rx is one of the following: In other embodiments, W is -B (OH) 2, A represents a 5-membered heterocycle including carbon N and Ca, R represents hydrogen or lower alkyl, and R2 is azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, following: In certain embodiments, the compound is represented in formula XVII: (XVII) where Ri, R3, R4 and W are as defined above, and p is an integer from 1 to 3. In certain embodiments, p is 1, and R3 is a hydrogen each occurring. In certain embodiments of the structures of the above compound, W represents: In certain embodiments of the structures of the above compound, R5 is a hydrogen or -C (X?) (X2) X3, wherein X: is a fluoride, and X2 and X3, if the halogens are also fluoride. In certain embodiments of the structures of the above compound, R is a lower alkyl. In certain embodiments of the structures of the above compound, R represents a side chain of a residue of amino acid selected from Gly, Ala, Val, Ser, Thr, lie and Leu. In certain embodiments of the structures of the above compound, Ri is a peptidyl moiety in which it is a substrate for a cleaved post-proline enzyme. In certain embodiments of the propulsive inhibitor structures targets XVI and XVII, R4 represents a side chain of an amino acid residue represented in the formula: wherein Rd and R-ib each independently represents hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, carboxyl, carboxamide, carbonyl, or cyano, with the warning that either or both of R4a and R4b are hydrogen; R 4c represents a halogen, an amine, an alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, carboxyl, carboxamide, carbonyl, or cyano; Y z is zero or an integer in the range from 0 to 3. In certain embodiments of structures XIV and XV, R represents a side chain of an amino acid residue represented in the formula: wherein: R8 and R9 each independently represents a lower alkyl or a halogen; R 0 represents a lower alkyl, an aplo, a hydroxyl group or - (CH 2) m-C00H. In certain embodiments, R8 and R9 each independently represents a lower alkyl, more preferably methyl, ethyl or propyl, and even more preferably a methyl. In certain embodiments, Rio represents a lower alkyl, more preferably methyl, ethyl or propyl, and even more preferably a methyl. In other certain embodiments, R 0 represents an aryl, such as femlo or hydroxypheme (preferably para-hydroxy). In still other certain embodiments, R 0 represents a hydroxyl group. In certain embodiments, R? 0 represents - (CH2) m -COOH, where m = 0, 1 or 2, and preferably where m is 0 or 1. In certain embodiments, the pro-soft inhibitor is a protease activator and inhibits a protease different. For example, this can be activated by FAP and the resulting inhibitor G is selective for the proteasome. In certain embodiments of the structures of the above compound, R ± is not an efficient substrate for the target protease. For example, as a substrate, Ri preferably has a double number as a substrate for the target protease of less than 1 / second., and even more preferably less than 0 l / second, 0.001 / second or even 0.0001 / second. In certain embodiments, A is a peptidyl moiety of 2 to 5 amino acid residues or equivalents thereof. In certain embodiments, A is a dipeptidyl moiety, for example, derived from naturally occurring amino acids or analogs thereof. In certain embodiments, the structure of the peptidyl A moiety may include one or more non-hydrolysable analogs of a peptide bond, except for the link linking A to G. In certain modalities, A is represented by: In certain embodiments of the present invention, the compounds represented by the formula: A-G do not inhibit the selected target enzyme, or other enzymes to an appreciable extent. In certain embodiments of the present invention, the pro-soft inhibitors are themselves inactive, but become active in the body when the RA group is removed to release the inhibitory portion of the enzyme G. In certain embodiments, the present invention is to the aforementioned compound, wherein Rx is one of the following: Mode D A representative class of the compounds for use in the method of the present invention are represented by the formula XVIII (XVIII) or a pharmaceutically acceptable salt thereof, wherein: R1 represents H, alkyl, alkoxy, alkenyl, alkynyl, amino, alkylamino, acylamino, cyano, sulfonylamino, acyloxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, or a polypeptide chain of 1 to 8 amino acid residues; R? and R3 each independently represents H, lower alkyl, and aralkyl, or R2 and R3 together with the atoms to which they bond, form a 4- to 6-membered heterocyclic ring; R'1 and R5 each independently represent H, halogen, or alkyl, or R4 and R5, together with the carbon to which they are bonded, form a 3-6 membered carbocyclic or heterocyclic ring; R6 represents a functional group that is reacted with a residue of the active site of a target protease to form a covalent adduct; R7 is absent or represents one or more substituents on ring A, each of which is independently selected from H, lower alkyl, lower alkenyl, lower alkyl, hydroxyl, oxo, ether, thioether, halogen, carbonyl, thiocarbonyl, amino, amido, cyano, nitro, azido, alkylammon, acylammon, ammoacyl, cyano, sulfate, sulfonate, sulfonyl, sulfonylamm, ammonium sulfonyl, alkoxycarbonyl, acyloxy, aplo, cycloalkyl, heterocyclyl, heteroaryl, or polypeptide chains of 1 to 8 amino acid residues; R8 represents H, aplo, alkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaralkyl, or a polypeptide chain of 1 to 8 amino acid residues; L is absent or represents an alkyl, alkenyl, alkyl, - (CH2) mO (CH2) m-, - (CH2) mNR2 (CH2) m-, or (CH?) MS (CH2) m-; X is absent or represents -N (R8) -, -O-, or -S-; And it is absent or represents -C (= 0) -, -C (= S) -, or -S02-; m is, independently for each one presented, an integer from 0 to 10; and n is an integer from 0 to 3, preferably 0 or 1.

In certain embodiments, R1 represents H or lower alkyl, R? and R3 each independently represents H, lower alkyl, or aralkyl, or R2 and R3 together with the atoms to which they bind, form a 5-membered heterocyclic ring, R4 represents H or alkyl lower, and R5 represents H. In a certain additional embodiment, the stereochemical designations at C3 and C4 are R and S respectively. In certain other embodiments, R6 represents cyano, boronic acid, -C (= NH) NH2, -CH = NR12, or -C (= 0) -R12, wherein: R9 represents O or S; R10 represents N3, SH2, NH2, N02, or OLR13, and R ?: represents a lower alkyl, amino, OLR13, or a pharmaceutically acceptable salt thereof, or R10 and R, together with the phosphorus to which they are attached, form a 5- to 8-membered heterocyclic ring; R12 represents H, alkyl, alkenyl, alkynyl, (CH2) p-R13, - (CH2) q-OH, - (CH2) q-0-alkyl, - (CH2) q-0-alkenyl, - (CH2) q -0-alkynyl, - (CH2) q-0- (CH2) P-R13, (CH2) q-SH, - (CH2) qS-alkyl, - (CH2) qS -alkenyl, - (CH2) qS-alkynyl, - (CH2) qS- (CH2) p-R13, - C (O) C (O) NH2, C (0) C (0) 0R14, or -C (ZX) (Z2) (Z3); R 13 represents H, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, or heterocyclyl; R1 represents H, alkyl, alkenyl, or LR13; Z1 represents a halogen; Z2 and Z3 independently represent H or halogen; p is, independently for each one that is presented, an integer from 0 to 8; Y q is, independently for each one presented, an integer from 1 to 8. In another embodiment, R6 represents CN, CHO, or C (= 0) C (Z :) (Z2) (Z3), where Z1 represents a halogen, and Z2 and Z! represents H or halogen. In certain such embodiments, R6 represents C (= 0) C (Z1) (Z2) (Z3), where Z1 represents fluorine, and Z2 and Z3 represent H or fluorine. In certain embodiments, R 6 is a group represented by B 1) (Y 2) wherein Y 1 and Y 2 are independently OH or a group that hydrolyzes to OH (that is, to form a boronic acid), or together with the boron atom at which are linked form a ring of 5 to 8 members that is hydrolysable to a boronic acid Modality E A representative class of compounds for use in the method of the present invention are represented by formula XIX (XIX) where R1 represents H, alkyl, alkoxy, alkenyl, alkynyl, amino, alkylamino, acylamino, cyano, sulfonylamino, acyloxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, or a polypeptide chain of 1 to 8 amino acid residues; R 2 represents H, lower alkyl, or aralkyl; R3 and R independently represent H, halogen, or alkyl, or R3 and R4 together with the atoms to which they bind, form a 3 to 6 membered heterocyclic ring; R1 'represents H, halogen, lower alkyl, or aralkyl; R6 represents a functional group that is reacted with a residue of the active site of a target protease to form a covalent adduct; R7 represents H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaralkyl, or polypeptide chains of 1 to 8 amino acid residues; L is absent or represents an alkyl, alkenyl, alkynyl, - (CH2) m0 (CH2) m-, - (CH2) mNR2 (CH2) m-, and (CH2) mS (CH2) m-; X is absent or represents -N (R7) -, -O-, or -S-; And it is absent or represents -C (= 0) -, -C (= S) -, or -S02-; m is, independently for each one presented, a whole from 0 to 10; and n is an integer from 1 to 6. In certain embodiments, R1 represents H or lower alkyl, R3 and R4 together with the atoms to which they are bound form a 5-membered ring, and n is 2. In certain other embodiments R1 represents H or lower alkyl, R3 represents H, R4 represents H or lower alkyl, R5 represents H, and n is 2. In certain embodiments, R1 is a polypeptide chain of 2 to 8 amino acid residues, wherein the proline is the residue that it links directly. More preferably R1 is a polypeptide chain of 2 amino acid residues In certain embodiments above, R6 represents cyano, boronic acid, -P (= R8) R9R10, C (= NH) NH2, -CH = NR11, and -C (= 0) -R11, wherein R8 represents O or S; R9 represents N-,, SH2, NH2, N02, and OLR12, and R10 represents a lower alkyl, ammo, OLR12, or a pharmaceutically acceptable salt thereof, or R9 and R10, together with the phosphorus to which they are attached, form a 5- to 8-membered heterocyclic ring; R11 represents H, alkyl, alkenyl, alkyl, (CH2) P-R12, - (CH2) q-OH, - (CH2) q-0-alkylene, - (CH2) q-0-alkenyl, - (CH2 ) q-0-alkyl, - (CH2) q-0- (CH2) P-R12, - (CH2) q- SH, - (CH2) qS-alkyl, - (CH2) qS-alkenyl, - (CH2) qS-alkynyl, - (CH2) qS- (CH2) p-R12, -C (0) C (O) NH2, -C (O) C (O) OR13, or -C (ZJ) (Z2) (Z3); R 12 represents H, alkyl, alkenyl, aryl, cycloalkyl, cycloalkenyl, and heterocyclyl; R 13 represents H, alkyl, alkenyl, and LR 12; Z1 represents a halogen; Z2 and Z3 independently represent H or halogen; p is, independently for each one that is presented, an integer from 0 to 8; and q is, independently for each one presented, an integer from 1 to 8. In another embodiment, Rs represents CN, CHO, or Cl ^ OlCfZ1) (Z2) (Z3), where Z1 represents a halogen, and Z2 and Z3 represent H or halogen. In certain such embodiments, R6 represents C (= 0) C (Z1) (Z2) (Z3), where Z1 represents fluorine, and Z2 and Z3 represent H or fluorine. In certain embodiments, R6 represents a group -BYY1) (Y2), wherein Y1 and Y2 are independently OH or a group that is hydrolysed to OH (that is, thereby a boronic acid is formed), or together with the The boron to which they are bound form a ring of 5 to 8 members which is hydrolysable to a boronic acid. In certain embodiments, R3 and R4 together with the atoms to which they bond form a ring of 5 members, which is substituted with one or more groups selected from hydroxyl, lower alkyl (eg, methyl), lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl (eg, hydroxymethyl), and lower-alkoxy-alkyl. In more defined embodiments, the substituent group is selected from the group consisting of lower alkyl, lower hydroxyalkyl and lower alkyl alkoxy. In such more preferred embodiments, the substituent group is located at the 5-position of the ring. In other more specific embodiments, the substituent group is hydroxyl, which is preferably located at the 4-position of the ring. In certain embodiments, the substituent group on the 5-membered ring containing R3 and R4 is selected from the group consisting of lower alkyl (eg, methyl), hydroxyl, lower hydroxyalkyl (eg, hydroxymethyl) and lower-alkoxy-lower alkyl. In certain preferred embodiments, the substituent group has a cis stereochemical ratio up to R6. Such stereochemical relationships are particularly advantageous for compounds having substituents in the 4 or 5 position of the 5-membered ring, as discussed immediately above.

In certain embodiments of the invention, an objective compound has a structure of formula XX: (XX) or a pharmaceutically acceptable salt thereof, wherein: R: represents H, alkyl, alkoxy, alkenyl, alkyl, amino, alkylamino, acylamino, cyano, sulfonylamino, acyloxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, or a chain of polypeptide of 1 to 8 amino acid residues; R 2 represents H, lower alkyl, or aralkyl; R3 and R4 independently represent H, halogen, or alkyl, or R3 and R4 together with the carbon to which they bond, form a heterocyclic ring of 3 to 6 members; R 5 represents H, halogen, lower alkyl, or aralkyl, preferably H or lower alkyl; R6 represents a functional group that is reacted with a residue of the active site of the target protease to form a covalent adduct; R7 represents H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaralkyl, or a polypeptide chain of 1 to 8 amino acid residues; R 14 represents H, alkyl, alkoxy, alkenyl, alkyl, or aralkyl, preferably H; A is absent or represents -NHC (= NH) -, or R14 and A together with the nitrogen to which they bond form a heterocyclic ring; L is absent or represents an alkyl, alkenyl, alkynyl, (CH2) m0 (CH2) m-, - (CH2) mNR2 (CH2) m-, and - (CH2) mS (CH2) m- X is absent or represents -N (R7) -, -O-, or -S-; And it is absent or represents -C (= 0) -, -C (= S) -, or -S02-; m is, independently for each one presented, an integer from 0 to 10; and n is an integer from 1 to 6. In certain embodiments, R 1 represents H or lower alkyl, R 3 and R 4 together with the carbon to which they are bound form a 5-membered ring, and n is an integer from 1 to 4. In certain embodiments , R14 is H, A is absent, and n is 4. In certain other embodiments, R14 is H, A is -NHC (= NH) -, and n is 3. In certain embodiments, A and R14 together with the nitrogen to which they form an imidazole ring, and n is 1.

In certain embodiments, R6 represents boronic acid, CN, -S02Z, -P (= 0) Z1, -P (= R8) R9R10, -C (= NH) NH2, -CH = NR, or -C (= 0) -R ?: where R8 is 0 u S; R9 represents N3, SH2, NH2, N02, or OLR12, and R10 represents a lower alkyl, amino, OLR12, or a pharmaceutically acceptable salt thereof, or R9 and R10, together with the phosphorus to which they are linked, form a heterocyclic ring from 5 to 8 members; R 11 represents H, alkyl, alkenyl, alkynyl, NH 2, - (CH 2) p-R 12, - (CH 2) q-OH, - (CH 2) q-0-alkylo, - (CH 2) q-0-alkenyl, - ( CH2) q-0-alkynyl, - (CH2) q-0- (CH2) p-R12, - (CH2) q-SH, - (CH2) qS-alkyl, - (CH2) qS-alkenyl, - (CH2) qS-alkynyl, - (CH2) qS- (CH2) P-R12, -C (0) NH2, -C (0) OR13, or CZZ1) (Z2) (Z3); R 12 represents H, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 13 represents H, alkyl, alkenyl, or LR 12; Z represents a halogen; Z2 and Z3 independently represent H or halogen; p is, independently for each one that is presented, an integer from 0 to 8; and q is, independently for each one that is presented, an integer from 1 to 8. In certain modalities, R6 represents CN, CHO, or C (= 0) C (Z1) (Z2) (Z3), wherein Z1 represents a halogen, and Z2 and Z3 represent H or halogen. In another embodiment, Rs represents C (= 0) C (Z1) (Z2) (Z3), where Z1 represents fluorine, and Z2 and Z3 represent H or fluorine. In certain embodiments, R6 represents a group -BYY1) (Y2), wherein Y1 and Y2 are independently OH or a group that is hydrolyzed to OH, or together with the boron atom to which they are bonded form a ring of 5 to 8 limbs that is hydrolysable to a boronic acid. In certain embodiments, R3 and R4 together with the atoms to which they bond form a 5-membered ring, which is substituted with one or more groups selected from hydroxyl, lower alkyl (eg, methyl), lower alkenyl, lower alkyl , lower alkoxy, lower hydroxyalkyl (for example, hydroxymethyl), and lower alkyl alkoxy. In more specific embodiments, the substituent group is selected from the group consisting of lower alkyl, lower hydroxyalkyl and infeporalkyl alkoxy. In such more preferred embodiments, the substituent group is located at the 5-position of the ring. In other more specific embodiments, the substituent group is hydroxyl, which is preferably located in the 4-position of the ring In certain embodiments, the substituent group on the 5-membered ring containing R3 and R4 is selected from the group consisting of lower alkyl (eg, methyl), hydroxyl, lower hydroxyalkyl (eg, hydroxymethyl) and lower-alkoxy-lower alkyl. In certain preferred embodiments, the substituent group has a cis stereochemical ratio up to R6. Such stereochemical relationships are particularly advantageous for compounds having substituents in the 4- or 5-position of the 5-membered ring, as discussed immediately above. In certain embodiments of the invention, an objective compound has a structure of formula XXI: (xxi) or a pharmaceutically acceptable salt thereof, wherein: R 1 represents H, alkyl, alkoxy, alkenyl, alkynyl, amino, alkylamino, acylamino, cyano, sulfonylamino, acyloxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, or a chain of polypeptide of 1 to 8 amino acid residues; R 2 represents H, lower alkyl, or aralkyl; R3 and R4 independently represent H, halogen, or alkyl, or R3 and R4 together with the carbon to which they bond, form a heterocyclic ring of 3 to 6 members; R'J represents H, halogen, lower alkyl, or aralkyl, preferably H or lower alkyl; R6 represents a functional group that is reacted with a residue of the active site of a target protease to form a covalent adduct; R 'represents H, aplo, alkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaralkyl, or a polypeptide chain of 1 to 8 amino acid residues; R15 is a functional group that has either a positive or negative charge at physiological pH, preferably an amine or carboxylic acid; L is absent or represents an alkyl, alkenyl, alkyl, - (CH2) m0 (CH2) m-, - (CH2) mNR2 (CH2) m-, and (CH2) mS (CH) m-; X is absent or represents -N (R7) -, -O-, or -S-; And it is absent or represents -C (= 0) -, -C (= S) -, or -S02-; m is, independently for each one presented, an integer from 0 to 10; and n is an integer from 1 to 6.

