MXPA00008927A - Modulators of protein tyrosine phosphatases (ptpases) - Google Patents

Abstract

The present invention provides novel compounds, novel compositions, methods of their use, and methods of their manufacture, where such compounds are pharmacologically useful inhibitors of Protein Tyrosine Phosphatases (PTPases) such as PTP1B, CD45, SHP-1, SHP-2, PTP&agr;, LAR and HePTP or the like. The compounds are useful in the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.

Description

MODULATORS OF PROTEINS TSROSINA PHOSPHATOSAS FIELD OF THE INVENTION The present invention relates to new compounds, to methods for their preparation, to compositions comprising the compounds, to the use of these compounds as medicaments and to their use in therapy, wherein such compounds of Formula 1 are inhibitors of the Tyrosine Protein. Pharmacologically useful phosphatases (PTPases), such as PTPIB, CD45, SHP-1, SHP-2, PTPa, LAR and HePTP or the like.

Formula 1 wherein A, R :, R2, R3, R4, R16 and R17 are more fully defined later.

REF .: 123137 BACKGROUND OF THE INVENTION It has been found that PTPases play a major role in the intracellular modulation and regulation of the fundamental cellular signaling mechanisms involved in metabolism, growth, proliferation and differentiation (Flint et al., The EMBO J. 12: 1937-46 (1993 ), Fischer et al, Science 253: 401-6 (1991)). Overexpression or altered activity of tyrosine phosphatases may also contribute to the symptoms and progression of various diseases (Wiener, et al., J. Nati, Cancer Inst. 86: 372-8 (1994), Hunter and Cooper, Ann. Rev. Biochem, 54: 897-930 (1985)). In addition, there is increased evidence to suggest that the inhibition of these PTPases can help treat certain types of diseases such as type I and II diabetes, autoimmune disease, acute and chronic inflammation, osteoporosis and various forms of cancer. Phosphorylation of the protein is now well recognized as an important mechanism used by cells to transduce signals during different stages of cell function (Fischer et al, Science 253: 401-6 (1991); FTint et al., The EMBO J. 12: 1937-46 (1993)). There are at least two major classes of phosphatases: (1) those that phosphorylate proteins (or peptides) that contain a phosphate group (s) in a serine or threonine moiety (called Ser / Thr phosphatases) and (2) those that remove one (some) tyrosine phosphate group (s) from the amino acid (called protein tyrosine phosphatases or PTPases). PTPases are a family of enzymes that can be classified into two groups: a) intracellular or transmembrane-free PTPases and b) receptor-type or transmembrane-type PTPases. The best known intrathoracic PTPases include a single conserved catalytic phosphatase field consisting of residues of 220-240 amino acids. Regions outside the PTPase fields are believed to play important roles in the ubcellular intracellular PTPase location (Mauro, L.J. and Dixon, J.E. TIBS 19: 151-155 (1994)). The first intracellular PTPase to be purified and characterized was PTPIB which was isolated from the human placenta (Tonks et al., J.B.BI., Ch., 263: 6722-6730 (1988)). Shortly thereafter, PTPIB was cloned (Charbonneau et al., Proc. Nati, Acad. Sci. USA 86: 5252-5256 (1989); Chernoff et al., Proc. Nati, Acad. Sci. USA 87: 2735-2789 (1989)). Other examples of intracellular PTPases include (1) T-cell PTPase (Cool et al., Proc. Nati, Acad. Sci. USA 86: 5257-5261 (1989)), (2) PTPase from the rat brain (Guan et al. , Proc. Nati, Acad. Sci. USA 87: 1501-1502 (1990) and ~ ~ (3) STEP of neuronal phosphatase (Lombroso et al., Proc. Nati. Acetd. Sci. USA 88: 7242-7246 (1991 )), (4) PTPases containing the ezrin field: PTP EG1 (Guet al., Proc. Nati, Acad. Sci: USA 88: 5867-57871 (1991)), PTPH1 (Yang and Tonks, Proc. Nati. Acad. Sci. USA 88: 5949-5953 (1991)), PTPD1 and PTPD2 (M ller et al., Proc. Nati. Acad. Sci. USA 91: 7477-7481 (1994)), FAP-1 / BAS (Sato et al., Science 268: 411-415 (1995); Banville et al. , J. Biol. Chem. 269: "22320-22327 (1994); Maeka et al., FEBS Let ^ ers 337: 200-206 (1994)), and PTPases containing the SH2 field: PTP1C / SH-PTP1 / SHP-1 (Plutzky et al., Proc. Nati. Acad. Sci. USA 89: 1123- 1127 (1992), Shen et al., Nature Lond. 352: 736-739 (1991)) and PTPlD / Syp / SH-PTP2 / SHP-2"(Vogel et al., Science 259: 1611-1614 (1993)).; Feng et al. , Science 259: 1607-1611 (1993); Bastein et al. , Biochem. Biophys. Res. Comm. 196: 124-133 (1993)). Fos photons ina-pro tein phosphatase of lower molecular weight (LMW-PTPase) shows very little sequence identity to the intracellular PTPases described above. However, this enzyme belongs to the PTPase family due to the following characteristics: (i) it has the PTPase active site motif: Cys-Xxx-Xxx-Xxx-Xxx-Xxx-Arg (Cirri et al., Eur, J, Biochem 214: 647-657 (1993)); (ii) this residue of Cys forms a fo-int ermediary foss during the catalytic reaction similar to the situation with "classical" PTPases * (Cirri et al., supra; Chiarugi et al., FEBS Lett 310: 9-12 (1992)); (iii) the total doubling of the molecule shows a surprising degree of similarity to that of PTPIB and Yersinia PTP (Su et al., Nature 370: 575-578 (199)). - PTPases of the receptor type consist of a) an extracellular putative ligand-ligand extracellular field, b) a t ransmembrane segment r i o, and c) an intracellular catalytic region. The structures and sizes of the putative ligand-extracellular fields of the PTPases of the receptor type are very divergent. In contrast, the intracellular catalytic regions of the PTPases of the receptor type are highly homologous to each other and to the intracellular PTPases. More PTPases of the receptor type have two fields of catalytic PTPase duplicated in pairs. The first PTPases of the receptor type to be identified were (1) CD45 / LCA (Ralph, SJ, EMBO J. 6: 1251-1257 (1987)) and (2) LAR (Streuli et al., J. Exp. Med. 168: 1523-1530 (1988)) that were recognized as belonging to this class of enzymes based on PTPIB homology (Charbonneau et al., Proc Nati Acad Sci USA USA 86: 5252-5256 (1989)). CD45 is a family of high molecular weight glycoproteins and is one of the most abundant glycoproteins of the leukocyte cell surface and appears to be expressed exclusively in cells of the hema t opoyé ti co system (Tro bridge and Thomas, An , R ev, Imm ol., 12: 85-116 (1994)). The identification