In certain embodiments, R1 represents H or lower alkyl, R3 is H and R4 is lower alkyl, or R3 and R4 together with the carbon to which they are bound form a 5-membered ring, and n is an integer from 1 to 4. In certain modalities, n is an integer from 1 to 4 and R1"5 is a functional group that has either a positive or negative charge on the physiological pH.In more definite modalities n is an integer from 1 to 4 and R15 is selected from the group which consists of amine, carboxylic acid, ylidazole, or functionally guanidine In certain embodiments, R6 represents boronic acid, CN, -SOzZ1, -P (= 0) Zx, -P (= R8) R9R10, -C (= NH) NH2 , -CH = NR ", O -C (= 0) -Rxl where R8 is 0 u S; R9 represents N3, SH? , NH2, N02, or OLR12, and R10 represents a lower alkyl, ammo, OLR12, or a pharmaceutically acceptable salt thereof, or R9 and R10, together with the phosphorus to which they are linked, form a 5- to 8-membered heterocyclic ring; R 11 represents H, alkyl, alkenyl, alkyl, NH 2, - (CH 2) p-R 12, - (CH 2) q-OH, - (CH 2) q-0-alkylo, - (CH 2) q-0-alkenyl, - (CH2) q-0-alkyl, - (CH2) q-0- (CH2) p-R12, (CH2) q-SH, - (CH2) qS-alkylene, - (CH2) q- S -alkenyl, (CH2) qS-alkanol, - (CH2) qS- (CH2) p-R12, -C (0) NH2, -C (0) 0R13, O-CYZ1) (Z2) (Z3); R 12 represents H, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocyclyl; R 13 represents H, alkyl, alkenyl, or LR 12; Z1 represents a halogen; Z2 and Z3 independently represent H or halogen; p is, independently for each one that is presented, an integer from 0 to 8; and q is, independently for each one that is presented, an integer from 1 to 8. In certain embodiments, R6 represents CN, CHO, or C (= 0) C (Zt) (Z2) (Z3), wherein Z1 represents a halogen , and Z2 and Z3 represent H or halogen. In another embodiment, R6 represents C (= 0) C (Z1) (Z2) (Z3), where Z1 represents fluorine, and Z2 and Z3 represent H or fluorine. In certain embodiments, Rs represents a group -BYY1) (Y2), wherein Y1 and Y2 are independently OH or a group that is hydrolyzed to OH, or together with the boron atom to which they bond they form a ring of 5 to 8 limbs that is hydrolysable to a boronic acid. In certain embodiments, R3 and R4 together with the atoms to which they are bound form a 5-membered ring substituted with one or more selected groups hydroxyl, lower alkyl (e.g., methyl), lower alkenyl, lower alkynyl, lower alkoxy, hydroxy-lower alkyl (e.g., hydroxymethyl), and alkoxy-mferalkyl. In more defined embodiments, the substituent group is selected from the group consisting of lower alkyl, lower hydroxyalkyl and lower alkyl alkoxy. In such more preferred embodiments, the substituent group is located at the 5-position of the ring. In other more specific embodiments, the substituent group is hydroxyl, which is preferably located at the 4-position of the ring. In certain modalities, the substituent group in the 5-member ring containing R! and R 4 is selected from the group consisting of lower alkyl (eg, methyl), hydroxyl, lower hydroxyalkyl (eg, hydroxymethyl) and lower alkoxyalkyl. In certain preferred embodiments, the substring group has a stereochemical relationship to Rs. Such stereochemical relationships are particularly advantageous for the compounds having the substituents in the 4- or 5-position of the 5-membered ring, as discussed immediately above.

Another aspect of the invention relates to inhibitors having a structure of formula XXII: (XXII) or a pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of a 4-8 membered heterocycle including N and a Ca carbon; Z is C or N; W is selected from the group consisting of CN, -CH = NR5, a functional group which is reacted with a residue of the active site of the target protease, R1 is selected from the group consisting of an amino acid residue terminally linked to C or analogous amino acid, an analogous peptide or peptide terminally linked to C, or wherein the bond between R1 and N is a thioxamide bond, R 2 represents one or more substitutions on ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkyl, carbonyl, carboxyl, ester, formate, ketone, thiocarbonyl, thioester, thioacetate, thioformate, amino, acylamm, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - (CH2) ra-0-alkenyl lower, - (CH2) n-0- (CH?) m-R7, - (CH2) m-SH, - (CH2) m- S - lower alkyl, (CH2) m- S-lower alkenyl, or - (CH2) n-S- (CH2) m-R7, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, T T > 10 NC or ^ R, wherein at least one R 2 is selected from the group consisting of -OH, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl, preferably at least one of lower alkyl (e.g., methyl), lower alkoxy, lower hydroxyalkyl (eg, hydroxymethyl), and lower alkoxyalkyl; when Z is N, R3 is absent, when Z is C, R3 is selected from the group consisting of hydrogen, halogen, lower alkyl, lower alkenyl, lower alkyl, carbonyl, thiocarbonyl, ammo, acylammon, amido, cyano, nitro, azido, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, (CH?) m-OH, - (CH?) m-0-lower al, - (CH2) m-0-lower alkenyl, - (CH2) n-0- (CH2) m-R7, - (CH2) m-SH, (CH?) MS-lower alkyl, - (CH2) mS-lower alkenyl, and - (CH;) nS- (CH2) m-R7; R 'is selected from the group consisting of hydrogen, alkyl, alkenyl, alkyl, -C (X1) (X2) X3, - (CH2) m-R7, - (CH?) N-OH, - (CH2) n- 0-alkyl, - (CH2) n-0-alkenyl, - (CH2) n-0-alkyl, - (CH2) n-0- (CH2) m-R7, - (CH2) n -SH, - (CH2) nS-alkyl, - (CH?) NS-alkenyl, - (CH2) nS-alkanol, - (CH2) nS- (CH?) M -R ', - C (0) C (0) NH2, and -C (O) C (O) OR7 '; R6 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkyl, aryl, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-alkyl, - ( CH2) mO-alkenyl, - (CH2) m-0-alkyl, - (CH2) m-0- (CH2) m-R7, (CH?) M-SH, - (CH?) Ra-S- alkyl, - (CH2) m- S -alkenyl, (CH?) mS-alkenyl, - (CH2) mS- (CH2) m-R7, R8 OR R8 NH2 O I I / I I I I - (CH 1; 2? I - (CH2) n- C-N- (CH2) n- NH2- -C- NH2 - (CH2) n-C-0-R7 Rs R9 OOO or IIII II II - (CH2) r, -C- alkyl, - (CH2) n-C-alkenyl, - (CH2) n-C-alkynyl, and - (CH2) n- C- ( CH2) m-R7 each R7 is independently selected from aryl, aralkyl, cycloalkyl, cycloalkyl, and heterocyclyl; each R7 'is independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl and heterocyclyl; R8 and R9 are each independently selected from hydrogen, alkyl, alkenyl, - (CH2) m-R7, -C (= 0) -alkyl, -C (= 0) -alkenyl, -C (= 0) -alkynyl, and -C (= 0) - (CH?) m-R7; or R8 and R9 are taken together with the N atom to which they are linked they complete a heterocyclic ring having from 4 to 8 atoms in the ring structure; R10 represents hydrogen, -CH3, or - (CH2) n-CH3; R '; 0 is O u S; Rr > 1 is selected from the group consisting of N3, SH, NH? , DO NOT? , and OR7 '; Rb2 is selected from the group consisting of hydrogen, lower alkyl, amine, OR7 ', or a pharmaceutically acceptable salt thereof, or R1'1 and R52 are taken together with the P atom to which they are linked they complete a heterocyclic ring having from 5 to 8 atoms in the structure of the ring; X1 is a halogen; X2 and X3 are each selected from hydrogen and halogen; Y1 and Y2 are each independently selected from OH and a group capable of hydrolyzing OH, including cyclic derivatives where Y1 and Y2 are connected by means of a ring having from 5 to 8 atoms in the structure of the ring; m is zero or an integer in the range from 1 to 8, and n is an integer in the range from 1 to 8. In certain embodiments, W is selected from the group consisting of CN and BfY1) (Y2). In certain modalities, A is a ring of five members, Z is C, and W is BÍY1) (Y2). In more specific embodiments, Z has the absolute stereochemical configuration of L-proline. In certain embodiments, A is a five-membered ring, Z is C, and R2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, R 2 is selected from the group consisting of lower hydroxyalkyl and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring. In certain embodiments, A is a five-membered ring, Z is C, and R2 is selected from the group consisting of hydroxyl, lower alkyl (such as methyl), lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl. In certain of such preferred embodiments, Z has the absolute stereochemical configuration of L-prolma and R2 is located at the 5-position of the ring for lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl and in the 4-position for hydroxyl. In more such preferred embodiments, R2 has a cis-to-tequi-chemical relationship for W. Another aspect of the invention relates to inhibitors having a structure of Formula XXIII- Y2 Y1 (XXIII) or a pharmaceutically acceptable salt thereof, wherein R1 is selected from the group consisting of an amino acid residue thermally bonded to C or amino acid analogue, to a peptide thermally bonded to C or analogously ; wherein the bond between R1 and N is a thioxamide bond; R2 represents one or more substitutions to ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as a carboxyl, ester, formate, or ketone), thiocarbonyl (such as a thioester, thioacetate, or thioformate), ammo, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido , - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - (CH2) m-0-lower alkenyl, - (CH2) n-0- ( CH?) M-R7, - (CH?) M-SH, - (CH2) mS-lower al, - (CH2) mS-lower alkenyl, or - (CH2) nS- (CH2) m-R7, azido, cyano, Isocyanate, thiocyanate, isothiocyanate, cyanate, > wherein, at least one R 2 is selected from the group consisting of -OH, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl, preferably at least one of lower alkyl (e.g., methyl), lower alkoxy, hydroxyalkyl lower (e.g., hydroxymethyl), and lower alkoxyalkyl, R6 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, alkyl, aplo, - (CH2) m-R7, - (CH?) m-OH, - (CH2) m-0-alkylene, - (CH2) ra-0-alchemyl, - (CH2) m-0-alk? N? Lo, - (CH?) M-0- (CH2) m-R7 , - (CH2) m-SH, - (CH2) mS-alkyl, - (CH?) MS-alkenyl, - (CH2) mS-alkenyl, - (CH2) mS- (CH?) m-R7, Rβ O R 8 NH 2 O / M / II II (CH?) M - N (CH 2) n - C - N (CH 2) n - NH 2 - C - NH 2 - (CH 2) n - C - O - R 7 R9 0 0 0 O I I II II II - (CH), - C -alkyl- (CH2) n- C -alkenyl- (CH ^ - C -alkyl, y- (CH2) n-C- (CH2) m -R7 R7 is selected from the group consisting of aplo, cycloalkyl, cycloalkenyl, and heterocyclyl; R8 and R9 are each independently selected from hydrogen, alkyl, alkenyl, - (CH2) m-R7, -C (= 0) -alkyl, -C (= 0) -alkenyl, -C (= 0) -alkyl, and -C (= 0) - (CH?) mR, or R8 and R9 taken together with the N atom to which they are bonded complete a heterocyclic ring having from 4 to 8 atoms in the ring structure, R10 represents hydrogen, - CH3, or - (CH2) n-CH3; Y1 and Y2 are each independently selected from OH and a group capable of hydrolyzing to OH, including cyclic derivatives where Y1 and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure, m is zero or an integer in the range from 1 to 8; and n is an integer in the range from 1 to 8. In certain modalities, the carbon it carries BÍY1) (Y2) has the absolute stereochemical configuration of L-prolma. In certain such preferred embodiments, R2 it is selected from the group consisting of hydroxyl, lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring for lower alkyl (such as methyl), lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl or at the 4-position for hydroxyl. In such still more preferred embodiments, R2 has a cis-stereochemical relationship for B Y1) (Y2). Another aspect of the invention relates to compounds having a structure of Formula XXIV: (XXIV) or a pharmaceutically acceptable salt thereof, wherein A is a 3-8 membered heterocycle including carbon N and Ca; W is a functional group which reacts with an active site residue of an objective protease to form a covalent adduct; R1 is selected from the group consisting of hydrogen, a peptide or amino acid thermically bonded to C analogue thereof, and an ammo protecting group; where optionally where the link between R1 and the N to which it binds is a thioxamide bond; R2 represents one or more substitutions to ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as a carboxyl, ester, formate, or ketone), thiocarbonyl (such as a thioester, thioacetate, or thioformate), amino, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - (CH2) m-0-lower alkenyl, - (CH2) n-0- (CH ?) m-R ', - (CH?) m-SH, - (CH2) mS-lower alkyl, - (CH2) mS-lower alkenyl, or - (CH2) nS- (CH2) m-R7, azido, cyano, TT -N: isocyanate, thiocyanate, isothiocyanate, cyanate, or C ???C R 10, wherein at least one R 2 is selected from the group consisting of -OH, lower alkyl, lower alkoxy, lower hydroxyalkyl, and alkoxyalkyl lower, preferably at least one lower alkyl (eg, methyl), lower alkoxy, lower hydroxyalkyl (eg, hydroxymethyl), and lower alkoxyalkyl; R3d is selected from the group consisting of hydrogen and a substituent that does not conjugate the electron pair of the nitrogen from which it hangs; R4a and R4b are each independently selected hydrogen, lower alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, carboxyl, carboxamide, carbonyl, and cyano, with the proviso that either or none of R4a and R4b are hydrogen; R 4c is selected from the group consisting of halogen, amine, alkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, carboxyl, carboxamide, carbonyl, and cyano; each R6 is independently selected from aryl, aralkyl, cycloalkyl, cycloalkenyl, and heterocyclyl; z is zero or an integer in the range from 1 to 3; m is zero or an integer in the range from 1 to 8; and n is an integer in the range from 1 to 8 In certain embodiments, W is selected from the group consisting of CN and BtY1) (Y2), wherein Y1 and Y2 are each independently OH, or a group capable of hydrolyzing OH, including cyclic derivatives where Y1 and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure In certain embodiments, A is a five-membered ring, and W is B (Y :) (Y2 ). In more than certain modalities, Ca has the absolute stereochemical configuration of L-prolma. In certain embodiments, A is a ring of five members and R2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, R 2 is selected from the group consisting of lower alkyl (such as methyl), lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring. In certain embodiments, A is a ring of five members, and R2 is selected from the group consisting of hydroxyl, hydroxyl, lower alkyl, hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, Ca has the absolute stereochemical configuration of L-prolma and R2 is located at the 5-position of the ring for lower alkyl (such as methyl), lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl or at the position 4 for hydroxyl. In more such preferred embodiments, R2 has a cis-stereochemical relationship for W. Another aspect of the invention relates to compounds having a structure of Formula XXV (XXV) or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3a, R4a, Rb, R4c and W are as defined above by Formula XXIV, and p is an integer from 1 to 3. In certain embodiments, p is 1 and R3a is hydrogen. In certain embodiments, W is selected from the group consisting of CN and BfY1) (Y2), wherein Y1 and Y2 are each independently OH, or a group capable of hydrolyzing OH, including cyclic derivatives where Y1 and Y2 are connected by means of a ring having from 5 to 8 atoms in the structure of the ring. In certain modalities, W is BÍY1) (Y2). In more than certain embodiments, the carbon carrying W has the absolute stereochemical configuration of L-prolma. In certain embodiments, R 2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In certain embodiments, R 2 is selected from the group consisting of lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl. In more such preferred embodiments, p is 1 and R2 is located at the 5-position of the ring. In certain modalities, R2 is selected from group consisting of hydroxyl, lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl. In certain such preferred embodiments, p is 1, the carbon bearing W has the absolute stereochemical configuration of L-proline and R2 is located at the 5-position of the ring for lower alkyl (such as methyl), lower hydroxyalkyl (such as hydroxymethyl) ) and lower alkoxyalkyl or in the 4-position for hydroxyl. In more such preferred embodiments, R 2 has a cis-stereochemical relationship for W. In certain embodiments, R 2 is azido, cyano, isocyanate, ΔT "N = G. thiocyanate, isothiocyanate, cyanate, C_______C R8 in certain embodiments, p is 1, the carbon carrying W has the absolute stereochemical configuration of L-proline and R2 is located at the 5-position of the ring. Yet another aspect of the present invention relates to a compound having a structure of Formula XXVI: or a pharmaceutically acceptable salt thereof, wherein A is a heterocycle of 3 to 8 members including N and carbon Ca; B is a C3_8 ring, or a bicyclic or tricylic ring system fused C7_? 4; W is a functional group that reacts with an active site residue of a target protease to form a covalent adduct, such as, for example, -CN, -CH = NR5, 2 R1 is selected from the group consisting of hydrogen, a peptide or amino acid terminally linked to C or analog thereof, and an amino protecting group wherein optionally where the bond between R1 and the N to which it is attached is applied is a thioxamide bond; R 2 represents one or more substitutions to ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as a carboxyl, ester, formate, or ketone), thiocarbonyl (such as a thioester , thioacetate, or thioformate), amino, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - ( CH2) m-0-lower alkenyl, - (CH2) n-0- (CH?) M-R7, - (CH2) m-SH, - (CH2) mS-lower alkyl, - (CH2) mS-lower alkenyl , or - (CH2) nS- (CH2) m-R7, azido, cyano, TT isocyanate, thiocyanate, isothiocyanate, cyanate, -NE-, = Co_ C______rC R t wherein at least one R 2 is selected from the group consisting of -OH, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl, preferably at least one of lower alkyl (eg, methyl), lower alkoxy, lower hydroxyalkyl (eg, hydroxymethyl), and lower alkoxyalkyl; Rb is selected from the group consisting of hydrogen, alkyl, alkenyl, alkyl, -C (X1) (X2) X3, - (CH2) m-Re, - (CH?) N-OH, - (CH?) N- 0-alkyl, - (CH2) n-0-alkenyl, - (CH2) n-0-alkyl, - (CH?) N-0- (CH2) m-R6, - (CH2) n- SH, - (CH2) nS-alkylene, - (CH?) NS-alkenyl, - (CH2) nS-alkanol, - (CH2) nS- (CH2) m -R6, -C (0) C (0) NH ?, and -C (O) C (O) OR7, each R6 is independently selected from aryl, aralkyl, cycloalkyl, cycloalkenyl, and heterocyclyl, each R; is independently selected from hydrogen, alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, and heterocycle, R8 represents hydrogen, -CH3, or - (CH2) n-CH3; Y1 and Y2 are each independently selected from -OH, or a group capable of hydrolyzing a hydroxyl group, including cyclic derivatives wherein Y1 and Y2 are connected by means of a ring having from 5 to 8. atoms in the ring structure (such as pinacol or the like), Rb0 is O u S; R51 is selected from the group consisting of N3, SH2, NH ?, NO? or -OR7; Rr > 2 represents hydrogen, a lower alkyl, an amine, -OR ', or a pharmaceutically acceptable salt thereof, or R53 and R52 are taken together with the phosphorus atom to which they are linked they complete a heterocyclic ring having from 5 to 8 atoms in the structure of the ring; X1 represents a halogen, X2 and X3 are each independently selected from hydrogen and halogen; m is zero or an integer in the range from 1 to 8; and n is an integer in the range from 1 to 8. In certain embodiments, W is selected from the group consisting of CN and B (YX) (Y2), wherein Y1 and Y2 are each independently OH, or a capable group of hydrolyzing OH, including cyclic derivatives where Y1 and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure. In certain modalities, A is a ring of five members, and W is BÍY1) (Y2) In more than certain modalities, Ca has the absolute stereochemical configuration of L-prolma. In certain modalities, A is a ring of five members and R2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, R 2 is selected from the group consisting of lower hydroxyalkyl (hydroxymethyl) and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring. In certain embodiments, A is a five-membered ring, and R2 is selected from the group consisting of hydroxyl, lower alkyl, lower hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, Ca has the absolute stereochemical configuration of L-prolma and R2 is located at the 5-position of the ring for lower alkyl (such as methyl), lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl or at the position 4 for hydroxyl. In more such preferred embodiments, R2 has a cis-stereochemical relationship for W. In certain embodiments, R2 is azido, cyano, isocyanate, © T -NE = C thiocyanate, isothiocyanate, cyanate, 8. In certain embodiments, p Ca has the absolute stereochemical configuration of L-prolma and R2 it is located at position 5 of the ring. Another aspect of the invention relates to compounds having a structure of Formula XXVII: or a pharmaceutically acceptable salt thereof, wherein B, R1, R2 and W are as defined above by Formula XXVI, and p is an integer from 1 to 3. In certain embodiments, p is 1. In certain embodiments, W is selected from the group consisting of CN and BÍY1) (Y2), wherein Y1 and Y2 are each independently OH, or a group capable of hydrolyzing OH, including cyclic derivatives where Y1 and Y2 are connected by means of a ring which has from 5 to 8 atoms in the structure of the ring. In certain modalities, W is BfY1) (Y2). In more than certain embodiments, the carbon carrying W has the absolute stereochemical configuration of L-prolma. In certain embodiments, R 2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In certain of such preferred embodiments, R2 is selected from the group consisting of lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring. In certain embodiments, R 2 is selected from the group consisting of hydroxyl, lower alkyl, hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, p is 1, the carbon bearing W has the absolute stereochemical configuration of L-proline and R2 is located at the 4-position of the ring for hydroxyl or in the 5-position for lower alkyl (such as methyl) , lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl. In more such preferred embodiments, R2 has a cis-stereochemical relationship for W. In certain embodiments, R2 is azido, cyano, socianate, f 0 thiocyanate, isothiocyanate, cyanate, or C ^ = C R8 _ In certain modalities, p is 1, the carbon that carries W has the absolute stereochemical configuration of L-prolma and R2 is located at the 5-position of the ring. Another aspect of the invention relates to compounds that have a structure of Formula XXVIII (XXVIII) or a pharmaceutically acceptable salt thereof, wherein A is a 4-8 membered heterocycle including N and a carbon; W is a functional group that reacts with an active site residue of the target protease to form a covalent adduct, such as, for example, -CN, -CH = NR5, R1 represents a C-terminally linked peptide or peptide analog that is a substrate for an activated enzyme; wherein optionally the bond between R1 and the N to which it is linked is a thioxamide bond; R 2 represents one or more substitutions to ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as a carboxyl, ester, formate, or ketone), thiocarbonyl (such as a thioester) , thioacetate, or thioformate), ammo, acylamm, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - (CH2) m- 0-alken? Lo lower, - (CH2) n-0- (CH?) M -R ', - (CH2) m-SH, - (CH2) mS-lower al, - (CH2) mS-alkenyl lower, or - (CH2) nS- (CH2) m-R7, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, or C-rrr: CR (wherein at least one R 2 is selected from the group consisting of -OH, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl, preferably at least one of lower alkyl (e.g., methyl), alkoxy lower, lower hydroxyalkyl (eg, hydroxymethyl), and lower alkoxyalkyl, R3 is selected from the group consisting of hydrogen and a substituent that does not conjugate the electron pair of the nitrogen to which it is attached, such as a lower alkyl; R4 is selected from the group consisting of hydrogen and a small hydrophobic group such as a halogen, lower alkyl, lower alkenyl, or lower alkyl, Rb is selected from the group consisting of hydrogen, alkyl, alkenyl, alkyl, -C (X1) (X2) X3, - (CH2) m-R6, - (CH) n-OH, - (CH2) n-0-alkylene, - (CH2) n-0-alkenyl, - (CH2) n -0-alkyl, - (CH2) n-0- (CH2) m -R6, - (CH2) n-SH, - (CH2) nS-alkylene, - (CH) nS-alkenyl, - ( CH2) nS-alkanol, - (CH2) nS- (CH2) m-R6, -C (0) C (0) NH2, -C (0) C (0) OR7; R6 represents, for each occurrence, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R7 represents, for each occurrence, hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R8 represents hydrogen, -CH3, or - (CH2) p-CH3; and Y1 and Y2 are independently or join OH or a group capable of hydrolyzing a hydroxyl group, including cyclic derivatives wherein Y1 and Y2 are connected by means of a ring having from 5 to 8 atoms in the ring structure (such as pinacol or similar), R0 is O u S; R51 is selected from the group consisting of N3, SH, NH ?, NO? and -OR7; R2 is selected from the group consisting of hydrogen, lower alkyl, amine, -OR7, or a pharmaceutically acceptable salt thereof; or Rbl and R52 are taken together with the phosphorus atom to which they are linked they complete a heterocyclic ring having from 5 to 8 atoms in the ring structure; X: it is a halogen; X2 and X3 are each independently selected from hydrogen and halogen; m is zero or an integer in the range from 1 to 8; and n is an integer in the range from 1 to 8. In certain embodiments, W is selected from the group consisting of CN and BÍY1) (Y2). In certain modalities, A is a ring of five members, and W is BÍY1) (Y2). In more than certain embodiments, Ca has the absolute stereochemical configuration of L-proline. In certain embodiments, A is a five-membered ring, Z is C, and R2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, alkyl lower, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, R 2 is selected from the group consisting of lower hydroxyalkyl (such as hydroxymethyl) and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring. In certain embodiments, A is a five-membered ring and R2 is selected from the group consisting of hydroxyl, lower alkyl, lower hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, Ca has the absolute stereochemical configuration of L-prolma and R2 is located at the 4-position of the hydroxyl ring or in the 5-position for lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl.

In more such preferred embodiments, R2 has a cis-stereochemical relationship for W. In certain embodiments, R2 is azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, © T -Rs o. In certain modalities, Ca has the stereochemical configuration absolute of L-proline. In more than certain modalities, R2 is located in position 5 of the ring. One aspect of the invention relates to compounds having a structure of Formula XXIX: (XXIX) or a pharmaceutically acceptable salt thereof, wherein L is absent or is -XC (0) -; R1 is selected from the group consisting of H, lower alkyl, lower acyl, lower aralkyl, lower aracyl, lower heteroaracyl, carbocyclyl, aryl, and ArSO? -; wherein optionally when L is absent the bond between R1 and the N to which it is linked is a thioxamide bond; R2 represents one or more substitutions to ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl (such as a carboxyl, ester, formate, or ketone), thiocarbonyl (such as a thioester, thioacetate, or thioformate), amino, acylamino , amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - (CH2) m-0-lower alkenyl, - (CH2) n-0- (CH?) M-R7, - (CH?) M-SH, - (CH2) mS-lower alkyl, - (CH2) mS-lower alkenyl, or - (CH2) nS- ( CH2) m-R7, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, © TN ^ CC = C R10, u, wherein at least one R 2 is selected from the group consisting of -OH, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl, preferably at least one lower alkyl (e.g., methyl), lower alkoxy, lower hydroxyalkyl (eg, hydroxymethyl), and lower alkoxyalkyl; R3 is selected from the group consisting of hydrogen, lower alkyl, lower hydroxyalkyl, lower thioalkyl, and lower aralkyl; R 4 is selected from the group consisting of H and lower alkyl, or R 1 and R 4 together are phthaloyl, to form a ring, - R 6 represents, for each one, an aryl substituted or unsubstituted, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R8 represents hydrogen, -CH3, or - (CH2) n-CH3; W is selected from the group consisting of BÍY1) (Y2) and CN; Y1 and Y2 are independently selected from OH or a group which is hydrolysable to OH, or together with the boron atom to which they are bonded form a ring of 5 to 8 members which is hydrolysable to OH; X is selected from the group consisting of O and NH. In certain modalities, W is BÍY1) (Y2). In certain embodiments, R 2 is selected from the group consisting of hydroxyl, lower alkyl, lower alkenyl, lower alkyl, lower alkoxy, lower hydroxyalkyl, and lower alkoxyalkyl. In more such preferred embodiments, R 2 is selected from the group consisting of lower hydroxyalkyl and lower alkoxyalkyl. In more such preferred embodiments, R2 is located at the 5-position of the ring. In certain embodiments, R 2 is selected from the group consisting of hydroxyl, lower alkyl, hydroxyalkyl, and lower alkoxyalkyl. In certain such preferred embodiments, Ca has the absolute stereochemical configuration of L-prolma and R2 is locates at the 4-position of the hydroxyl ring or in the 5-position for lower alkyl, lower hydroxyalkyl and lower alkoxyalkyl. In more such preferred embodiments, R2 has a cis-stereochemical relationship for w.