of CD45 and LAR as elements of the PTPase family was quickly followed by the identification and cloning of several different elements of the PTPase group of the receptor type. Thus, 5 different PTPases, (3) PTPa, (4) PTPß, (5) PTPd, (6) PTPe, and (7) PTP ?, were identified in an early study (Krueger et al., EMBO J. 9: 3241-3252 (1990)). Other examples of PTPases of the receptor type include (8) PTP? (Barnea et al., Mol Cell. Biol. 13: 1497-1506 (1995)) which, like PTP? (Krueger and Saito, Proc. Nati, Acad. Sci. USA 89: 7417-7421 (1992)) contains a field similar to carbonic anhydrase in the extracellular region, (9) PTPμ (Gebbink et al., FEBS Letters 290: 123-130 (1991)), (10) PTPK (Jiang et al., Mol Cell. Biol. 13: 2942-2951 (1993)). Based on structural differences, receptor-type PTPases can be classified into subtypes (Fischer et al., Science 253: 401-406 (1991)); (I) CD45; (II) LAR, PTPd, (11) PTPs; (III) PTPb, (1.2) SAP-1 (Matozaki et al., J. Biol. Chem. 269: 2075-2081 (1994)), (13) PTP-U2 / GLEPP1 (Seimiya et al., Oncogene 10: 1731-1738 (1995), Thomas et al., J. Biol. Chem. 269X 19953-19962 (1994)), and (14) DEP-1; (IV) PTPa, PTPe. All PTPases of the receptor type except Type IV contain two PTPase fields. New PTPases are uniquely identified, and it is anticipated that 500 different species will be found in the human genome, that is, close to the predicted size of the tyrosine kinase protein superfamily (Hanks and Hunter, FASEB J. 9: 576- 596 (1995)). PTPases are the biological counterparts to protein tyrosine kinases (for its acronym in English, PTKs). Therefore, an important function of PTPases is to control, down-regulated, the activity of PTKs. However, a more complex picture of the function of PTPases is now emerging. Several studies have shown that some PTPases can act effectively as positive mediators of cell signaling. As an example, PTP1D containing the SH2 field appears to act as a positive mediator in activation of insulin-stimulated Ras (Noguchi et al., Mol.Cell. Biol. 14: 6674-6682 (1994)) and transduction of the mitogenic signal induced by the growth factor (Xiao et al., J. Biol. Chem. 269: 212 -21248 (1994)), whereas the PTP1C homolog appears to act as a negative regulator of proliferation stimulated by the factor of growth (Bignon and Siminovitch, Clin. Immunol, Immunopahtol., 73: 168-179 (1994)). Another example of PTPases as positive regulators has been provided by studies designed to define the activation of the Src family of tyrosine kinases. In particular, several lines of evidence indicate that CD45 is positively regulating hematopoietic cell activation, possibly through the C-terminal tyrosine phosphorylation of Fyn and Lck (Chan et al., Annu, Rev. Immunol. : 555-592 (1994)). The double-specificity protein tyrosine phosphatases (dsPTPases) define a subclass within the PTPase family that can hydrolyse phosphate from the fortiori as well as fos-serine / threonine. The dsPTPases contain the signal sequence of PTPases: Hi s -Cys -Xxx-Xxx-Gly-Xxx-Xxx-Arg. At least three dsPTPases have been shown for kinase regulated by the inactivated extracellular signal and forylated defects (ERKs) / protein kinase activated by the mitogen (MAPK): MAPK phosphatase (CL 100, 3CH134) (Charles et al., Proc. Nati, Acad. Sci. USA 90: 5292-5296 (1993)); PAC-1 (Ward et al., Nature 367: 651-654 (1994)); rVH6 (Mourey et al., J. Biol. Chem. 271: 3795-3802 (1996)). The transcription of dsPTPases is induced by different stimuli, for example, oxidative stress or heart attack (Ishibashi et al., J. Bol. Chem. 269: 29897-29902 (1994); Keyse and E slie, Nature 359: 644- 647 (1992)). In addition, they can be involved in cell cycle regulation: cdc25 (Millar and Russell, Cell 68: 407-410 (1992)); KAP (Hannon et al; Proc. Nati, Acad. Sci. USA 91: 1731-1735 (1994)). Interestingly, the dephosphorylation of tyrosine of cdc2 by a double specific phosphatase, cdc25, is required for the induction of mitosis in yeast (see again by Walton and Dixon, Annu, Rev. Biochem. 62: 101-120 ( 1993)). PTPases were originally identified and purified from tissue and cell lysates using a variety of artificial substrates and therefore their 'natural function of dephosphorylation was not well known. Because tyrosine phosphorylation by tyrosine kinases is usually associated with cell proliferation, cellular transformation, and cell differentiation, it is assumed that PTPases were also associated with these events. This association has now been proven to be the case with many PTPases. PTPIB, a phosphatase whose structure was recently elucidated (Barford et al., Science 263: 1397-1404 (1994)) has been shown to be involved in the maturation of the insulin-induced oocyte (Flint et al., The EMBO J 12: 1937-46 (1993)) and recently it has been reported that the overexpression of this enzyme can be involved in ovarian and breast cancers associated with pl85c_erb B2 (Wiener, et al., J. Nati. 86: 372-8 (1994); Weiner et al., Am. J. Obstet, Gynecol. 170: 1177-883 (1994)). The mechanism of maturation of the oocyte induced by insulin has been correlated with the ability of PTPIB to block the activation of S6 kinase. The association with cancer is recent evidence suggesting that the over-exposure of PTPIB is statistically correlated with increased levels of pl85c_erb B2 in breast and ovarian cancer. The role of PTPIB in the etiology and progression of the disease has not yet been elucidated. Therefore, PTPIB inhibitors can help clarify the role of PTPIB in cancer and in some cases provide therapeutic treatment for certain forms of cancer. The activity of a number of other phosphatases recently described is presently under investigation. Two of these: SHP-1 and Syp / PTPlD / SHPTP2 / PTP2C / SHP-2 have recently been implicated in the activation of Platelet-Derived Growth Factor and responses induced by the Epidermal Growth Factor (Li et al., Mole. Cell. Biol. 14: 509-17 (1994)). Since both growth factors are involved in normal cell processing as well as disease states such as cancer and arteriosclerosis, it is hypothesized that inhibitors of these phosphatases could also show therapeutic efficacy. Accordingly, the compounds of the present invention which exhibit inhibitory activity against various PTPases are indicated in the treatment or management of the foregoing diseases.