Mode F A representative class of compounds for one in the method of the present invention is represented by formula XXX: (XXX) wherein R 1 is selected from the group consisting of H, alkyl, alkoxy, alkenyl, alkynyl, amino, alkylamino, acylamino, cyano, sulfonylamino, acyloxy, aryl, cycloalkyl, heterocyclyl, heteroaryl, and polypeptide chains from 1 to 8 amino acid residues; R2 is selected from the group consisting of H, lower alkyl, and aralkyl; R3 is selected from the group consisting of (a) lower alkyl; (b) RaRbN (CH2) m- wherein Ra is a pyridinyl or pyrimidinyl moiety optionally substituted with alkyl (C? _4), alkoxy (C? _4), halogen, trifluoromethyl, cyano or nitro; or phenyl optionally mono- or independently disubstituted with alkyl (C? _4), (C? _4) alkoxy or halogen; Rb is hydrogen or alkyl (C? _8) and m is 2 or 3; (c) cycloalkyl (C3_? 2) optionally monosubstituted in the 1-position with hydroxyalkyl (C? _3); (d) Rc (CH2) n- wherein either Rc is phenyl optionally substituted with alkyl (C? _4), (C? _4) alkoxy, halogen or phenylthio optionally monosubstituted on the phenyl ring with hydroxymethyl; or is alkyl (C? -8); a carbocyclic bicylic [3.1.1] portion optionally substituted with alkyl (C? _8); a pyridinyl or naphthyl moiety optionally substituted with (C 4 -4) alkyl, alkoxy (Ci) or halogen; cyclohexene; or adamantyl and n is 1 to 3; or Rc is phenoxy optionally substituted with alkyl (C-4), (C 4 -4) alkoxy or halogen and n is 2 or 3; (e) (Rd)? CH (CH2) 2- where each Rd independently is phenyl optionally substituted with (C? -4) alkyl, (C: 4) alkoxy, or halogen; (f) Re (CH2) p- wherein Re is 2-oxopyrrolidinyl or alkoxy (C? _4) and p is 2 to 4; and (g) Rq wherein R9 is: indanyl; a portion pyrrolidinyl or piperidinyl optionally substituted with benzyl; a [2.2.1] - or [3.1.1] carbocyclic bicyclic portion optionally substituted with alkyl (C? _8); adamantyl; or (C? -8) alkyl optionally substituted with hydroxy, hydroxymethyl or phenyl optionally substituted with alkyl (C? _4), (C? -4) alkoxy or halogen; R 4 is selected from the group consisting of H, halogen, and lower alkyl; R is selected from the group consisting of H, lower alkyl halogen, and aralkyl, preferably H or lower alkyl; R6 is a functional group that is reacted with an active site residue of the target protease to form a covalent adduct; R 'is selected from the group consisting of alkyl, alkoxy, alkenyl, alkynyl, aminoalkyl, aminoacyl, acyloxy, aryl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, or heteroaralkyl; R8 is selected from the group consisting of H, aryl, alkyl, aralkyl, cycloalkyl, heterocyclyl, heteroaryl, heteroaralkyl, and polypeptide chains of 1 to 8 amino acid residues; L is absent or selected from the group consisting of alkyl, alkenyl, alkynyl, (CH2) mO (CH2) m-, (CH?) MNR? (CH?) M- and - (CH2) mS (CH2) m-; X is absent or selected from the group consisting of -N (R8) -, -0-, and -S-; And it is absent or selected from the group consisting of -C (= 0) -, -C (= S) -, and -S02-; m is, independently for each one presented, an integer from 0 to 10; and n is an integer from 1 to 6. In certain embodiments, R1 is H or lower alkyl and R4 and R5 are both hydrogen. In certain such embodiments, R3 is lower alkyl. In certain such preferred embodiments, R3 is selected from the group consisting of methyl, ethyl, and isopropyl. In certain embodiments R3 is a substituted lower alkyl. In certain such embodiments, R 3 is substituted with a group selected from halogen, hydroxyl, carbonyl, thiocarbonyl, alkoxy, amino, amido, amid, cyano, nitro, alkylthio, heterocyclyl, aplo, and heteroapyl. In certain embodiments, X, Y, and L are absent and R1 is a polypeptide chain of 2 to 8 amino acid residues. In certain such embodiments, R1 is a polypeptide chain of 2 amino acid residues. In such embodiments, the bond between R1 and N may be a thioxamide bond. In certain other modalities, R6 is selected from group consisting of boronic acid, CN, -S02Z1, -P (= 0) Z1, -P (= R9) R10RX1, -C (= NH) NH2, -CH = NR12, or -C (= 0) -R12 wherein R9 is selected from the group consisting of 0 and S; R10 is selected from the group consisting of N3, SH2, NH ?, NO ?, and OLR13, and R is selected from the group consisting of lower alkyl, amino, and OLR13, or a pharmaceutically acceptable salt thereof; or R10 and R11, together with the phosphorus to which they are bound, form a heterocyclic ring of 5 to 8; R12 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, NH2, - (CH2) P-R13, - (CH2) q-OH, - (CH?) Q-0-alkyl, - (CH2) q-0-alkenyl, - (CH2) q-0-alkynyl, - (CH?) Q-0- (CH?) P -R13, - (CH2) q-SH, - (CH2) qS-alkyl ?, - (CH2) qS-alkenyl, - (CH2) qS-alkynyl, - (CH2) qS- (CH2) P-R13, C (0) NH ?, C (0) 0R14, and CtZ1) (Z2) (Z3); R13 is selected from the group consisting of H, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, and heterocyclyl; R14 is selected from the group consisting of H, alkyl, alkenyl, and LR13; Z1 is a halogen; Z2 and Z3 are independently selected from H and halogen; p is, independently for each one that is presented, a whole from 0 to 8; and q is, independently for each one presented, an integer from 1 to 8. In certain embodiments, R6 is selected from the group consisting of CN, CHO, and C (= 0) C (Z1) (Z2) (Z3), wherein Z1 is a halogen and Z2 and Z3 are independently selected from H and halogen. In another embodiment, R6 is selected from the group consisting of C (= 0) C (Z1) (Z2) (Z3), wherein Z1 is fluoride and Z2 and Z3 are independently selected from H and fluoride. In certain embodiments, R6 is a group -BYY1) (Y2), wherein Y3 and Y2 are independently OH or a group that is hydrolysable up to boronic acid, or together with the boron atom to which they bond they form a ring of 5 up to 8 members which is hydrolysable to a boronic acid. In certain embodiments, exemplary compounds of the present invention include: or enantiomers or diastereomers thereof. Also included are compounds of the formulas I-XXX, wherein one or more amide groups are replaced by one or more thioxamide groups. Also included are such peptidomimetics such as olefms, phosphnates, aza-amino acid analogs and the like. Also considered as equivalents are any compounds which can be hydrolytically converted into any of the aforementioned compounds including boronic acid esters and halides and carbonyl equivalents including acetals, hemiacetals, ketals and hemiketals and cyclic dipeptide analogues. As used herein, the definition of each expression, for example, alkyl, m, n, etc., when this occurs more than once in any structure, is understood to be independent of its definition elsewhere is independent of its definition elsewhere in the same structure. The pharmaceutically acceptable salts of the objective compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, for example, of non-toxic organic or inorganic acids. For example, such non-toxic salts conventional include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, palmitic, maleic, hydroxy-alkyoic, phenylacetic, glutamic, benzoic, salicyclic, sulfanilic, 2-acetoxy-benzoic? co, fumaric, toluenesulfonic, methanesulfonic, ethanesulfonic, oxalic, isothionic and the like. The pharmaceutically acceptable salts of the present invention can be synthesized from the target compound which contains a basic or acid portion by conventional chemical methods. Generally, the salts were prepared by reacting the free or acid base with stoichiometric amounts or with an excess of the inorganic or organic acid forming the desired salt or base in a suitable solvent. The pharmaceutically acceptable salts of the acids of the objective compounds are also easily prepared by conventional methods such as treating an acid of the present compounds with an appropriate amount of a base such as an alkalimetral or alkali metal hydroxide (eg, sodium, potassium, lithium, calcium or magnesium) or an organic base such as amine, piperidma, pyrrolidine, benzilamma and similar, or a quaternary ammonium hydroxide such as tetramethylammonium hydroxide and the like. The contemplated equivalents of the compounds described above include the compounds which otherwise correspond to it and which have the same general properties thereof (for example, the ability to inhibit the proteolysis of GLP-1 or other peptide hormone or precursor thereof), wherein one or more simple variations of the substituents are made which do not adversely affect the effectiveness of the compound in use in the contemplated method. In general, the compounds of the present invention can be prepared by the methods illustrated in the general reaction schemes as, for example, described below or by modifications thereof, using readily available starting materials, reagents and conventional synthesis methods. In these react, this is also possible to make use of variants which are known, but are not mentioned here. In certain embodiments, the compounds are inhibitors of DPIV with a Kx for DPIV inhibition of 10 nm or less, more preferably 1.0 nm or less and even more preferably 0.1 or even 0.01 nM or less. Surely, the inhibitors with the Kx values in the picomolar and even in the femtomolar range are contemplated.

Another aspect of the present invention relates to the pharmaceutical compositions of the dipeptidylpeptidase inhibitors described herein, particularly the compounds and their uses in treating and / or priming (inhibiting) disorders which may be ameliorated by altering the homeostasis of the peptide hormones. In a certain embodiment, the compounds have hypoglycemic and antidiabetic activities and can be used in the treatment of disorders caused by aberrant glucose metabolism (including storage). In particular embodiments, the compositions of the subject methods are useful as msulinotropic agents, or to potentiate the msulinotropic effects of such molecules as GLP-1. In this regard, the present method can be useful for the treatment and / or prophylaxis of a variety of disorders including one or more of: hyperlipidemia, hyperglycemia, obesity, impaired glucose tolerance, insulin resistance and diabetic complications. For example, in certain embodiments the method involves the administration of a compound, preferably at a predetermined interval for a period of 24 hours, in an amount effective to ameliorate one or more aberrant indices associated with disorders of glucose metabolism (e.g. , intolerance to glucose, insulin resistance, hyperglycemia, hyperinsulmia, and Type II diabetes). The effective amount of the compound may be about 0.01, 0.1, 1, 10, 30, 50, 70, 100, 150, 200, 250, 500 or 1000 mg / kg of the subject. (n) GLP-1 effects agonism The compounds useful in the methods for the subjects possess, in certain modalities, the ability to lower blood glucose levels, to mitigate obesity, to alleviate impaired glucose tolerance, to inhibit neogenesis of hepatic glucose, and lower blood lipid levels and to inhibit aldose reductase These are useful for the prevention and / or therapy of hyperglycemia, obesity, hyperlipidemia, diabetic complications (which include, retinopathy, nephropathy, neuropathy, cataracts, coronary artery disease and arteriesclerosis), and also for hypertension related to obesity and osteoporosis Diabetes mellitus is a disease characterized by hyperglycemia that occurs from an absolute or relative decrease in insulin secretion, decreased insulin sensitivity, or insulin resistance. The morbidity and mortality of this decrease results from vascular, renal, and neurological complications. An oral glucose tolerance test is a clinical test used to diagnose diabetes. In a test of tolerance to oral glucose, the physiological response of a patient to a glucose load or immunogenic test is evaluated. After ingesting glucose, the patient's physiological response to the immunogenic glucose test is evaluated. Generally, this is done by determining the patient's blood glucose levels (the glucose concentration in the patient's plasma, serum, or whole blood). ) for several predetermined points in time In one embodiment, the present invention provides a method for agonizing the action of GLP-1. It has been determined that the isoforms of GLP-1 (GLP-1 (7-37) and GLP-1 (7-36)), which are derived from preproglucagon in the intestine and the hindbrain, have msulinotrophic activity, ie they modulate the metabolism of glucose. The DPIV unfolds the isoforms to activate the peptides. Thus, in certain embodiments, the compounds of the present invention can agonize the msulinotrophic activity by interfering with the degradation of the bioactive GLP-1 peptides. (m). Agonism of the effects of other peptide hormones In another embodiment, the agents in question can be used to agonize (e.g., mimic or enhance) the activity of peptide hormones, e.g., GLP-2, GIP and NPY.

To further illustrate, the present invention provides a method for agonizing the action of GLP-2. It has been determined that GLP-2 acts as a trophic agent, to promote gastrointestinal tissue growth. The effect of GLP-2 is particularly marked by the increased growth of the small intestine, and is therefore named in the present "mtestinotrophic" effect. It is known that DPIV cleaves GLP-2 into a biologically inactive peptide. Thus, in one embodiment, the inhibition of DPIV interferes with the degradation of GLP-2, and therefore increases the plasma half-life of that hormone. In other embodiments, the method in question can be used to increase the half-life of other proglucagon-derived peptides, such as glicentin, oxintomodulm, pancreatic glycerin-related polypeptides (GRPP), and / or intermediate peptide-2 (IP-2) . For example, it has been shown that glicentma causes the proliferation of the intestinal mucosa and also inhibits the pepstalsis of the stomach, and has been elucidated by what is useful as a therapeutic agent for diseases of the digestive tract, so it is emphasized in the present invention. Thus, in one aspect, the present invention relates to the therapeutic and related uses of compounds for promote the growth and proliferation of the gastrointestinal tissue, more particularly, the tissue of the small intestine. For example, the method in question can be used as part of a regimen for treating injury, inflammation, or resection of intestinal tissue, for example, where improved growth and repair of the epithelial intestinal mucosa is desired.With respect to the tissue of the small intestine, such growth is conveniently measured as an increase in the mass of the small intestine and its length, relative to an untreated control. The effect of compounds in the small intestine also shows an increase in the height of the crypt plus the hair shaft. Such an activity is referred to herein as a "mtestinotrophic" activity. The effectiveness of the method in question may also be perceptible as an increase in crypt cell proliferation and / or a decrease in apoptosis of the small intestine epithelium. These cellular effects may be noticed more significantly with respect to the jejunum, including the distal jejunum and particularly the proximal jejunum, and also in the distal ileum. A compound is considered to have a "testinotrophic effect" if a test animal exhibits a weight in the small intestine with significant increase, increased height in the axis of the crypt more hair or cell proliferation of the crypt increased, or decreased apoptosis of the small intestine epithelium when treated with the compounds (or genetically engineered to express them). A convenient model for determining such gastrointestinal growth is described by US Patent 5, 834, 428. In general, patients who would benefit from any increased small bowel mass and consequently increased mucosal function in the small intestine are candidates for the treatment by the method in question. Particular conditions that can be treated include various forms of inlet channel, including celiac inlet channel which is the result of a toxic reaction to wheat gliam, and is marked by a tremendous loss of hair of the intestine; tropical entry channel that is the result of infection and is marked the partial palliation of hair, hypogammaglobulmemic input channel that is usually observed in patients with variable common immunodeficiency or hypogamaglobulmemia and is marked by a significant decrease in hair height. The therapeutic efficacy of the treatment can be monitored by means of an enteric biopsy to examine the morphology of the hair, by means of the biochemical evaluation of absorption of nutrients, by the weight gain of the patient, or by the improvement of the symptoms associated with these conditions. Other conditions that can be treated by the method in question, or for the method in question to be useful prophylactically, include radiation enteritis, infectious or post-mfective enteritis, regional enteritis (Crohn's disease), small bowel damage due to toxic agents or other chemotherapeutic agents, and patients with small bowel syndrome. More generally, the present invention provides a therapeutic method for treating diseases of the digestive tract. The term "digestive tract" as used herein means a tube through which food passes, which includes the stomach and intestine. The term "diseases of the digestive tract" as used herein means diseases accompanied by a qualitative or quantitative abnormality in the mucosa of the digestive tract, including, for example, an ulcerative or inflammatory disease; congenital or acquired digestion and absorption disorder that include the malabsorption syndrome; disease caused by the loss of a function of the intestinal mucosal barrier; and gastroenteropathy in which proteins are lost. Ulcer disease includes, for example, gastric ulcer, duodenal ulcer, small intestinal ulcer, colonic ulcer, and rectal ulcer. Inflammatory disease includes, for example, esophagitis, gastritis, duodenitis, enteritis, colitis, Crohn's disease, proctitis, gastrointestinal Behcet, radiation enteritis, radiation colitis, radiation proctitis, enteritis, and medication. The malabsorption syndrome includes the essential malabsorption syndrome such as deficiency of the enzyme that breaks down disaccharides, malabsorption of glucose-galactose, malabsorption of fructose; secondary malabsorption syndrome, for example, disorder caused by mucosal atrophy in the digestive tract through intravenous nutrition or parenteral nutrition or elemental diet, disease caused by resection and deviation of the small intestine such as the syndrome short bowel syndrome, impasse syndrome, and indigestible malabsorption syndrome, such as the disease caused by the resection of the stomach, for example, discharge syndrome. The term "therapeutic agent for diseases of the digestive tract" as used herein means that agents for the prevention and treatment of diseases of the digestive tract, including for example, the therapeutic agent for the ulcer of the digestive tract, the therapeutic agent for tract disease inflammatory digestive, the therapeutic agent for atrophy of the mucosa in the digestive tract, therapeutic agents for wounds of the digestive tract, enhancing agent for the function of the digestive tract including the agent for the recovery of mucosal barrier function, and the improvement agent for the digestive and absorbent function. Ulcers include digestive ulcers and corrosions, and acute ulcers, namely acute mucosal lesions. The method in question, because it promotes the proliferation of intestinal mucosa, can be used in the treatment and prevention of pathological conditions of insufficiency in digestion and absorption, that is, the treatment and prevention of mucosal atrophy, or treatment of hypoplasia of the tissues of the digestive tract and decrease in these tissues through surgical removal as well as the improvement of digestion and absorption. In addition, the method in question can be used in the treatment of pathological mucosal conditions due to inflammatory diseases such as enteritis, Crohn's disease, and ulcerative colitis and also in the treatment that reduces the function of the digestive tract after an operation, for example, in the reduction of the syndrome as well as in the treatment of duodenal ulcer together with the inhibition of peristalsis of the stomach and rapid migration of food from the stomach to the jejunum. In addition, glicentin can be used to effectively promote the healing of a surgical invasion as well as to improve the notions of the digestive tract. Thus, the present invention also provides a therapeutic agent for the atrophy of the mucosa of the digestive tract, a therapeutic agent for wounds in the digestive tract and a drug for improving the functions of the digestive tract, comprising glycintin as active ingredients. Likewise, the compounds of the subject invention can be used to alter the plasma half-life of secretin, VIP, Fl, PACAP, GIP, and / or helodermin. Additionally, the method in question can be used to alter the pharmacokinetics of the peptide YY and neuropeptides Y, both members of the pancreatic polypeptide family, when the DPIV has been involved in the processing of those peptides in a manner that alters the selectivity of the receptor. It is believed that neuropeptides Y (NPY) act in the regulation of vascular smooth muscle tone, as well as in the regulation of blood pressure. NPY also decreases cardiac contractility. NPY is also the most powerful appetite stimulant known (Wilding et al., J. "Endocrinology 1992, 132, 299 302).

Centrally evoked food sucking (appetite stimulation) is predominantly mediated by NPY Yl receptors and causes an increase in body fat stores and obesity (Stanley et al, Physiology and Behavior 1989, 46, 173-177). According to the present invention, a method for the treatment of anorexia comprises administering to a host subject an effective amount of a compound (s) to stimulate the appetite and increase the stores of body fat which consequently substantially alleviates the symptoms of the anorexy . A method for the treatment of hypotension comprises administering to an host subject an effective amount of a compound (s) of the present invention to mediate vasoconstriction and increase blood pressure which therefore substantially alleviates the symptoms of hypotension. DPIV has also been implicated in the metabolism and deactivation of the growth hormone releasing factor (GHRF). GHRF is a member of the family of homologous peptides that includes glucagon, secretma, vasoactive intestinal peptide (VIP), peptide histidine ísoleucma (Fl), peptides that activate the pituitary adenylate cyclase (PACAP), the peptide Gastric inhibitor (GIP) and heloderma (Kubiak et al.

Res of Peptides 1994, 7, 153). GHRF is secreted by the hypothalamus, and stimulates the release of growth hormone (GH) from the anterior pituitary. Thus, the method in question can be used to improve clinical therapy for certain children deficient in growth hormone, and in clinical therapy of adults to improve nutrition and alter the composition of the body (muscle vs. fat). The method in question also it can be used in veterinary practice, for example, to develop cattle with the production of higher yielding milk and with less fat (iv). Assays of Insulmotrophic Activity In selecting a compound suitable for use in the method in question, it is noted that the msulmotrophic property of a compound can be determined by providing that compound to the animal cells, or by injecting that compound into the animals and monitoring the release of immunoreactive insulin. (IRI) in the medium or circulatory system of the animal, respectively The presence of IRI can be discovered through the use of a radiommunoassay that can specifically detect insulin The db / db mouse is a genetically obese and diabetic strain of mouse The mouse db / db develops hyperglycemia and hypermsulinemia concomitant with its development obesity and therefore, it serves as a model of obese type 2 diabetes (NIDDM). The db / db mice can be purchased from, for example, The Jackson Laboratories (Bar Harbor, Me.). In an exemplary embodiment, for the treatment of mice with a regimen that includes a compound (s) or control, blood samples from the subaltern-orbital sinus are taken before and at some time (eg, 60 mm) after dosing to each animal. Blood glucose measurements can be made by any of several conventional techniques, such as using a glucose meter. The blood glucose levels of the control and compound (s) dosed in animals are compared. The metabolic fate of exogenous GLP-1 can also be followed in both subjects with type II or non-diabetic diabetes, and the effect of a given candidate compound (s). For example, a combination of high pressure liquid chromatography (HPLC), specific radioimmunoassays (RIAs), and an enzyme-linked immunosorbent assay (ELISA), can be used, by means of which intact biologically active GLP-1 can be detected and its metabolites. See, for example, Deacon et al., Diabetes, 1995, 44, 1126-1131. To illustrate, after administration of GLP-1, intact peptides can be measured using an RIA directed to the NH2-thermodynamic or ELISA, while the difference in concentration between these assays and a specific COOH-terminal RIA allowed the determination of truncated NH2-terminal metabolites. Without the compound, hypodermic GLP-1 degrades rapidly in a time-dependent manner, forming a metabolite that co-elutes in HPLC with the GLP-1 amide (9-36) and has the same immunoreactive profile. For example, 30 minutes after the hypodermic administration of GLP-1 to diabetic patients (n = 8), the metabolite represents 88.5 + 1.9% of the increase in plasma immunoreactivity determined by the COOH-terminal RIA that was higher than the measured levels in healthy subjects (78.4 + 3.2%, n = 8, P <0.05). See Deacon et al., Supra. The GLP-1 mfundida intravenously was also extensively degraded. (v) Joint administration. Another aspect of the invention provides a joint therapy, wherein one or more other therapeutic agents are administered with the compound. Such joint treatment can be achieved by means of the simultaneous, sequential, or separate dosing of the individual components of the treatment. In one embodiment, a compound (s) is administered concomitantly with insulin or other msulinotropic agents, such as GLP-1, peptide hormones, such as GLP-2, GIP, or NPY, or a gene therapy vector that causes the ectopic expression of agents and hormones Peptide In certain embodiments, said peptide hormone agents or agents may be naturally occurring or synthetic variants of a peptide hormone, wherein one or more amino acids have been added, deleted, or substituted. In another illustrative embodiment, the compounds may be administered together with an Ml receptor antagonist. The cholinergic agents are powerful insulin-releasing modulators that act via muscarinic receptors. On the other hand, the use of such agents may have the added benefit of lowering cholesterol levels, increasing HDL levels . Suitable muscarinic receptor antagonists include substances that directly or indirectly block the activation of muscarinic cholinergic receptors. Preferably, such substances are selective (or are used in amounts that promote such selectivity) for the Ml receptor. Non-limiting examples include quaternary amines (such as metantemma, ípratropio, and propantelma), tertiary amines (eg, dicyclomine and scopolamma), and tricyclic amines (eg, telenzepma) Pirenzepma and methyl scopolamine are preferred. Other suitable muscarmyl receptor antagonists include benztropma (commercially available as COGENTIN from Merck), hexahydro-silane diphenidol hydrochloride (HHSID hydrochloride described in Lambrecht et al Trends m Pharmacol. Sci. 1989, 10 (Suppl), 60; (+/-) -3-quinuclidyl xanthene-9-carboxylate hemioxalate (QNX-hemioxalate; Birdsall et al., Trends m Pharmacol, Sci 1983, 4, 459; Telenzepma dihydrochloride (Coruzzi et al., Arch. Int. Pharmacodyn, Ther, 1989, 302, 232, and Ka ashima et al, Gen. Pharmacol, 1990, 21, 17), and atropine The dosages of such muscarinic receptor antagonists will generally be in question of the optimization outlined above. In the case of disorders of lipid metabolism, dosage optimization may be necessary regardless of whether the administration is timed with respect to the sensitivity window of lipid metabolism or not. Insulin and lipid metabolism, the above disorders, the compound (s) can also act chemically with prolactone inhibitors such as dopamma d2 agonists (for example, bromocpptma). The ion may include the co-administration of such prolactone inhibitors as ergo alkaloids that inhibit prolactm and dopamma agonists that inhibit prolactm. Examples of suitable compounds include 2-bromo-alpha-ergocpptma, 6-met? L-8-beta-carbobenc? Lox? Ammoet? L-10-alpha-ergolma, 8- acylammothernergy, 6-met? l-8-alpha- (N-acyl) ammo-9-ergolma, 6-met? l-8-alpha- (N-phenylacetyl) ammo-9-ergolma, ergocornma, 9, 10- d? h? drergocornma, ergolmas D-2-halo-6-alk? l-8-sust? tu? do, D-2-bromo-6-methyl-8-cyanomethylergolm, carbidopa, benserazide, and other dopadecarboxylase inhibitors , L-dopa, dopamma, and toxic salts thereof. The compound (s) used according to the invention can also be used in conjunction with agents that act on the ATP-dependent potassium channel of the β-cells, such as glibenclamide, glipizide, gliclazide, and AG-EE 623 ZW. compound (s) can also be advantageously applied in combination with other oral agents such as metformas and related compounds or glucosidase inhibitors such as, for example, acarbose. (saw ) . Hematopoietic agonists. In another aspect, the present invention provides a method for stimulating hematopoietic cells in culture or live m. In certain embodiments, the DPP IV pro-inhibitors include a targeting portion that is a substrate for a protease that is expressed in the bone marrow. In accordance with one aspect of the invention, a method is provided for stimulating the hematopoietic cells m vitro . The method involves (1) putting in contacting the hematopoietic cells with a sufficient amount of a DPP IV pro-inhibitor to increase the number of hematopoietic cells and / or the differentiation of such hematopoietic cells relative to the number and differentiation of hematopoietic cells An important aspect of the invention involves restoring or preventing a deficiency in hematopoietic cell number in a subject Such deficiencies may arise, for example, from genetic, disease, strain, or chemotherapy abnormalities (eg, from the treatment of cytotoxic drugs, treatment of spheroidal drugs, treatment of immunosuppressive drugs, etc.,) and radiation treatment. The inhibitors of the invention can be administered alone, or in combination with additional agents to treat the condition, for example, a different agent that stimulates the activation or proliferation of said lymphocytes or hematopoietic cells. For example, proinhibitors may be administered in conjunction with the exogenous growth factors and cytokines that are selected to achieve a particular result specifically. For example, if it was desired to stimulate a particular hematopoietic cell type, then the growth factors and cytokines that stimulate the proliferation and differentiation of such a cell type are used.

Thus, it is known that micleukems-1, 2,3, 4,5, 6,7, 9,10, 11,12, 13, and 17 are involved in the differentiation of the lmfocito. Metaleukins 3 and 4 are involved in the differentiation of mastoid cells. The factor that stimulates the Colony of Granulocyte Macrophages (GMCSF), Mterleucma-3 and Interleukin-5 are involved in the differentiation of the eosmophile. GMCSF, a factor that stimulates the Colony of Macrophages (MCSF) and IL-3 are involved in the differentiation of the macrophage. The GMCSF, GCSF and IL-3 are involved in neutrophil differentiation. GMSCF, IL-3, IL-6, IL-11 and TPO are involved in the differentiation of the platelet. The ligand Flt3 is involved in dendritic cell growth. The GMCSF, IL-3, and the eptropoietma are involved in erythrocyte differentiation. Finally, the self-renewal of primitive pluripotent progenitor cells capable of sustaining hematopoiesis requires SCF, ligand Flt3, G-CSF, IL-3, IL-6 and IL-11. Various combinations to achieve a desired result will be clear by those of ordinary skill in the art. (vn) Proteasome inhibitors. In other modalities, pro-soft inhibitors produce portions of the inhibitor that are inhibitors of potent and highly selective proteasome and can be used to inhibit proteasome function. Inhibition of proteasome function has a variety of practical and prophylactic therapeutic applications. However, because the proteasome is ubiquitous to living cells, there is a desire to provide embodiments of the inhibitor in question that releases a proteasome inhibitor using a targeting portion that unfolds to or in proximity to the projected target cells. . For example, embodiments of proteasome inhibitors may include targeting portions that are substrates for proteases that are expressed in tumors or other cells that undergo undesired proliferation, or expressed in the tissue surrounding the tumor or other proliferating cells. objective. For example, the targeting portion can be a substrate for a protease expressed in the stromal layer adjacent to a tumor. In certain embodiments, the proteasome inhibitors of the present invention provide a method for reducing the rate of degradation of p53 and other tumor suppressors. Such inhibitors are contemplated because they have an important practical application in the treatment of diseases in which cells proliferate, such as cancer, restenosis and psoriasis.

In certain embodiments, proteasome inhibitors may be used to inhibit the process of cellular mternalization or viral antigens in antigenic peptides that bind to MHC molecules in an animal, and which, therefore, are useful for treating autoimmune diseases by preventing tissue rejection. Finally, the present invention relates to the use of proteasome inhibitors to treat specific conditions in animals that are mediated or exacerbated, directly or indirectly, by the functions of the proteasome. These conditions include inflammatory, such as tissue rejection, organ rejection, arthritis, infection, dermatoses, inflammatory bowel disease, asthma, osteoporosis, osteoarthritis and autoimmune diseases such as lupus and multiple sclerosis; proliferative diseases such as cancer, psoriasis and restenosis; and rupture of accelerated muscle proteins that accompanies various physiological and pathological states and responsible for a large scale for the loss of muscle mass (atrophy) following nerve injury, fasting, fever, acidosis, and certain endocpnopathies. of the present invention inhibit the growth of cancer cells. Thus, the compounds they can be used to treat cancer, psoriasis, restenosis or other cell proliferative diseases in a patient who needs them. By the term "cancer treatment" or "treating cancer" is meant the description of an activity of compounds of the present invention, wherein said activity prevents or alleviates or ameliorates any of the specific phenomena known in the art normally associated with the pathology. known as "cancer." The term "cancer" refers to the spectrum of pathological symptoms associated with the initiation or progression, as well as the metastasis, of malignant tumors. By the term "tumor" is meant, for the purpose of the present invention, a new tissue growth in which the multiplication of cells is unrestrained and progressive. The tumor that is particularly relevant to the invention is the malignant tumor, one in which the primary tumor has invasion or metastasis properties or which shows a higher degree of anaplasia in binding of benign tumors. Thus, "cancer treatment" or "treating cancer" refers to an activity that prevents, alleviates or ameliorates any of the primary phenomena (initiation, progression, metastasis) or secondary symptoms associated with the disease. Cancers that are treatable are widely divided into the carcinoma categories, lmfoma and sarcoma. Examples of carcinomas that can be treated by the composition of the present invention include, but are not limited to: adenocarcinoma, adenocarcinoma of acinic cells, cortical adrenal carcinomas, alveoli cell carcinoma, anaplastic carcinoma, basal cell carcinoma, basal cell carcinoma, carcinoma bronchiolar carcinoma, bronchogenic carcinoma, renaladmol carcinoma, embryonal carcinoma, anometroid carcinoma, fibrolamolar liver cell carcinoma, follicular carcinomas, giant cell carcinomas, hepatocellular carcinoma, mtraepidermal carcinoma, metaepithelial carcinoma, lepomancer carcinoma, medullary carcinoma, melanotic carcinoma, menigual carcinoma, Mesometonephric carcinoma, oat cell carcinoma, squamal cell carcinoma, sweat gland carcinoma, transitional cell carcinoma, and tubular cell carcinoma. Sarcomas that can be treated by the composition of the present invention include, but are not limited to: ameloioblastic sarcoma, angiolitic sarcoma, botpoid sarcoma, endometrial stromal sarcoma, E mg sarcoma, fascicular sarcoma, giant cell sarcoma, granulositic sarcoma, Myoblastic sarcoma, Juxcordial osteogenic sarcoma, Copex sarcoma, Leukocytic sarcoma (leukemia), Lymphatic sarcoma (Lymphoma sarcoma), Medullary sarcoma, Myeloid sarcoma (granulocytic sarcoma), austiogenic sarcoma, periosteal cell sarcoma reticulum sarcoma (histiocytic lymphoma), round cell sarcoma, needle cell sarcoma, smovial sarcoma, and telangiectatic audiogenic sarcoma. The tumors that can be treated by the composition of the present invention include, but are not limited to: Hodgkm's disease and lymphocytic lymphocytes, such as Burkitt's lmfoma, NPDL, NML, NH and diffuse lympholas. In other embodiments, certain proteasome inhibitors employed in the practice of the present invention are capable of preventing this activation of NF-kB.

The blocking of NF-kB activity is contemplated by having the important practical application in various areas of medicine, for example, inflammation, sepsis, AIDS and the like. In certain embodiments, the compounds of the present invention can be formulated in the topical form for the treatment of skin disorders selected from psoriasis, dermatitis, lichen planus, acne, and disorders marked by hyperproliferation of superficial cells. In certain embodiments, the compounds of the present invention may be formulated in the topical form for the treatment of rampant hair growth. (vm) Pharmaceutical Compositions Although it is possible for a compound of the present invention to be administered alone, in certain cases it is preferable to administer the compound as a pharmaceutical formulation (composition). The protease inhibitors according to the invention can be formulated for administration in any convenient form for use in human or veterinary medicine. In certain embodiments, the compound included in the pharmaceutical preparation can be active, or it can be a prodrug, for example, capable of being converted to an active compound in a physiological environment. The compounds prepared as described herein, can be administered in several ways. forms, depending on the disorder to be treated and the age, condition, and body weight of the patient, as is well known in the art. For example, when the compounds are administered orally, they can be formulated as tablets, capsules, granules, powders, or syrups; or for parenteral administration, injections (intravenous, intramuscular, or hypodermic), drop infusion preparations, or suppositories can be formulated. For application via an ophthalmic mucous membrane route, they can be formulated as eye drops or ointments. These formulations can be prepared by conventional media, and, if desired, the active ingredient can be mixed with any conventional additive, such as an excipient, a binder, a disintegrating agent, a lubricant, a concealer, solubilizing agent, suspension aids, emulsifying agent, or a coating agent Although the dosage will vary, depending on the symptoms, age and body weight of the patient, the nature and severity of the disorder to be treated or prevention, route of administration and the form of the drugs, it is generally recommended, a daily dosage of from 0 01 to 2000 mg of the compound for an adult human patient, this can be administered in a single dose or in divided doses The precise time of administration and / or amount of the compound that will yield the most effective results in terms of treatment efficacy in a given patient will depend on the activity, pharmacokinetics, and bioavailability of a compound particular physiological condition of the patient (including age, sex, type of illness and condition, general physical condition, sensitivity to a given dosage, and type of medication), route of administration, etc. However, the above guidelines can be used as a basis for a good determination of the treatment, for example, to determine the optimal time and / or amount of administration that it will require no more routine experimentation that consists in supervising the subject and adjusting the dosage and / or time. The phrase "pharmaceutically acceptable" is used herein to refer to those ligands, materials, compositions, and / or dosage forms that are, within the scope of legitimate medical judgment, convenient for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problem or complication, corresponding to a reasonable benefit / risk ratio. The phrase "pharmaceutically acceptable carrier" as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulated material. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials that can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talcum powder; (8) excipients, such as cocoa butter and wax suppositories; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycepne, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) damping agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic solution; (18) Rmger solution, (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations. In certain embodiments, the pharmaceutical compositions of the present invention are non-pyrogenic, that is, they do not induce significant temperature elevations when administered to a patient. The term "pharmaceutically acceptable salts" refers to the relatively non-toxic organic and inorganic acid addition salts of the compounds. These salts can be prepared in situ during the final isolation and purification of the compound (s), or by reacting a separately purified compound (s) in its free base form with an organic or inorganic acid. convenient, and isolating the salt thus formed. Representative salts include the bromohydrate, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, valerylate, oleate, palmitate, stearate, laurate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succmate, tartrate, naphthylate, mesylate. , glucoheptonate, lactobionate, and lauryl sulfonate salts, and the like. (See, for example, Berge et al., J. Farm, Sci. 1977, 66, 1-19) In other instances, the compounds useful in the methods of the present invention may contain one or more acid functional groups and, therefore, both, capable of forming pharmaceutically acceptable salts with pharmaceutically acceptable bases. The term "pharmaceutically acceptable salts" in these examples refers to relatively non-toxic organic and inorganic acid addition salts of a compound (s). These salts can also be prepared in situ during the last isolation and purification of the compound (s), or by reactively reacting the purified compounds in their free acid form with a suitable base, such as hydroxide, carbonate, or bicarbonate. pharmaceutically acceptable metal cation, with ammonia, or with a pharmaceutically acceptable primary, secondary or tertiary amine The representative alkaline or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts and the like. Representative organic amines useful for the formation of base addition salts include ethylamma, diethylamine, ethylenediamma, ethanolamma, diethanolamma, piperacma, and the like (see, for example, Berge et al, supra) Wetting agents, emulsifiers, and lubricants, such as such as sodium laupl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, sabotics, and perfume agents, preservatives and antioxidants may also be present in the compositions. Examples of pharmaceutically acceptable antioxidants include: 1) water-soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium pyrosulfite, sodium sulfite, and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamma tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.