PTPases: the signaling pathway of the insulin / diabetes receptor Insulin is an important regulator of the different metabolic processes and plays a key role in the control of blood glucose. Defects related to its synthesis or signaling leads to diabetes mellitus. The binding of insulin to its receptor causes rapid (autogenous) phosphorylation of several tyrosine residues in the intracellular part of subunit b. Three tightly placed tyrosine residues (the 1150 field of tyrosine) must be phosphorylated to obtain the full activity of the insulin receptor tyrosine kinase (IRTK) which transmits the signal further downstream by the tyrosine phosphorylation of other cellular substrates, including the substrate 1 of the insulin receptor (IRS-1) (Wilden et al., J. Bio2, Chem. 267: 16660-16668 (1992); Myers and hite, Diabetes 42: 643-650 (1993); Lee and TPilch , Am. J. Physiol. 266: C319-C334 (1994), White et al., J. Biol. Chem. 263: 2969-2980 (1988")). The structure base for triple tyrosine function has been provided by recent IRTK X-ray studies, which show that ina-1150 tyrosine is self-inhibiting in its non-phosphorylated state (Hubbard et al., Nature 372: 746-754 (1994)). Several studies clearly indicate that the activity of the artificial IRTK can be reversed due to in vitro formation. (see Goldstein, Receiver 3: 1-15 (1993); Mooney and Anderson, J. Biol. Chem. 264: 6850-6857 (1989)), with the inactive iron field that is the most sensitive target for protein-tyrosine phosphatases (PTPases) when it is compared to the forylated di- and mono-fos forms (King et al., Biochem J. 275: 413-418 (1991)). Therefore, it is attractive to speculate that these functions of triple tirssin as a switch controlling the activity of IRTK. Indeed, IRTK appears to be closely regulated by PTP-mediated phosphorylation in vivo (Khan et al., J. Biol. Chem. 264: 12931-12940 (1989); Faure et al., J. Biol. Chem. 267: 11215-11221 (1992); Rothenberg et al., J. Biol. Chem. 266: 8202-8311 (1991)). The intimate coupling of PTPases to the insulin signaling pathway is further evidenced by the invention that differentially regulates the insulin activity of PTPase in hepatic cells in rats (Meyerovitch et al., Biochemistry 31: 10338-10344 (1992 )) and in livers of diabetic rats of alloxan (Boylan et al., J. Clin Invest 90: 174-179 (1992)). Relatively little is known about the identity of the PTPases involved in the regulation of IRTK. However, the existence of PTPases with activity towards the insulin receptor can be demonstrated as indicated above. In addition, when the strong PTPase pervanadate inhibitor is added to whole cells an almost complete insulin response can be obtained in adipocytes (Fantus et al., Biochemistry 28: 8864-8871 (1989); Eriksson et al., Diabetologia 39 : 235-242 (1995)) and skeletal muscle (Leighton et al., Biochem. J. 276: 289-292 (1991)). In addition, recent studies show that a new class of pexoxo-linked compounds acts as powerful hypoglycemic compounds in vivo (Posner et al., Supra). Two of these compounds were shown to be more potent inhibitors of the insulin phosphorylation of the insulin receptor than of the EGF receptor.The ubiquitously expressed SH2 field containing PTPase, PTP1D, was recently found (Vogel et al. ., 1993, supra), is associated with and forged IRS-1, but apparently not IR by itself (Kuhné et al., J. Biol. Chem. 268: 11479-11481 (1993); (Kuhné et al., J. Biol. Chem. 269: 15833-15837 (1994)).

Previous studies suggest that the PTPases responsible for the regulation of IRTK belong to the class of associated membrane (Faure et al., J. Biol. Chem. 267: 11215-11221 (1992)) and glycosylated molecules (Háring et al., Biochemistry 23: 3298-3306 (1984); Sale, Adv. Prot. Phosphatases 6: 159-186 (1991)). Hashimoto et al. have proposed that LAR should have a role in the physiological regulation of insulin receptors in intact cells (Hashimoto et al., J. Biol. Chem. 267: 13811-13814 (1992)). Their conclusion is reached by comparing the rate of dephosphorylation / inactivation of purified IR using recombinant PTPIB as well as the cytotoxic fields of LAR and PTPa. Antisense inhibition was recently used to study the effect of LAR on insulin signaling in a rat hepatic cell line (Kulas et al., J. Biol. Chem. 270: 2435-2438 (1995)). A suppression of LAR protein levels by approximately 60 percent was paralleled by an approximately 150 percent increase in insulin-induced autophosphorylation. However, only a modest 35 percent increase in IRTK activity was observed, whereas the insulin-dependent phosphatidyl inositol 3-kinase (Pl 3-kinase) activity was significantly increased by 350 percent. The reduced levels of LAR do not alter the basal level of activity or phosphogylation of the tyrosine of IRTK. The authors speculate that LAR could specifically phosphorylate tyrosine residues that are critical for the activation of Pl 3-kinase either on the insulin receptor by itself or on a downstream substrate. Although previous reports indicate a function of PTPa in signal transduction through src activation (Zheng et al., Nature 359: 336-339 (1992); den Hertog et al., EMBO J. 12: 3789-3798 (1993)) and interaction with GRB-2 (den Hertog et al., EMBO J. 13: 3020-3032 (1994); Su et al., J. Biol. Chem. 269: 18731-18734 (1994)), a recent study suggests a role for this phosphatase and its narrow relative PTPe as negative regulators of the insulin receptor signal (Meller et al., 1995 supra). This study also indicates that receptor-like PTPases play a significant role in the regulation of IRTK, whereas intracellular PTPases appear to have little, if any, activity towards the insulin receptor. Although it appears that the target of the negative regulatory activity of PTPases a and e is the receptor itself, the down-modulation effect of intraceluar TC-PTP appears to be due to a downstream function in the IR-activated signal. Although PTPIB and TC-PTP are closely related, PTPIB had only small influence on the phosphorylation configuration of insulin-treated cells. Both PTPases had different structural characteristics that determine their subcellular localization and therefore their access to defined cell substrates (Frangione et al., Cell 68: 545-560 (1992) 0 Faure and Posner, Glia 9: 311-314 (1993 )). Therefore, the lack of activity of PTPIB and TC-PTP towards the IRTK can, at least in part, be explained by the fact that they do not co-localize with the activated insulin receptor. observation, PTPIB and TC-PTP have been excluded as candidates for PTPases associated with "IR in hepatocytes based on subcellular localization studies (Faure et al., J. Bi ol. Ch. 267: 11215-11221 (1992) ). T ransmembranari a CD45 PTPase, which is believed to be a specific hematopoietic cell, was in a recent study found to negatively regulate the insulin receptor tyrosine kinase in the human multiple myeloma cell line U266 (Kulas et al., J. Bi. Ol. Ch., 271: 755-760 (1996)).

PTPases: somatostatin Somatostatin inhibits several biological functions that include cell proliferation (Lamberts et al., Molec.Endocrinol., 8: 1289-1297 (1994)). Although part of the anti-inflammatory activities of somatostatin are secondary to its inhibition of growth factor and hormone secretion (eg, growth hormone and epidermal growth factor), other antiproliferative effects of somatostatin they are due to a direct effect on target cells. As an example, somatostatin analogues inhibit the growth of pancreatic cancer presumably via the stimulation of a single PTPase, or a subset of PTPases *, rather than a general activation of PTPase levels in the cells (Lie et al., Pr.oc. Nati, Acad. Sci. USA 86: 2003-2007 (1989), Colas et al., Eur. J. Biochem. 207: 1017-1024 (1992)). In a recent study it is found that the somatostatin stimulation of somatostatin receptors SSTR1, but not SSTR2, stably expressed in CHO-K1 cells can stimulate PTPase activity and that this stimulation is sensitive to pertussis toxin. If the inhibitory effect of somatostatin on the secretion of growth factor and hormone is caused by a similar stimulation of the activity of PTPase in remnants of cells that produce hormones to be determined.

PTPases: the immune system / aut oimmunity Several studies suggest that CD45 PTPases of the receptor type have a critical function not only for the initiation of T cell activation, but also for maintaining the signaling cascade mediated by the T cell receptor. These studies are indicated in : (Weiss A., Ann Rev. Genet., 25: 487-510 (1991); Chan et al., Annu., Rev. Immunol., 12: 555-592 (1994); Trowbridge and Thomas, Annu., Rev. Immunol. 12: 85-116 (1994)). CD45 is one of the most abundant glycoproteins on the cell surface and is expressed exclusively in hemopoetic cells. In T cells, CD45 has been shown to be one of the critical components of the lymphocyte signal transduction machinery. In particular, the evidence has suggested that CD45 phosphatase plays or has a pivotal role in proliferation stimulated by T lymphocyte antigens after an antigen has been bound to the T cell receptor.

(Trowbrigde, Ann. Rev. Immunol, 12: 85-116 (1994)). Several studies suggest that the PTPase activity of CD45 plays a role in the activation of Lck, a lymphocyte-specific element of the Src-tyrosine kinase family protein (Mustelin et al., Proc. Nati. Acad. Sci. USA 86: 6302-6306 (1989); Ostergaard et al., Proc. Nati Acad. Sci. USA 86: 8959-8963 (1989)). These authors make the following hypothesis: that the activity of CD45 phosphatase activates Lck by the forcing of a C-terminal tyrosine residue, which, in turn, is related to the activation of T cells. Recent study found that recombinant p561ck is specifically associated with the cytoplasmic field protein of recombinant CD45, but not the cytoplasmic field of the related PTPa (Ng et al., J. Bi ol. Ch em. 2 11: 1295-1300 ( nineteen ninety six)) . The interaction of p561ck-CD45 appears to be mediated via an unconventional SH2 field interaction that does not require phosphorylated ina. In immature B cells, another element of the Src-tyrosine kinase family protein, Fyn, appears to be a selective substrate for CD45 compared to Lck and Syk (Katagiri et al., J. Bi ol. Ch. 270: 27987 -27990 (1995)). Studies using transgenic mice with a mutation for CD45-exon6 exhibit immature T cells. These mice do not respond to antigenic stimulation with the response mediated by the typical T cell (Kishihara et al., Ce l l 74: 143-56 (1993)). The inhibitors of CD45 phosphatase could therefore be very effective therapeutic agents in conditions that are associated with autoimmune diseases.

CD45 has also been shown to be essential for mast cell-mediated degranulation (Berger et al., J. Exp. Med. 180: 471-6 (1994)). These studies also occurred with mice that were deficient in CD45. In this case, an IgE-mediated degranulation was shown in the wild-type but not in CD45-deficient T cells of mice. These data suggest that CD45 inhibitors may also have a role in the symptomatic or therapeutic treatment of allergic disorders. Another newly discovered PTPase, an inducible lymphoid-specific tyrosine phosphatase protein (HePTP) has also been implicated in the immune response. This phosphatase is expressed in both the latent T and B lymphocytes, but not in non-hemopoietic cells. In the stimulation of these cells, the levels of mRNA of the HePTP gene are increased 10-15 times (Zanke et al., Eur. J. Imm., Or 22: 235-239 (1992)). In both the T and B cells, HePTP can function during sustained stimulation to modulate the immune response through the development of specific residues. However, its exact function remains to be defined. Likewise, the PTP1C specific for hematopoietic cells seems to act as a negative regulator and has an essential function in the development of immune cells. In accordance with the important function mentioned above of CD45, HePTP and PTP1C, selective PTPase inhibitors can be attractive drug candidates both as immunosuppressants and as immunostimulants. A recent study illustrates the potential of PTPase inhibitors as immunomodulators by demonstrating the ability of the vanadium-based PTPase inhibitor, BMLOV, to induce selective apoptosis of the B cells evident compared to T cells (Schieven et al., J. Bi ol. Ch., 270: 20824-20831 (1995)).