Formulations useful in the methods of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal, aerosol, and / or parenteral administration. The formulations may conveniently be presented in the form of unit dosage and can be prepared well by any method known in the art of pharmacy. The amount of active ingredients that can be combined with a carrier material to produce a single dosage form will vary, depending on the host to be treated and the particular mode of administration. The amount of the active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, out of 100%, this amount will range from about 1% to about 99% active ingredient, preferably from about 5% to about 70%, more preferably from about 10% to about 30%. Methods for preparing these formulations or compositions include the step of combining them in association with a compound (s) with the carrier and, optionally, one or more additional ingredients. In general, the formulations are prepared uniformly and they relate intimately in association to a ligand with the liquid carriers, or the finely divided solid carriers, or both, and then, if necessary, form the product. Formulations suitable for oral administration may be in the form of capsules, capsule seals, pills, tablets, dragees (using a seasoned base, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or suspension in an aqueous or non-aqueous liquid emulsion, or as a liquid emulsion of oil in water or water in oil, or as an elixir or syrup, or as pellets (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and / or as rinses, and the like, which contain a predetermined amount of a compound (s) as an active ingredient. A compound can also be administered as a bolus, electuary or paste. In solid dosage forms for oral administration (capsules, tablets, pills, dragees, powders, granules, and the like), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate and / or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and / or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and / or acacia; (3) Wetting agents, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) agents that retard the solution, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds; (7) wetting agents, such as, for example, acetyl alcohol and glyceryl monostearate; (8) absorbers, such as kaolin and bentonite clay; (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauric sulfate, and mixtures thereof; and (10) coloring agents. In the case of capsules, tablets and pills, the pharmaceutical compositions may also comprise buffering agents. Solid compositions of a similar type may also be employed as fillings in soft gelatin capsules and hard fillings using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols, and the like. A tablet can be made by compression or molding, optionally with one or more of the additional ingredients. Compressed tablets can be prepared using binders (e.g., gelatin or hydroxypropylmethyl cellulose), lubricants, inert diluents, preservatives, disintegrants (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), dispersing or surface-active agent. The molded tablets can be made by molding in a suitable machine with a mixture of powdered peptides or peptidomimetics moistened with an inert liquid diluent. Tablets and other solid dosage forms such as dragees, capsules, pills, and granules, can be registered or can optionally be prepared with coatings and shells, such as enteric layers and other layers well known in the art of pharmaceutical formulation. These may also be formulated to provide a controlled or slow release of the active ingredient that is used, for example, hydroxypropylmethyl cellulose in varying proportions to provide the profile of the desired release, other polymer matrices, liposomes, and / or microspheres. These may be sterilized for example, by filtration through a filter that retains bacteria, or sterilization agents incorporated in the form of sterile solid compositions that can be dissolved in sterile water, or some other sterile injectable medium immediately before use. These compositions may also contain optionally opacifying agents and which can be of a composition that they release only the active ingredients, or preferably, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner. Examples of included compositions that can be used include polymeric substances and waxes. The active ingredient may also be in the micro-encapsulated form, if appropriate, with one or more excipients described above. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may typically contain inert diluents used in the art, such as, for example, water or other solvents, solubilizing agents, emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, alcohol. benzyl, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean, and sesame oil), glycerol, tetrahydrofuryl alcohol, glycols of polyethylene, and fatty acid esters of sorbitan, and mixtures thereof.

In addition to the inert diluents, the oral compositions may also include adjuvants such as wetting agents, suspending agents, sweeteners, seasonings, dyes, perfumes and preservatives. The suspensions, in addition to the active compounds may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, cellulose metahydroxide, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. thereof. Formulations for rectal or vaginal administration can be presented as suppositories, which can be prepared by mixing one or more compound (s) with one or more suitable non-irritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a wax suppository or a salicylate which are in solid form at room temperature, but which are in liquid form at body temperature and which will therefore melt in the rectum or vaginal cavity and release the active agent. Formulations that are also suitable for vaginal administration also include louses, buffers, creams, gels, pastes, foams, or formulations of dew containing such carriers that are known in the art for what they are appropriate. Dosage forms for transdermal or topical administration of a compound (s) include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active component can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservative, buffer or propellants that may be required. Ointments, pastes, creams, and gels may contain, in addition to the compound (s), excipients, such as animal fats and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites. , silicic acid, talc, and zinc oxide, or mixtures thereof.

The powders and sprays may contain, in addition to a compound (s), excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powders, or mixtures of these substances. Sprays may additionally contain common propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane. The compound (s) can be administered alternatively by aerosol. This is done by preparing an aqueous aerosol, liposomal preparation, or solid particles that they contain the compound. A non-aqueous suspension (e.g., fluorocarbon propellant) could be used. Sonic nebulizers are preferred because they minimize the exposure of the agent to the cut, which can result in degradation of the compound. Ordinarily, an aqueous aerosol is made by formulating an aqueous solution or suspension of the agent together with conventional pharmaceutically acceptable carriers and stabilizers. Carriers and stabilizers vary with the requirements of the particular compound, but typically include nonionic surfactants (Tweens, Pluronics, or polyethylene glycol, harmless proteins such as serum albumin, sorbitan esters, oleinic acid, lecithin, amino acids such as glycine, solutions buffers, salts, sugars, or sugar alcohols Aerosols are usually prepared from isotonic solutions Medications that can be administered in inhalants or aerosol formulations according to the invention include protease inhibitor prodrugs useful in inhalation therapy which can be present in a form that is soluble or substantially soluble in the selected propellant system The particle size of the particulate medicament must be such as to allow inhalation of substantially all of the medication in the lungs after administration of the aerosol formulation will desirably be less than 20 microns, preferably in the range of 1 to 10 microns, eg, 1 to 5 microns. The size of the medicament particles can be reduced by conventional means, for example, by grinding or micronization. Administration of the drug may be indicated for the treatment of mild acute or chronic symptoms, moderate or severe or for prophylactic treatment. It will be appreciated that the precise dose administered will depend on the age and condition of the patient, the particular particulate medication used and the frequency of administration will ultimately be at the discretion of the attending physician. When combinations of drugs use the dose of each component of the combination, it will generally be used for each component when used alone. Typically, the administration may be one or more times, for example 1 to 8 times per day, providing for example, 1, 2, 3 or 4 breaths each time. Preferably, the administration may be once a day. For administration, the drug is suitably inhaled from a nebulizer, from an inhaler with a pre-measured dose, or as a dry powder from an inhaler for dry powders (eg, sold as TURBUHALER®) or a dry powder inhaler that uses gelatin, plastic or other capsules, cartridges or ampoules. A diluent or carrier, generally non-toxic and chemically inert to the medicament; for example, lactose, dextran, mamthol, glucose or any additive that will give a desired flavor to the medicament, can be added to the powdered medicament. The micronized mixture can be suspended or dissolved in a liquid propellant mixture which is stored in a container which is sealed with a metering valve and fixed to the plastic actuator. The used propellants can be halocarbons of different chemical formula. The frequently used halocarbon propellants are trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethane, tetrafluoroethane, and 1,1-difluoroethane. Low concentrations of a surfactant such as sorbitan trioleate, lecithin, disodium dioctyl sulfosuccinate, or oleinic acid can also be used to improve physical stability. Transdermal patches have the added advantage of providing a controlled supply of a compound (s) to the body. Such dosage forms can be made by dissolving or dispersing the agent in the appropriate medium. Enhancers can also be used to increase the flow of the compound (s) through the skin. The proportion of such a flow can be controlled by providing a membrane that controls the proportion or dispersing the peptidomimetic in a matrix of the polymer or gel. Ophthalmic formulations, ointments for odors, powders, solutions, and the like, are also contemplated to be within the scope of this invention. The pharmaceutical compositions of this invention suitable for parenteral administration comprise one or more compounds (s) in combination with one or more pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, or sterile powders that can simply be reconstituted into solutions sterile injectables or prior-use dispersions which may contain antioxidants, buffers, bacteriostats, solutes which deliver the isotonic formulation with the blood of the projected container or suspending or thickening agents. Examples of suitable aqueous and non-aqueous carriers which may be employed in the pharmaceutical compositions of the invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol and the like), and suitable mixtures thereof, vegetable oils, oils such as olive oil, and injectable organic esters, such as ethyl oleate. The proper fluency can to be maintained, for example, by the use of coating materials, such as lecithin, by maintaining the size of the particles required in the case of dispersions, and by the use of surfactants. These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial agents and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable pharmaceutical form can be caused by the inclusion of agents that delay absorption such as aluminum monostearate and gelatin. In some cases, to prolong the effect of a drug, it is desirable to delay the absorption of the drugs from the hypodermic or intramuscular injection. This can be achieved by the use of a liquid suspension of crystalline material or amorphous material that have poor water solubility. The rate of absorption of the drug then depends on its proportion of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a The drug administered parenterally is carried out by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made from microencapsulation matrices of compound (s) in biodegradable polymers such as polylactide-polyglycolide. Depending on the proportion of drugs for the polymer, and the nature of the particular polymers employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissue.

When the compounds (s) of the present invention are administered as pharmaceuticals to humans and animals, these may be given per se or as a pharmaceutical composition, for example, 0.1 to 99.5% (more preferably, 0.5 to 90%) of active ingredient. in combination with a pharmaceutically acceptable carrier. The agent preparations can be given orally, parenterally, topically, or rectally. These are taken of course by means of convenient forms for each administration route. For example, these are administered in tablets or in the form of capsules, by injection, inhalation, eye lotions, ointments, suppositories, infusion; topical lotion or ointment; and rectally by suppositories. Oral administration is preferred. The phrases "parenteral administration" and "parenterally administered" as used herein means modes of administration other than enteral and topical administration, usually by injection, and include, without limitation, intravenous, intramuscular, intraarterial, tratacal, intracapsular, metatrabital , mtracardiaca, mtradermal, mtraperitoneal, transtracheal, hypodermic, subcuticular, mtraarticular, subcapsular, subarachnoid, traspmal and mtrasternal injection, and infusion. The phrases "systemic administration," "systemically administered" "peripheral administration" and "peripherally administered" as used herein means administration of a ligand, drugs, or other material other than the central nervous system, such that it enters the patient's system and therefore, is related to metabolism and other processes, for example, hypodermic administration. These compounds (s) can be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as for example, by dew, rectally, mtravagmally, parenterally, tranceternally and topically, as powders, ointments or drops, which include buccally and sublmgually. The addition of the active compound of the invention to the animal feed is preferably carried out by preparing a premix of the appropriate feed containing the active compound in an effective amount and incorporating the premix in the complete proportion. Alternatively, an intermediate concentrate or food supplement containing the active ingredient may be mixed in the food. The manner in which mixtures of ready-mix and complete proportions can be prepared and administered is described in reference books (such as Applied Animal Nutrition; San Francisco: Freedman, 1969; or Livestock Feeds and Feeding; Corvallis: O S B Books, 1977). Without taking into account the selected route of administration, the compound (s) that can be used in a convenient hydrated form and / or the pharmaceutical compositions of the present invention, is formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of ability In the art The current dosage levels of the active ingredients in the pharmaceutical compositions of this invention may vary to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. (? x) Pharmaceutical packages and Manufacturing. One aspect of the present invention provides a packaged pharmaceutical comprising one or more inhibitors of the present invention, formulated in a pharmaceutically acceptable excipient, in association with the instructions (written and / or pictorial) describing the recommended dosage and / or administration of the formulation to a patient. Such instructions may include details for treating or preventing diseases, and optionally, warnings of possible side effects and drug-drugs or drug-food interactions. Another aspect of the invention relates to the use of the inhibitors in question in the manufacture of a medicament for the treatment of a disorder for which the inhibition of the target protease of the inhibitory G portion provides a therapeutic benefit to a patient. Exemplary disorders are listed below. Yet another aspect of the invention relates to a method for running a pharmaceutical business that includes: to manufacture one or more of the inhibitors in question; and b. To market to health care providers, the benefits of using the preparation to treat or prevent any of the diseases or indications cited herein. In certain modalities, the commercial method in question may include providing a distribution network for the sale of the preparation. This may include providing the instructional material to patients or physicians to use the preparation to treat and prevent any of the diseases or indications cited herein. (x) Combinatorial Collections. The compounds of the present invention, particularly collections of variants having several representative classes of substituents, are treatable for combinatorial chemistry and other parallel synthesis schemes (see, for example, PCT WO 94/08051). The result is that large collections of related compounds, for example, a variegated collection of compounds represented above, can be rapidly separated by exclusion in high throughput assays to identify compounds that lead to the potential protease inhibitor, as well as to refine the specificity, toxicity, and / or cytotoxic-cmético profile of a main compound. Simply as an illustration, a combinatorial collection for the purposes of the present invention is a mixture of chemically related compounds that can be excluded by exclusion together for a desired property. The preparation of many related compounds in a single reaction greatly reduces and simplifies the number of exclusion separation processes that need to be carried out. The separation by exclusion for the appropriate physical properties can be done by conventional methods. The diversity in the collection can be created in a variety of different levels. For example, the aryl groups of the substrate used in the combinatorial reactions may be diverse in terms of the aryl portion of the core, for example, a variegation in term of the ring structure, and / or may be varied with respect to others. substituents A variety of techniques are available in the art to generate combinatorial collections of small organic molecules such as the protease inhibitors in question. See for example, Blondelle et al. Anal Trends Chem 1995, 14, 83; US patents 5,359,115 and 5,362,899 of Affymax: patent of E.U.A. 5,288,514 of Ellman: PCT publication WO 94/08051 of Still et al .; US patents 5,736,412 and 5,712,171 of ArQule; Chen et al. J. Am. Chem. Soc. 1994, 116, 2661: Kerr et al. J. Am. Chem. Soc. 1993, 115, 252; PCT publications WO92 / 10092, WO93 / 09668 and WO91 / 07087; and PCT publication WO93 / 20242) of Lerner et al. Accordingly, a variety of collections in the order of about 100 to 1,000,000 or more diversomers of the protease inhibitors in question can be synthesized and can be protected for a particular activity or property. In an exemplary embodiment, a collection of candidate protease inhibitor diversity can be synthesized using a scheme adapted to the techniques described in PCT publication WO 94/08051 by Still et al., Which is linked to a polymer count by a hydrolysable group or photolyzable, optionally located in one of the positions of the candidate agonists or a substituent of a synthetic intermediate. According to the Still et al technique, the collection is synthesized in a set of accounts, each account includes a set of labels that identify the particular diver in that account. The collection of the count can then be "placed" with proteases for which an inhibitor is required. The diversomers can be released from the bill, for example, by hydrolysis.