PTPases: X-cell cell-cell interactions Focal adhesion plaques, an in vitro phenomenon in which specific contact points are formed when fibroblasts grow on appropriate substrates, resemble, at least in part, cells and their natural environments. Several focal adhesion proteins are phosphorylated on tyrosine residues when the fibroblasts adhere and expand on the extracellular matrix (Gumbiner, Neuron 11, 551-564 (1993)). However, the aberrant tyrosine phosphorylation of these proteins can lead to cell transformation. The intimate association between PTPases and focal adhesions is supported by the discovery of several intracellular PTPases with N-terminal fields resembling ezrin, for example, PTPMEG1 (Gu et al., Proc. Nati. Acad. Sci. USA 88: 5867-5871 (1991)), PTPH1 (Yang and Tonks, Proc. Nati. Acad, Sci. USA 88: 5949-5953 (1991)) and PTPD1 (Maller et al., Proc. Nati. Acad. Sci. USA 91 : 7477-7481 (1994)). 'The ezrin-like field shows similarity to several proteins that are thought to act as links between the cell membrane and the cytoskeleton. PTPD1 was found to be phosphorylated by and associated with c-src in vitro and the hypothesis is formed that it is involved in the regulation of focal adhesion phosphorylation (Meiller et al., Supra). PTPases can be opposed to the action of tyrosine kinases, including that responsible for phosphorylation of focal adhesion proteins, and therefore can function as natural inhibitors of transformation. TC-PTP, and especially the truncated form of this enzyme (Cool et al., Proc. Nati, Acad. Sci. USA 87: 7280-7284 (1990)), can inhibit the transformation activity of v-erb and v- FMS (Lammers et al., Biol. Chem. 268: 22456-22462 (1993); Zander et al., Oncogene 8: 1175-1182 (1993)). Furthermore, it is found that the transformation by the oncogenic form of the HER2 / neu gene was expressed in NIH 3T3 fibroblasts overexpressing PTPIB (Brown-Shimer et al., Cancer Res. 52: 478-482 (1992)). The expression level of PTPIB was found to be increased in a mammary cell line transformed with neu (Zhay et al., Cancer Res. 53: 2272-2278 (1993)). The intimate relationship between tyrosine kinases and PTPases in the development of cancer is further evidence by the recent discovery that PTPe is highly expressed in murine mammary tumors in transgenic mice that overexpress c-neu and v-Ha s -ra s, but do not c-myc or int-2 (Elson and Leder, J. Biol. Chem. 270: 26116-26122 (1995)). In addition, the human gene encoding PTPg was delineated at 3p21, a chromosomal region which is frequently suppressed in renal and lung carcinomas (LaForgia et al., Pro c. Na ti. A ca d. S ci USA 88: 5036 -5040 (1991)). In this context, it seems significant that PTPases appear to be involved in the control of fibroblast growth. In a recent study it was found that 3T3 Swiss cells collected at high density contained a membrane-associated PTPase whose activity on an average is 8 times higher than that of cells collected at low or medium density (Pallen and Tong, Pro c. Na ti US Acad., USA 88: 6996-7000 (1991)). It is hypothesized by the authors that the cell growth density dependent inhibition involves the regulated elevation of the activity of the PTPase (s) in question. In agreement with this observation, a new receptor-type PTPase, bound to a membrane, DEP-1, shows levels of expression (> = 10 times) improved with increased cell density of human embryonic lung fibroblasts WI-38 and fibroblast cell line AG1518 (Ostman et al., Proc. Nati. Acad. Sci. USA 91: 9680-9684 (1994)). Two PTPases, PTP * and PTPμ of the closely related receptor type, can mediate homophilic cell-cell interaction when expressed in nonadherent insect cells, which suggest that these PTPases should have a normal physiological function in cell-to-cell signaling ( Gebbink et al., J. Biol. Chem. 268: 16101-16104 (1993); Brady-Kalnay et al. , J. Cell. Biol. 122: 961-972 (1993); Sap et al. , Mol. Cell. Biol. 14: 1-9 (1994)). Interestingly, PTPk and PTPμ do not interact with each other, despite their structural similarity (Zondag et al., J. Biol. Chem. 270: 14247-14250 (1995)). From the studies described above, it is evident that PTPases may have an important function in regulating normal cell growth. However, as noted above, recent studies indicate that PTPases can also function as positive mediators of intracellular signaling and thus induce or enhance mitogenic responses. The increased activity of certain PTPases must result, therefore, in cell transformation and tumor formation. Indeed, in a study of overexpression of PTPa it was found that it leads to the transformation of the fibroblasts of the rat embryo (Zheng, supra). In addition, a new PTP, SAP-1, was found to be highly expressed in colorectal and pancreatic cancer cells. SAP-1 is delineated to the region ql3.4 of chromosome 19 and must be related to the carcinoembryonic antigen delineated or mapped to 19ql3.2 (Uchida et al., J. Biol. Chem. 269: 12220-12228 (1994)). ). In addition, the dsPTPase, cdc25, cdc2 to Thrl4 / Tyr-15 of s f os are designed and therefore function as a positive regulator of mitosis (see Hunter, Cell 80: 225-236 (1995)). The inhibitors of specific PTPases, therefore, are likely to be e 'significant therapeutic value in the treatment of certain forms of cancer.

PTPases: aggregation of platelets Recent studies indicate that PTPases are centrally involved in platelet aggregation. Activation of platelets induced by the agonist results in calpain-catalyzed cleavage of PTPIB with a 2-fold concomitant stimulation of PTPase activity (Frangioni et al., EMB O J. 12: 4843-4856 (1993)). The cleavage of PTPIB leads to the subcellular relocation of the enzyme and correlates with the transition from reversible to irreversible platelet aggregation in the platelet-rich plasma. In addition, the SH2 field containing PTPase, SHP-1, was found to translocate to the This is the case in platelets after stimulation of thrombin in a manner dependent on aggregation (Li et al., FEBS Lett 343: 89-93 (1994)). Although some details in the two previous studies were recently questioned, there is agreement above all that PTPIB and SHP-1 play a significant functional role in platelet aggregation (Ezumi et al., J. Biol. Chem. 210: 11927-11934 ( nineteen ninety five)) . According to these observations, the treatment of platelets with the PTPase inhibitor pervanadate leads to a significant increase in the secretion, aggregation and tyrosine phosphorylation, (Pumiglia et al., Biochem J. 286: 441-449 (1992)) .

PTPases: osteoporosis The speed of bone formation is determined by the number and activity of the tissues, which in turn is determined by the rate of proliferation and differentiation of the cells of the parent of the cells, respectively. Histohorphorus studies indicate that the number of osteoblasts is the primary determinant of the rate of bone formation in humans (Gruber et al., Mineral Elezctrolyte Metab 12: 246-254 (1987), is observed in Lau et al. ., Biochem. J. 251: 23-36 (1989)). Acid phosphatases / PTPases can be involved in the negative regulation of osteoblast proliferation. Thus, fluoride, which has phosphatase inhibitory activity, has been found to increase spinal bone density in theoporotics by increasing the proliferation of osteoblasts (Lau et al., Supra). Consistent with this observation, an osteoblastic acid phosphatase with PTPase activity was found to be highly sensitive to the mitogenic concentrations of fluoride (Lau et al., J. Biol. Chem. 260: 4653-4660 (1985); al., J. Biol. Chem. 262: 1389-1397 (1987): Lau et al., Adv. Protein Phosphatases 4: 165-198 (1987)). Interestingly, it was recently found that the level of membrane-bound PTPase activity increased dramatically when the osteoblast-like cell line UMR 106.06 was developed on the type I matrix of collagen compared to tissue culture plates. not coated. Since a significant increase in PTPase activity was observed in fibroblasts captured by density-dependent growth (Pallen and Tong; Proc. Nati. Acad. Sci. 88: 6996-7000 (1991)), it should be speculated that the Increased PTPase activity directly inhibits cell growth. The mitogenic action of fluoride and other phosphatase inhibitors (molybdate and vanadate) can thus be explained by its inhibition of acid phosphatases / PT Pa s that negatively regulate osteoblast cell proliferation. The nature of the complex of PTPase envelopment in bone formation is further suggested by the recent identification of a new receptor-like PTPase, regulated by parathyroid, OST-PTP, expressed in bone and teste (Mauro et al., J. Bi Ol. Ch em. 269: 30659-30667 (1994)). OST-PTP is up-regulated following the differentiation and formation of primary osteoblast matrix and subsequently down-regulated in osteoblasts which are actively mineralizing bones in the culture. It can be hypothesized that PTPase inhibitors can prevent differentiation via inhibition of OST-PTP and other • PTPases, which leads to continuous proliferation. This could be in accordance with the aforementioned effects of fluoride and the observation that tyrosine phosphatase-inhibiting orthovanadate appears to improve osteoblast proliferation and matrix formation (Lau et al., En do cr inolo gy 1 1 6: 2463-2468 (1988)). In addition, it was recently observed that vanadate, vanadil and pervanadate all increase the growth or development of the UMR106 osteoblast-like cell line. Vanadil and pervanadate were stronger stimulators of cell growth than vandate. Only vanadate was able to regulate cell differentiation when measured by cellular alkaline phosphatase activity (Cortizo et al., Mol Cell, Biochem 145: 97-102 (1995)).