The structures of the compounds useful in the present invention easily lead to efficient synthesis. The nature of the structures of the compounds in question, as generally stated above, allows the rapid combinatorial pooling of such compounds. For example, as in the scheme set forth below, an activated aryl group, such as a triflolate of aplo or bromide, attached to an account or other solid support can be linked to another group by performing a Stille or Suzuki coupling with a stannous aplo or a boronic acid of aryl. If the second aryl group is functionalized with an aldehyde, an amine substituent can be added through a reductive animation. Alternatively, the second aplo group could be functionalized with a starting group, such as a phthalate, tosylate, or halide, capable of being relocated to an amine. Or, the second aplo group can be functionalized with an amine group capable of undergoing reductive animation with an amine, for example, CyKNH2. Other possible coupling techniques include the reactions of amines mediated by transition metals. The resulting secondary amines can then be further functionalized by an acylation, alkylation, or arylation to generate an amine or tertiary amide which can then be split from the ream or support. These reactions are usually quite gentle and have been applied successfully in combinatorial solid phase synthesis schemes. In addition, the wide range of substrates and coupling patterns suitable and available for these reactions allows a rapid collection of large, diverse collections of compounds to be tested in the assays as set forth herein. For certain schemes, and for certain substitutions in various substituents of the subject compounds, one skilled in the art recognizes the need to mask certain functional groups with an appropriate protecting group. Such techniques are well known in the art and are easily applied to combinatorial synthesis schemes. d ~ ^ OHCLAr'-SnR, or ^ ~ ^ pe l a OI IC Ar'-B (OÍ-l) -, Pearl \ Ar catalyst - Ar 'Ar - CHO Cy- -NH-, NaBI I ,, pearl pearl R AC Many variations in the previous trajectories and related ones allow the synthesis of widely diverse collections of compounds which can be test as protease inhibitors. Variations, modifications and other implementations of what is described herein will happen to those of ordinary experience without departing from the spirit and scope of the invention. In this way, the invention is not to be limited only to the preceding illustrative description. For additional illustrative features can be used with the invention, including the embodiments described herein, refers to the documents listed herein and incorporated for reference in their entirety. All the operational combinations between the illustrative modalities described and those features described below are considered to be potentially patentable embodiments of the invention. Exemplification The invention is now generally described, it will be more readily understood by reference to the following examples which are included merely for purposes of illustration of certain aspects and embodiments of the present invention, and are not intended to limit the invention. Example 1 General procedure for the synthesis of amino acids containing dipeptide (boron) containing thioxo-amide (Xaa- (C (S)) - (boron) Xaa 'Introduction Initially, a form protected by the B terminal of an amino acid (boron) analog is acylated with an activated form of an amino acid protected by N (u oligopeptide) to give a dipeptide analogue (or oligopeptide) containing protected (boron) amino acid N and protected by B. The N-protected (boron) amino acid analogue and protected by B is then transformed to the corresponding thioxoamide compound using, for example, example, Lawesson reagent.

Finally, the analogue (or dipeptide oligopeptide of (boron) amino acid containing thioxo-amide is deprotected to provide the dipeptide (or oligopeptide) of (boron) amino acid containing thioxo-amide. Application for the preparation of Ala-boroPro (thioxoamide) ida) to a stirred solution of N-Boc-L-Alanine (1.9 g, 10 mmol) and L -boroPro (pn). HCl (2.9 g, 10 mmol) in anhydrous DMF (30 mL) were added HATU (4.0 mg, 10.5 mmol) and N, -diisopropylethylamine (DIPEA, 4.0 mL, 23 mmol) at 0 ° C under argon atmosphere. The cooling bath was stirred and the resulting mixture was stirred at room temperature for 1 hr, and then concentrated m vacuo under 30 ° C. The residue was dissolved in ethyl acetate (100 mL), washed sequentially with KHS0"(0.1 M, 3 x 15 mL), aqueous NaHCO3 (5%, 3 x 10 mL), brine (3 x 10 mL) and dried (MgSO4) and evaporated. The crude product was purified by flash column chromatography on silica gel (1: 1, hexanes / EtOAc) to provide the pure coupling product as a white powder which was added to a stirred suspension of Lawesson's reagent (1.8 g, 4.5 mmol) in anhydrous toluene (100 mL) at room temperature. The resulting mixture was then stirred at 80 ° C for 4 h. After removal of the solvent, the crude product was purified by flash column chromatography on silica gel (2: 1, hexanes / EtOAc) to give N-Boc-Ala -boropro (pn) (thioxoamide) as a white powder. 3.1 g of this thioxoamide (7.1 mmol) was dissolved in anhydrous dichloromethane (40 mL), cooled to -78 ° C, a solution of boron tetrachloride in dichloromethane (35 mL, 1.0 M) was added and stirred for 1 hr. The resulting mixture was evaporated to dryness under reduced pressure and co-evaporated using anhydrous methanol (3 x 15 mL). The residue was then partitioned between water (30 mL) and ether (30 mL). The aqueous phase was separated and washed with ether (2 x 20 mL). The aqueous phase was concentrated in vacuo and then purified by semi-preparative HPLC-RP, lyophilized to provide the target compound Ala -boroPro (thioxoamide) as a white powder. 1 H NMR (D0, pll 2.01, d): 1.51 (d, J = 6.7 Hz, 3H, CH3), 1.83-1.90 (m, 1H, -CH2CHAHBCHB-), 2.08-2.25 (m, 3H, -CH2CHAHBCHB-) , 3.50-3.56 (m, 1H, -CH2CH2CHB-), 3.62-3.69 (m, 1H, -NCH? HHCH2CH2-), 3.92-4.00 (m, 1H, -NCHAHBCH2CH2-), 4.55 (q, J = 6.6 Hz , 1 H, CH 3 CHNH 2 -); 1: LB NMR (D20, pH 2.01, d): 9 5; LC-MS (ESI +) for C7H15BN202S m / z (reite intensity): 369.2 ([2 x (M-H20) + H] +, 21), 203.1 ([M + H] +, 58), 186.1 ([M - NH2] +, 100). HRMS: calc'd for C7H16BN202S, [M + H] "", 203-1026, found 203.1030. Example 2 DPIV Inhibition Assay The inhibitor solution is prepared by dissolving 3-5 mg of inhibitor in pH 2 solution (HCl 0.01 N), such that the concentration of the solution is equal to 1 mg / 10 μ. A 10 μL sample of this solution is then added to 990 μL of buffer solution pH 8 (0 1 M HEPES, 0.14 M NaCl), and the solution was allowed to stand at room temperature overnight. The enzyme solution is prepared by diluting 20 μL of DPIV (2.5 μM concentration) in 40 mL of buffer solution of pH 8. The substrate solution is prepared by dissolving 2.0 mg of L-alanyl-L-prolm-para-nitroanilide in 20 mL of solution pH buffer 8 250 μL of enzyme solution is added to well # B1 to # H1, # A2 to # H2, and # A3 to # H3 of a 96-well plate, while well # A1 receives 250 μL of solution pH 8 buffer instead of enzyme solution. 90 μL of buffer solution pH 8 is then added to column 5 (from well # A5 to # H5). A 1:10 dilution is then made by adding inhibitor solution to # A5 and the solution is mixed well before transferring 10 μL of this solution from # A5 to # B5. The solution in # B5 then mixes well before transferring 10 μL of this solution from # B5 to # C5 The solution in # C5 then mixes well before transferring 10 μL of this solution from # C5 to # D5 . The solution in # D5 is then mixed well before transferring 10 μL of this solution from # D5 to # E5. The solution in # E5 is then mixed well before transferring 10 μL of this solution from # E5 to # F5. The solution in # F5 is then mixed well before transferring 10 μL of this solution from # F5 to # G5. The solution in # G5 is then mixed well before transferring 10 μL of this solution from # G5 to # H5. An aliquot of 30 μL is then transferred from # H5 through # H3 for row H, and the contents mix well. The analogous procedure is repeated for rows G, F, E, D, C, B, and A sequentially. The plate is then stirred on a plate shaker for 5 min before allowing the plate to incubate at room temperature for an additional 5 rain. Once the plate has been allowed to incubate, 30 μL of substrate is added to each well except well # A1. The plate is then placed on a plate shaker for 5 minutes before allowing the plate to incubate at room temperature for 25 mm. The absorbance is then read immediately at a wavelength of 410 nm. EXAMPLE 3 Selectivity for Dipeptidyl Peptidase isoforms The assay described in Example 2 is used to determine the IC50 values for various compounds of the invention. In this example, the assay is conducted for DPIV and DP8 or DP9. The ratio of IC50 values for each compound tested is calculated in order to determine the selectivity of the DPIV isoform. The IC50 values were measured at the same pH throughout the test. Preferred compounds of the invention inhibit DPIV at least 10 times, preferably at least 100 times, greater than that which inhibits DP8 and / or DP9, that is, it has an IC50 at least 10 (or 100) times lower against DPIV than against DP8 and / or DP9.

Example 4 Inhibition DPP IV: Thioxamide v. Oxoamide The inhibitory activity of a compound can be easily tested. DP-IV is purified from pork bark by the method of Barth et al. (Acta Biol. Med. Germ. 32: 157, 1974) and Wolf et al. (Acta Biol. Med. Germ. 37: 409, 1978) and human placenta by the method of Puschel et al. (Eur. J. Biochem. 126: 359, 1982). A compound is then selected for its ability to inhibit DP-IV protease activity with respect to a natural substrate. For example, the activity of DP-IV, isolated from porcine kidneys by the method of Wolf et al. (ACTA Bio, Month: Ger. 37: 409, 1972), was measured using Ala-Pro-p- nitroanilide as a substrate. Briefly, a reaction containing 50 micromol of sodium heppes (pH 7.8), 10 Micromol of Ala-Pro-p-nitroanilide, 6 milliunities of DP-IV, and 2% of (vol / vol) dimethylformamide in a total volume of 1.0 mL. The reaction was initiated by the addition of enzyme and reaction ratios were measured at 25 C; the formation of reaction product (para-nitroanilide) in the present and absence of a test compound can be detected photometrically, for example, at 410 nm.

Inhibitor IC50 (pH IC50 (pH index of 2.0) 8.0) inactivation Ala - 0. 26 nM 1. 4 uM 5, 400 boroPro Exact mass 186 12 b Ti Exact mass 2 fi 07 b Exact mass 1 88 13 Val - "^ - 73 nM 220 nM 3.0 boroAla and thioxamide -, HN.? BH" H N -tf \ ^ OH S ~ Exact mass 04 11 b Exact mass 160 10 b Ti Exact mass 176 08 b Exact mass r i Val - 44 nM 5. 9 uM 130 boroPro Thioxamide P -. H I I. "'Exact mass ¿s' t 13 b Exact mass s > - ' i a b Ti Exact mass: 73 1 Gly- 1 nM 7 uM 7, 000 boroPro H -d Exact futesa i "1¡ Gly- \ 3 nM 1. 9 uM 630 boroPro GJ Thioxamide" - '' lf ^ exact tobsa '86 J8 42 nM 72 nM 1.7 fotase etacta 2 ¿Thioxamide 160 nM 40 uM 250 H: del \ (\. «. Analogous -'-" t 3 II \ c 1 'NVP- HO LAF237 futesa exact? 819 (B b exact futesa .1. I 'J N- d \ 24 nM 170 nM 7.1 (Benzyl) - Gly- [1 boroPro - d A 1 f futesa exact tri i i Thioxamide b Exact futesa _ iO 1 Asp- 17 nM 28 UM 1, 700 boroPro Thioxamide exact futesa 2 ^ C C. b Exact futesa < I b Ti Exact futesa _t > i Aad- > or 4.5 nM 7.4 uM 1, 600 boroPro fute: sa exact 2r > tí 'Aad- -? .. c 1.6 nM 19 uM 12, 000 boroPro Thioxamide "") f \ H N' it '\ _d, | Exact futesa _ "'• 12 b Exact futesa "'iil' f Trp- /" "- 1.6 nM 700 nM 440 boroPro t - Thioxamide HM I 1, / HN ^ { futesa exact 317 M Arg- 1.8 nM 7.1 uM 3,900 boroPro Exact futesa. 't' h Arg- HN .. N H 1,. 2 nM S in N / A boroPro "" T inhibition NH Thioxamide r f 'H N, r? Exact futesa 2 OS 15 Pro- 1. 1 nM 23 uM 21, 000 boroPro M T \ OH M I li 0 l OH C. ' I, .3N O, P mol 212 05 Pro- 6. . 4 nM 7 uM 1, 100 boroPro Thioxamide «II í 3? d "" ~ ~ 'H futesa exact 2¿f? 1 Example 5 Inhibition X-BoroLeu Proteasome: Thioxamide v. Oxoamide The 26S proteasome is the multiple catalytic protease responsible for most of the protein turnover in eukaryotic cells, including proteolytic degradation of damage, oxidation or misfolded proteins, as well as processing or degradation of key regulatory proteins required for several cellular functions (Ciechanover, Cell 79: 13-21 (1994); Coux et al., Ann. Rev. Biochem. 65: 801-847 (1995); Goldberg et al., Chemistry &Biology 2: 503-508 (1995)). Protein substrates are first labeled for degradation by covalent conjugation to multiple molecules of a small protein, ubiquitin. The resulting polyubiquitinated protein is then recognized and degrades by the 26S proteasome. Constructing the catalytic core of the 26S proteasome is proteasone 20S, a multiple subunit complex of approximately 700 kDa molecular weight. Coux et al. (Ann.Rev. Biochem. 65-801-847 (1995)) teaches that the 20S proteasome is not itself degraded ubiquitous proteins, but possesses multiple peptidase peptidase activity. Based on substrate preferences, Coux et al. characterizes these activities as chemotype type, trypsin type, post-glutamyl hydrolase, preferred branched chain amino acid, and preferred small neutral amino acid. Coux et al. it also teaches that a dramatic activation of 20S proteasome activity can be induced by several m vitro treatments, such as heating up to 55 degrees C, incubation with basic polypeptides, sodium dodecyl sulfate (SDS), guanidma HCl or fatty acids, dialysis against water, or by physiological regulators such as PA28 or PA700 McCormack et al. (Biochemistry 37 7792-7800 (1998)) teaches that a variety of peptide substrates, including Suc-Leu-Leu-Val-Tyr-AMC, Z-Leu-Leu-Arg-AMC, and Z-Leu-Leu-Glu - 2NA, where Suc is N-succinyl, AMC is 7 -am? No-4-methylcoumarm, and 2NA is 2-naphthylamine, are cleaved by the 20S proteasome. The trajectory of ubiquitma-proteasome plays a central role in a large number of physiological processes. Deshaies (Trends in Cell Biol. 5: 428-434 (1995)) and Hoyt (Cell 91: 149-151 (1997)) teach that the regulated proteolysis of cell cycle proteins, including cyclos, cymase-dependent cymase inhibitors , and tumor suppressor proteins, it is required for progression of the controlled cell cycle and that the proteolysis of these proteins occurs through the path of ubiquitma-proteasome. Palombella et al., WO 95/25533 teaches that the activation of the transcription factor NF-kappa-B, which plays by itself a central role in the regulation of genes involved in immune and inflammatory responses, is dependent on mediated degradation. by proteasome of an inhibitory protein, Ikappa-B-. alpha .. Goldberg and Rock, WO 94/17816 describes that the continuous replacement of cellular proteins by the ubiquitma-proteasome path plays an essential role in antigen presentation. The inhibition of proteasome activity in this way offers a new promising approach for therapeutic intervention in these and other conditions directly or indirectly mediated by the proteolytic function of the proteasome Goldberg et al. (Chemistry &Biology 2: 503-508 (1995)) teaches that proteasome inhibitors block the inflammatory response m alive in animal models of human disease. The compounds can be selected for their ability to inhibit the ATP-ubiquitme-dependent degradative process by measuring proteolysis in culture cells (Rock et al, Cell, vol 78: 761 (1994)). For example, the degradation of long-lived intracellular proteins can be measured in C2C12 myoblast cells in mice. Cells are incubated with 35S-methasone for 48 hours to label long-lived proteins and then hunt for 2 hours with unlabeled methionine-containing medium. After the hunting period, the cells are incubated for 4 hours in the presence or absence of the test compound. The amount of protein degradation in the cell can be measured by quantifying the soluble radioactivity of trichloroacetic acid that is released from the proteins pre-labeled in the growth medium (m indicator of cellulose proteolysis). The compounds can also be tested for their ability to reduce muscle breakdown m alive. The urinary excretion of the amino acid 3-methyl (3-MH) is probably the most well-characterized method to study the degradation of myofibrillar protein in vivo (see Young and Munro, Federation Proc. 37: 229-2300 (1978)). ). 3 -Methilhistidma is a post-translationally modified amino acid that can not be reused for synthesis of the protein, and it is known that it occurs only in actma and myosin. This occurs in actin isolated from all sources, including cytoplasmic actin of many different cell types. It also occurs in the heavy muscle fiber miosm chain of fast pull (white, type II), but is absent from cardiac muscle miosm and slow muscle pull muscle miosm (red, type I). Due to its presence in actin from other skeletal muscle tissues, other tissues will contribute to urinary 3-MH. Skeletal muscle has been estimated to contribute 38-74% of urinary 3-MH in normal rats and 79-86% of urinary 3-MH in rats treated with corticosterone (100 mg / kg / day subcutaneously) for 2-4 days ( Millward and Bates, Biochem, J. 214: 607-615 (1983), Kayali, et al., Am. J. Physiol. 252: E621-E626 (1987)). High-dose glucocorticoid treatment can be used to induce a state of muscle wasting in rats. Rats treated with daily subcutaneous injections of corticosterone (100 mg / kg) cause an approximately 2-fold increase in urinary 3-MH. The increase in excretion of 3-MH is transient, with a peak increase after 2-4 days of treatment and a return to basal values after 6-7 days of treatment (Odedra, et al., Biochem. : 617-627 (1983); Kayali, et al., Am. J.