PTPases: microorganisms Dixon and colleagues have drawn attention to the fact that PTPases can be a key element in the pathogenic properties of Yersinia (see Clemens et al., Molecular Microbiology 5: 2617-2620 (1991)). This discovery was quite surprising since tyrosine phosphatase is considered to be absent from bacteria. The genus Yersinia comprises 3 species: Y. Pestis (responsible for the bubonic plague), Y -pseudoturberculosis and Y.

Enterocolitica (which causes' enteritis and mesenteric lymphadenitis). Interestingly, a specific double phosphatase, VH1, has been identified in Vaccinia virus (Guan et al., Nature 350: 359-263 (1991)). These observations indicate that PTPases can play critical roles in microbial and parasitic infections, and they also point to PTPase inhibitors as a principle of putative, new treatment of infectious diseases.

BRIEF DESCRIPTION OF THE INVENTION The present invention relates to compounds of the general formula I, wherein A, Ri, z, R3, R, R16 and R17 are as defined in the detailed part of the present disclosure, wherein such compounds are pharmacologically useful inhibitors of Tyrosine Protein Phosphatases (PTPases) such as PTPIB, CD45, SHP-1, SHP-2, PTP, LAR and HePTP or the like. The present compounds are useful for the treatment, prevention, elimination, alleviation, or amelioration of an indication related to type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autism. oin unit and AIDS, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, priorative disorders including cancer and psoriasis, diseases with synthesis or effects of growth hormone, decreased or increased, diseases with synthesis decreased or increased levels of hormones or cytokines that regulate the release of / or the growth hormone response, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases. In another aspect, the present invention includes within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable diluent or carrier. In another aspect of the present invention, a method is provided for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, priorative disorders including cancer and psoriasis, diseases with synthesis or effects of growth hormone, decreased or increased, diseases with decreased or increased synthesis of hormones or Cytokines that regulate the release of / or the response to growth hormone, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases. The method of treatment can be described as the treatment, prevention, elimination, alleviation or improvement of one of the above indications, which comprises the step of administering to the subject a neurologically effective amount of a compound of the invention, or a pharmaceutically salt acceptable of it. A further aspect of the invention relates to the use of a compound of the present invention for the preparation of a pharmaceutical composition for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance. , obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with synthesis or effects of growth hormone, diminished or increased, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of / or the response to growth hormone, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases.

DESCRIPTION OF THE INVENTION The present invention relates to a Compound of Formula 1 wherein A, Ri, R2, R3, R, R and R17 are as defined below; Formula 1 In the above Formula I - - A is together with the double bond in Formula 1 indolyl, benzo [] t-phenoyl or, benzo [b] furani lo, indazolyl, benzo [b] i soxa zol il or, benzimidazolyl, benz t hi a zolyl, benzoxazolyl, 9H-1-ene [2, 3-c] chromenyl, 4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl, 4, 5, 6, 7-tetrahydro-thieno [ 2, 3-b] pyridyl, 4, 5, 6, 7-tetrahydro-thieno [2,3-c] pyridyl, 4,5,6,7-tetrahydro-thieno [3,2-c] pyridyl, 4, 5,6,7-tetrahydro-thieno [3,2- b] pyridyl, 4,7-dihydro-5H-thieno [2, 3-c] pyranyl, 4,7-dihydro-5H-thieno [2, 3 - c) ti opi rani 1 oo 4, 5, 6, 7 - t et rahidro- 4, 7 -et anon-thieno [2, 3-b] pyridyl; Ri is hydrogen, COR5, OR6, CF3, nitro, cyano, SO3H, S02NR7R8, PO (OH) 2, CH2PO (OH) 2, CHFP0 (0H) 2, CF2PO (OH) 2, C (= NH) NH2, NR7R8 or it is selected from the following heterocycles with 5 elements: HN -S NC R- e s wherein R 2, R 13, and R 4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylC 6 -Cal, and the alkyl and aryl groups are optionally substituted; R2 is COR5, OR6, CF3, nitro, cyano, S03H, S02NR7R8, PO (OH) 2, CH2PO (OH) 2, CHFPO (OH) 2, CF2PO (OH) 2, C (= NH) NH2, NR7R8 or select from the following heterocycles with 5 element os: R3, Ri6 and R17 are independently hydrogen, halo, nitro, cyano, thaltenenet, alkyl of 1 to 6 carbon atoms, aryl, arylC6-alkyl, hydroxy, OXO, carboxy, carboxy-Ci- C6alkyl, alkyloxycarbonyl of 1 to 6 carbon atoms, aryloxycarbonyl, arylC? - C6alkyl 1 oxycarbonyl, alkyloxy of 1 to 6 carbon atoms, C? -C6alkyl 1 oxyCalkyl, aryloxy, arylC? -C6alkyloxy, arylCi-CealkyloxyCi-Cealkyl, thio, alkylthio of 1 to 6 carbon atoms, Ci-CealkylthioCi-Cealkyl, arylthio, arylC-C6alkylthio, aIlC? -C6a 1 qu and 11 IoCi-C6a 1 qu i 1, NR7R8, C? -C6alkylaminoC? -C6alkyl, arICi-C6alkylaminoC? -C6alkyl, di (arylCi-C6alkyl) aminoC? -C6alkyl, alkylcarbonyl of 1 to 6 carbon atoms, CiC'6a lqui 1 carboni 1 -C.sub.-C6alkyl, arylCi-Ca.sub.1 carbon 1, arylC.sub.12 -C.salkylcarbonylCi-Csalkyl, at 1 qui 1 carboxy of 1 to 6 carbon atoms, Ci-CsalkylcarboxyCi-Ce-alkyl, arylcarboxy, ary1 carboxyC ? -C6alqui lo, arilC? -C6-alqu ilcarboxi, arylC? -C6alkylcarboxyC? -C6alkyl, alkylcarbonylamino of 1 to 6 carbon atoms, Ci-CealkylcarbonylaminoCi-Cealkyl, -carbonylNR7C? -C6alkylCOR ??, arylCi-C6alkylcarbonylamino, alky1Ci-C6alkylcarbonylaminoC? -C6alkyl , CONR7R8, or C? ~ C6alkylCONR7R8 wherein the aryl and alkyl groups are optionally substituted and Rn is NR7R8, or C? -C6alkylNR7Rs; or R3 is wherein R.sub.2, R.sub.13, and R.sub.14 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylC? -C6alkyl, and the alkyl and aryl groups are optionally substituted; R 4 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, aryl, α-C 1 -C 6 alkyl, NR 7 R 8, alkyloxy of 1 to 6 carbon atoms; wherein the alkyl and aryl groups are optionally substituted; R5 is hydroxX, alkyl of 1 to 6 carbon atoms, aryl, to rilC? -C6a 1 qui 1 o, alkyloxy of 1 to 6 carbon atoms, C? -C6a to 1-oxyCi-C6alkyloxy, aryloxy, to riCC ? -Cea 1 qu i 1 oxy, CF3, NR7R8; wherein the alkyl and a r i 1 groups are optionally substituted; Re is hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arcC? -C6alkyl; wherein the alkyl and aryl groups are optionally substituted; R7 and R3 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-1α, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylC?-C6a, 1-carboni , at 1 qui 1 carboxy of 1 to 6 carbon atoms or arylCi-Cßalkylcarboxy wherein the alkyl and aryl groups are optionally substituted; or R7 and R8 are together with the nitrogen to which they are linked forming a cyclic ring system, saturated or partially saturated or aromatic tricyclic bicyclic, containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can be optionally substituted with at least one C 1 -C 6 -alkyl, aryl, C 1 -C 6 -alkalkyl, hydroxy, oxo, C 1 -C 6 -alkyloxy, C 1 -C 6 -cycloalkyl, C 1 -C 6a-1-oxyCi-C-alkyl, NR 9 R 10 C? -C6alkyl-C -Calkyl lo, wherein R9 and R? 0 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkyl, alkylcarbonyl of 1 to 6 atoms of carbon, arylcarbonyl, arylCi-Cßalkylcarbonyl, alkylcarboxyl of 1 to 6 carbon atoms or arylC? -C6alkylcarboxy; wherein the alkyl and aryl groups are optionally substituted; or R7 and R8 are independently a red, 5-, 6- or 7-element, cyclic saturated or partially saturated, imide or lactam amine; or a salt thereof with a pharmaceutically acceptable base or acid, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.DEFINITIONS Signal transduction is a collective term used to define all cellular processes that show the activation of a given cell or tissue. Examples of signal transduction, which are not intended to be in any way limiting the scope of the claimed invention, are cellular events that are induced by polypeptide hormones and growth factors (eg, insulin, growth factors I and II). insulin-like, growth hormone, epidermal growth factor, platelet-derived growth factor), cytokines (eg, interleukins), extracellular matrix components, and cell-cell interactions.

Phosphotyrosine recognition units / tyrosine phosphatase recognition units / pTyr recognition units are defined as areas or fields of proteins or glycoproteins that have affinity for molecules containing phosphorylated tyrosine residues (pTyr). Examples of pTyr recognition units, which are not proposed to be in any way restrictive of the scope of the claimed invention, are: PTPases, SH2 field and PTB fields. PTPases are defined as enzymes with the ability to dephosphorylate the proteins or proteins contained in pTyr. Examples of PTPases, which are not intended to be in a limiting manner for the scope of the claimed invention, are: 'Classic' PTPases (intracellular PTPases (eg PTPIB, TC-PTP, PTP1C, PTP1D, PTPD1, PTPD2) and PTPases of the receptor type (eg PTPa, PTPe, PTPβ, PTPy, CD45, PTPK, PTPμ), double-specific phosphatases (VH1, VHR, cdc25), LMW-PTPases or acid phosphatases Fields of SH2 (homology fields) 2 of Src) are non-catalytic protein modules that bind to pTyr (fossil residue fot iros ina) that contains proteins, that is, the SH2 fields are pTyr recognition units.The SH2 fields, which consist of residues of -100 amino acids, are found in a number of different molecules involved in signal transduction processes.The following is a non-limiting list of proteins containing SH2 fields: Src, Hck, Lck, Syk, Zap70, SHP- 1, SHP-2, STATs, Grb-2, Shc, p85 / Pl3K, Gap, vav (see Russell et al, FEBS Lett. 304: 15-20 (1992); Pa are, Nature 373: 573-580 (1995); Sawyer, Biopolymers (Peptide Science) 47: 243-261 (1998); and references here). As used herein, the term "attached" or "-" (eg, -CORn which indicates the carbonyl attachment point to the table or structure) means a stable covalent bond, certain preferred points of the linking points are obvious to those skilled in the art. The terms "halogen" or "halo" include fluorine, chlorine, bromine, and iodine. The term "alkyl" includes methylene and unsaturated aliphatic hydrocarbon groups of 2 to 6 carbon atoms, straight chain saturated of 1 to 6 carbon atoms, unsaturated aliphatic hydrocarbon groups of 2 to 6 carbon atoms and branched saturated of 1 to 6 carbon atoms, unsaturated aliphatic hydrocarbon groups of 5 to 6 carbon atoms and saturated cyclic -3 to 6 carbon atoms, and branched or straight chain unsaturated aliphatic hydrocarbon groups of 2 to 6 carbon atoms and saturated branched or straight chain of 1 to 6 carbon atoms, substituted with unsaturated aliphatic and saturated cyclic hydrocarbon groups of 3 to 6 carbon atoms, having the specified number of carbon atoms. For example, this definition will include but not be limited to methyl (Me), ethyl (Et), propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, isopropyl (i) -Pr), isobutyl (_i-Bu), tere-butyl (t-Bu), sec-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, methylcyclopropyl, ethylcyclohexenyl, but eni Iciclopent ilo, and similar before. The term "substituted alkyl" represents an alkyl group as defined above wherein the substituents are independently selected from halo, cyano, nitro, t-riha-1-ornethyl, carbamoyl, hydroxy, oxo, COR5, alkyl, to 6 carbon atoms, alkyloxy of 1 to 6 carbon atoms, aryloxy, arylC-Csal, loxy, thio, alkylthio of 1 to 6 carbon atoms, arylthio, aryl, C6-C6a, 1-tio, NR7R8, alkylamino of 1 to 6 carbon atoms, arylamino, ar i lC? -C6a 1 qu i 1 amino, di (arylC? _- Cßa lqui 1) amino, alkylcarbonyl of 1 to 6 carbene atoms, ar i lCi-Cßa lqu lcarbonyl, 1-carboxy having 1 to 6 carbon atoms, arylcarboxy, arylCi-C6a 1 -carboxy, 1-carbon-1-aminocarbon having 1 to 6 carbon atoms, -Cx-C6a-1 and 1-aminoCORn, arylCi-C6alkylcarbonylamino, tetrahydrofuranyl, morpholinyl, piperazinyl, -CONR7R8, -C? -Cea 1 qu i 1 -CONR7R8, or an amine of 5, 6 or 7 elements, cyclic saturated or partially saturated ada, imida or lactama; wherein RH is hydroxy, alkyl of 1 to 6 carbon atoms, aryl, to rilCi-Ceal which, alkyloxy of 1 to 6 carbon atoms, aryloxy, arylC? -C6alkyloxy and R5 is defined as above or NR7R8, wherein R, R8 are defined as above. The term "cyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic ring system" represents but is not limited to aziridinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, 2-imide zolimin, imidazolidinyl, pyrazolyl, 2 -pira zolini 1, 1, 2, 3 - 1 ria z ol i lo, 1, 2, 4 - 1 r ia zol ilo, morpholinyl, pipér idinilo, thiomorpholinyl, piperazinyl, indolyl, isoindolyl, 1,2,3,4-tetrahydro -quinolinyl, 1, 2, 3, 4-tetrahydro-isoquinolinyl, 1,2,3,4-tetrahydroquinoxalinyl, indolinyl, indazolyl, benzimidazolyl, ben zotria zoli lo, purinyl, carbazolyl, acridinyl, pheno tia z ini 1 o, fenoxa z ini lo, iminodibencil or, iminoes t ilbenilo. The term "alkyloxy" (eg, methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an "alkyl" group as defined above having the indicated number of carbon atoms attached through a bridge "of Oxygen The term "alkyloxyalkyl" represents an "alkyloxy" group linked through an alkyl group as defined above having the indicated number of carbon atoms The term "alkyloxyalkyloxy" represents an "alkyloxyalkyl" group attached through a Oxygen atom as defined above having the indicated number of carbon atoms The term "aryloxy" (e.g., phenoxy, naphthyloxy, and the like) represents an abilic group as defined later bound through an oxygen bridge. The term "arylalkyloxy" (e.g., phenethyloxy, naphthyl iloxy and the like) represents an "arylalkyl" group as defined below attached through an oxygen bridge. The term "ar i lalqui loxialqui 1 or" represents an "arylalkyloxy" group as defined above linked through an "alkyl" group defined above having the indicated number of carbon atoms.