Physiol. 252: E621-E626 (1987)). Glucocorticoids have been shown to activate the proteolytic pathway dependent on ATP-ubiquitin in skeletal muscle (Wmg and Goldberg, Am. J. Physiol. 264: E668-E676 (1993)) and proteasone inhibitors are therefore expected to inhibit muscle wasting that occurs after glucocorticoid treatment.

Inhibitor IC50 IC50 index (ph (ph inactivation 2.0) 7.6) Ala-boroLeu 31 nM 100 nM 3.2 Accurate mass 20215 Ala-boroLeu 0.85 92 uM 110 Thioxamide uM Asp-boroLeu 4.6 uM 10 uM 2.2 Thioxamide Phe-boroLeu 16 nM 120 nM 7.5 free of OH H i Velcade! H-N OH O T Exact mass 27818 Phe-boroLeu 0.71 14 uM 20 Thioxamide uM Exact mass 29416 Gly-boroLeu 14 nM 160 nM 11 Exact mass 18813 Gly-boroLeu 4.9 uM 100 uM 20 H Thioxamide H N ^? - N- ^ B-0H s dd " Exact mass 20411 Pyz-Gly- 1.2 boroLeu Exact Mass 29415 N- (Pirazin-2- 77 nM 350 nM 4.5 carbothio) -Gly- boroLeu Exact mass 310 13 N- (Pirazin-2- 5.8 uM 22 uM 3.8 carbonyl) -Gly- boroLeu Thioxamide Exact mass 31U 13 Pyz -Gly- 3. 9 uM 2. 4 mM 620 boroLeu PerTioxamide exact 326 10 Incorporation for reference All patents of E.U.A. and the patent application publications of E.U.A. cited herein are incorporated herein by reference.

Equivalent Those skilled in the art will recognize, or be able to determine using no more than one routine experiment, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (64)

1. CLAIMS 1. A compound represented by: characterized in that A represents a 4-8 membered heterocycle including carbon N and Ca; RT represents an amino acid analogue or amino acid residue thermally linked to C, or a peptide analog or peptide thermally bound to C, or ; wherein the bond between Rx and N is a thioxamide bond; R? is absent or represents one or more substitutions for ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkyl, carbonyl, carboxyl, ester, formate, ketone, thiocarbomyl, thioester, thioacetate, thioformate, ammo, acylammon, amido, nitro, sulfate, sulfonate, sulfonamido, - (CH2) m-R7, - (CH2) m-OH, - (CH2) m-0-lower alkyl, - (CH2) m-0-alken - the lower, - (CH2) n-0- (CH?) m-R7, - (CH2) m-SH, - (CH2) mS-lower al, - (CH2) mS-lower alkenyl, or - (CH2) n_S- (CH2) m-R7, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, © © N ^ = C -Rs R3 represents hydrogen or a halogen, lower alkyl, lower alkenyl, alkynyl, N, E, B, carbonyl, thiocarbonyl, amino, acylamino, amido, nitro, sulfate, sulfonate, a sulfonamido, - (CH2) m-R7, - (CH2) m-0H, - (CH2) m-0-lower alkyl, - (CH2) m-0-lower alkenyl, (CH?) N-0- (CH2) m-R7, - (CH2) m-SH, - (CH2) mS -lower alkyl, - (CH?) mS-lower alkenyl, or - (CH2) nS- (CH2) m-R7, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, -R « or R6 represents hydrogen, a halogen, alkyl, alkenyl, alkynyl, aryl, - (CH2) m-R7, - (CH2) m-OH, - (CH2) mO-alkyl, - (CH2) m-0-alkenyl, - (CH2) m-0-alkynyl, - (CH2) m-0- (CH?) M-R7, - (CH2) m-SH, - (CH2) mS-alkyl, - (CH2) mS-alkenyl, - (CH) mS-alkynyl, - (CH2) mS- (CH2) m-R7, Rs i. Rs NH2 (CH2) m- N. (CH,) n- C - N • I I R9 ~ ^ (C ^) n- NH2- C- NH2 0 0 0 I I • II,, • I I - (CB2) n - C - G - R7 - (CH2) n - C - alkyl - (C feJn - C - alkenyl or 0 I I I I - (CH2) n - C - alkynyl (CHz) - - C - (CH2) m- R7 R7 represents, each occurring, a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R8 represents hydrogen, -CH3, or - (CH2) n-CH3; Y! and Y ?, independently, they are OH, or a group capable of hydrolyzing to a hydroxyl group, or Yx and Y2 are connected by means of ring having from 5 to 8 atoms in the ring structure which is capable of hydrolyzing to two groups hydroxyl; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8.
2. 2. The compound in accordance with the claim 1, characterized in that Yx and Y2, independently, are OH.
3. 3 The compound in accordance with the claim 2, characterized in that the compound is represented by: 4 The compound in accordance with the claim 3, characterized in that R2 is present; and R2 is azido, cyano, T T isocyanate, thiocyanate, isothiocyanate, cyanate, N C ( C? = C R8 5. The compound according to claim 3, characterized in that R2 is present; and R2 is azido, cyano, T T isocyanate, thiocyanate, isothiocyanate, cyanate, cr 6. The compound according to claim 3, characterized in that R2 is present; and R2 is C ^ = C R8. 7. The compound according to claim 3, characterized in that R2 is present; and R2 is = C CH3 •. The compound in accordance with the claim 3, characterized in that R2 is present; y-C = g? _: CHes The compound according to any preceding claim, characterized in that Ri is wherein R36 is a lower alkyl or a halogen; R38 is hydrogen; or R-36 and R38 together form a 4-7 membered heterocycle including carbon N and Ca, and R? 0 represents an amino acid analog or amino acid residue thermally linked to C, or a peptide or peptide analogue thermally bonded to C, or an ammo protected group. The compound according to any preceding claim, characterized in that R 2 is absent, or represents lower alkyl or halogen. 11. The compound according to any preceding claim, characterized in that R3 is hydrogen. 12. The compound according to any preceding claim, characterized in that the carbon Ca exists substantially in the R configuration. The compound according to any preceding claim, characterized in that the carbon Ca exists substantially in the S configuration. The compound according to any preceding claim, characterized in that the carbon Ca exists in a racemic mixture. of configurations R and S. 15. The compound according to any preceding claim, characterized in that Y3 and Y2 are OH. 16. The compound according to any preceding claim, characterized in that Ri is a proline, glutamate, or alanine residue. 17. The compound according to any preceding claim, characterized in that R is an alanine residue. 18. A compound selected from the group consisting of: and enantiomers, diastereomers and salts thereof. 19. A compound represented by or an enantiomer or diastereomer thereof, 20. A compound represented by or an enantiomer or diastereomer thereof. 21. A compound according to any preceding claim, characterized in that the compound is a protease inhibitor. 22. The compound according to claim 21, characterized in that the compound inhibits dipeptidyl peptidase IV with a Ki of 50 nM or less. 23. The compound according to claim 22, characterized in that the compound inhibits dipeptidyl peptidase VIII and IX with a Ki of 100 microM or greater. The compound according to any preceding claim, characterized in that the compound is effective when administered orally. 25. A compound represented by: X ai '-Xaa2' -Xaa? -Xaa2- characterized because Xaa-! Xaa2 ', and Xaa2 each independently represents an amino acid or analog that is presented naturally of the same; Xaa, is an amino acid or analog that occurs naturally thereof, wherein Xaax contains a thioxamide group; is -CN, -CH = NR5, Rb represents H, alkyl, alkenyl, alkynyl, C (X!) (X2) X3, - (CH2) m -R6, - (CH2) n-OH, - (CH2) n-0-alkyl, - (CH? ) n-0-alkenyl, - (CH2) n-0-alkynyl, - (CH2) n-0- (CH2) m -R6, - (CH2) n-SH, - (CH2) nS-alkyl, - ( CH 2) n S -alkenyl, - (CH 2) n S-alkynyl, - (CH 2) n S- (CH 2) m -R 6, -C (O) C (O) NH 2, or -C (O) C (O) OR 7; R6 independently represents each a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R7 independently represents each hydrogen present, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; Y-i and Y2 can independently or together be OH, or a group capable of hydrolyzing to a hydroxyl group, including cyclic derivatives wherein Y1 and Y2 are connected by ring having from 5 to 8 atoms in the ring structure; R.) 0 represents 0 u S; Rbl represents N3, SH, NH2, N02 or -0R7; R2 represents hydrogen, a lower alkyl, an amine, -OR7, or a pharmaceutically acceptable salt, or R5i and R? Í? taken together with the phosphorus atom to which they are bound complete to a heterocyclic ring that has from 5 to 8 atoms in the ring structure; X-i represents a halogen; X and X3 each represents a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. 26. A compound represented by: characterized in that A represents a 4-8 membered heterocycle including carbon N and Ca; W represents -CN, -CH = NR5, Rj represents a peptide or peptide analogue terminally linked to C which is a substrate for an activated enzyme; R is absent or represents one or more substitutions for ring A, each of which is independently a halogen, lower alkyl, lower alkenyl, lower alkynyl, carbonyl, thiocarbonyl, ammo, acylamino, amido, nitro, sulfate, sulfonate, sulfonamido , - (CH2) m-R6, - (CH2) m-0H, - (CH2) m-0-lower alkyl, - (CH) m-0-lower alkenyl, - (CH2) n-0- (CH2) m-R6, - (CH2) m-SH, - (CH2) mS-lower alkyl, - (CH2) mS-lower alkenyl, or - (CH) nS- (CH2) m-R6, azido, cyano, isocyanate, thiocyanate, T isothiocyanate, cyanate, NrrrrC (0, R3 represents a hydrogen or lower alkyl, R represents hydrogen, halogen, a lower alkyl, a lower alkenyl, or a lower alkyl, R5 independently represents each occurrence H, an alkyl, an alkenyl, an alkyl, -C (X?) (X2) X3, (CH2) m-R6, - (CH2) n-OH, - (CH2) n-0-alkylene, - (CH2) n-0-alkenyl, - (CH2) n-0-alkyl, - (CH2) n-0- (CH2) m -R6, - (CH2) n-SH, - (CH2) nS-alkyl, - (CH?) NS- alkenyl, - (CH2) nS-alkanol, - (CH2) n- S- (CH2) m -R6, -C (0) C (0) NH2, or -C (O) C ( O) 0R7; R6 independently represents each a substituted or unsubstituted aryl, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R7 independently represents each hydrogen, or a substituted or unsubstituted alkyl, alkenyl, aplo, aralkyl, cycloalkyl, cycloalkenyl, or heterocycle; R8 represents hydrogen, -CH3, or - (CH2) n-CH3; Y] and Y2 can independently or together be OH, or a group capable of hydrolyzing to a hydroxyl group, including cyclic derivatives wherein Yi and Y2 are connected by ring having from 5 to 8 atoms in the ring structure; R50 represents O u S; R51 represents N3, SH, NH2, N02 or -0R7; Rb2 represents hydrogen, a lower alkyl, an amine, -0R7, or a pharmaceutically acceptable salt, or R5? Y Rb2 taken together with the phosphorus atom to which they are bound complete to a heterocyclic ring having from 5 to 8 atoms in the ring structure; X-i represents a halogen; X2 and X3 each represents a hydrogen or a halogen; m is zero or an integer in the range of 1 to 8; and n is an integer in the range of 1 to 8. The compound according to claim 26, characterized in that A represents a 5-membered heterocycle including carbon N and Ca. 28. The compound according to claim 26 or 27, characterized in that it is -B (Y?) (Y2). 29. The compound according to claim 26, 27 or 28, characterized in that R2 is absent or represents a halogen or lower alkyl. 30. The compound according to claim 26, 27, 28 or 29, characterized in that R4 represents hydrogen or lower alkyl. 31. The compound according to claim 26, 27, 28, 29 or 30, characterized in that R5 represents H or alkyl. 32. The compound according to claim 26, 27, 28, 29, 30, or 31, characterized in that Yi and Y2 are OH. 33. The compound according to claim 26, 27, 28, 29, 30, or 31, characterized in that it is B (OH) ?. 34. The compound according to claim 26, characterized in that the compound is represented by: 35. The compound according to claim 34, characterized in that R2 is absent or represents a halogen, lower alkyl, azido, cyano, isocyanate, thiocyanate, © T isothiocyanate, cyanate, N ^ = C, or C C R8. 36. The compound according to claim 34, characterized in that R4 represents hydrogen or lower alkyl. 37. The compound according to claim 34, characterized in that R2 is present; and R2 is azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, ©? -N ^ C C ^ C R8 , or 38. The compound according to claim 34, characterized in that R2 is present; and R2 is azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, or © T ^ = C 39. The compound according to claim 34, characterized in that R2 is present; and R2 is 40. The compound in accordance with the claim 34, characterized in that R2 is present; and R2 is C CH O C ?? = C CH3. 41. The compound according to claim 26, characterized in that the compound is represented by: 42. The compound according to claim 41, characterized in that R represents hydrogen, halogen, lower alkyl, azido, cyano, isocyanate, thiocyanate, isothiocyanate, cyanate, © T = C -Rs 43. The compound in accordance with the claim 41, characterized in that R4 represents hydrogen or lower alkyl. 44. The compound according to claim 41, characterized in that R2 is azido, cyano, isocyanate, © T thiocyanate, isothiocyanate, cyanate, -NE = C or C ^ = C R8 45. The compound according to claim 41, characterized in that R2 is azido, cyano, isocyanate, © T thiocyanate, isothiocyanate, cyanate, or -N = = C 46. The compound in accordance with the claim 41, characterized in that R2 is -RP 47. The compound according to claim 41, characterized in that R2 is -C CH "CHj 48 The compound according to any of claims 26 - 47, characterized in that R? is : 49. A pharmaceutical composition, characterized in that it comprises a pharmaceutically acceptable carrier; and a compound according to any of claims 1-48 or a pharmaceutically acceptable salt thereof. 50. A method for inhibiting the proteolytic activity of a post-split proline enzyme, characterized in that it comprises the enzyme with a compound according to any of claims 1-48. 51. The method according to claim 50, characterized in that the enzyme is a mammalian dipeptidyl IV peptidase (DPP IV). 52. A method for inhibiting the proteolytic activity of a post-split proline enzyme in a patient, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any of claims 1-48. 53. The method according to claim 52, characterized in that the method increases the patient plasma concentrations of a peptide hormone selected from the group consisting of glucagon-like peptide, NPY, PPY, secretin, GLP-1, GLP-2 , and GIP. 54. A method for regulating glucose metabolism in a patient, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any of claims 1-48. 55. The method according to claim 54, characterized in that the patient suffers from diabetes type II, insulin resistance, glucose intolerance, hyperglycemia, hypoglycemia, hyperinsulmemia, obesity, hyperlipidemia, or hyperlipoprotememia. 56. The method according to claim 54 or 55, characterized in that it further comprises administering to the patient a therapeutically effective amount of insulin, a msulmotropic agent or both. 57. The method according to any of claims 54-56, characterized in that it further comprises administering to the patient a therapeutically effective amount of a Ml receptor antagonist, a prolactone inhibitor, an agent acting on the ATP-dependent potassium channel. of ß cells, metformma, a glucosidase inhibitor or a combination of any of them. 58. A method for inhibiting the proteolytic activity of a proteasome, DP8, DP9, or prostate-specific antigen, characterized in that it comprises contacting a proteasome, DP8, DP9, or prostate-specific antigen with a compound according to any of the Claims 1-48. 59. A method for inhibiting the proteolytic activity of a proteasome, DP8, DP9, or prostate-specific antigen in a patient, characterized in that it comprises administering to a patient in need thereof a therapeutically effective amount of a compound in accordance with any of the Claims 1-48. 60. A packaged pharmaceutical, characterized in that it comprises a compound according to any of claims 1-48; and instructions for its use 61. The pharmacist packaged according to claim 60, characterized in that the instructions in relation to the use in the regulation of glucose metabolism or inhibition of a post-split enzyme of prolma 62. The pharmacist packed in accordance with claim 60, characterized in that the instructions regarding the use in the inhibition of a proteasome, DP8, DP9, or prostate-specific antigen. 63. The packaged pharmacist according to claim 60, characterized in that the compound is co-formulated with or co-packed with insulin, an insulinulotropic agent or both. 64 The pharmacist packaged in accordance with claim 60, characterized in that the compound is co-formulated with or co-packed with a Ml receptor antagonist, a prolactone inhibitor, an agent that acts on the β-cell ATP-dependent potassium channel, metformma, a glucosidase inhibitor. or a combination of any of them