The term "arylthio" (for example, phenylthio, naphthylthio and the like) represents an "aryl" group as defined below attached through a sulfur bridge. The term "alkyloxycarbonyl" (for example, methionyl, ethyl formate, and the like) represents an "alkyloxy" group as defined above linked through a carbonyl group. The term "aryloxycarbonyl" (for • example, f eni 1 formate, 2 -thia zol il formate and the like) represents an "aryloxy" group as defined above linked through a carbonyl group. The term "arylalkyloxycarbonyl" (for example, benzylformamide, fetalkylformate and the like) represents an "arylalkyloxy" group as defined above linked through a carbonyl group. The term "alkyloxycarbonyl" represents an "alkyloxycarbonyl" group as defined above attached through an "alkyl" group as defined above having the indicated number of carbon atoms.

The term "arylalkyl loxycarbonylalkyl" or "represents an" arylalkyloxycarbonyl "group as defined above attached through an" alkyl "group as defined above having the indicated number of carbon atoms. The term "alkylthio" (for example, methylthio, ethylthio, propylthio, cyclohexenyl, and the like) represents an "alkyl" group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. . The term "arylalkylthio" (for example, femmethylthio, pheny1 and i11, and the like) represents an "arylalkyl" group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term "alkylthioalkyl" represents an "alkylthio" group attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkyl" or "alkali" or "represents an" arylalkylthio "group attached through an alkyl group as defined above having the indicated number of carbon atoms.

The term "alkylamino" (for example, methylamino, diethylamino, butylamino, N-propyl-N-hexylamino, (2-cyclopentyl) propylamino, hexen-1-amino, pyrrolidinyl, piperidinyl and the like) represents one or two groups " alkyl "as defined above having the indicated number of carbon atoms attached through an amine bridge. The two alkyl groups can be taken together with the nitrogen to which they are attached forming a cyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one alkyl of 1 to 6 carbon atoms, aryl, arylCi-C-alkyl, hydroxy, oxo, alkyloxy of 1 to 6 carbon atoms, C? -C6a The C 1 -C 6alkyl, NR 9 R 10, C 1 -C 6a 1 and C 1 -C 6alkyl is substituted where the alkyl and aryl groups are optionally substituted as defined in the definition section and R 9 and R 10 are. define as above.

The term "arylalkyl lamino" (eg, benzylamino, di phenylethylamino and the like) represents one or two "arylalkyl" groups as defined above having the indicated number of carbon atoms attached through an amine bridge. The two "arylalkyl" groups can be taken together with the nitrogen to which they are attached to form a cyclic, bicyclic or tricyclic, saturated, partially saturated or aromatic ring system containing 3 to 14 carbon atoms and 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system may be optionally substituted with at least one alkyl substituent of 1 to 6 carbon atoms, aryl, arylC.-C6alkyl, hydroxy, oxo, alkyloxy of 1 to 6 carbon atoms. carbon, d-C6a lkyloxiC? -C6alkyl, NR9R? 0, C? ~ Cea 1 qui laminoCi-Cßa where the alkyl and aryl groups are optionally substituted as defined in the definition section and R9 and Rio are defined as above. The term "alkylaminoalkyl" represents an "alkylamino" group attached through an alkyl group as defined above having the indicated number of carbon atoms. The term "ar i lalqui lami noalqui lo" represents a "ari lalqui lamino" group bonded through an alkyl group as defined above having the indicated number of carbon atoms. The term "arylalkyl" (eg, benzyl, phenylethyl) represents an "aryl" group as defined below linked through an alkyl having the indicated number of carbon atoms or substituted alkyl group as defined above. The term "alkylcarbonyl" (eg, cyclohexylcarbonyl, pentylcarbonyl, 3-hexenylcarbonyl) represents an "alkyl" group as defined above having the indicated number of carbon atoms attached through a carbonyl group. The term "arylcarbonyl" (benzoyl) represents an "aryl" group as defined above linked through a carbonyl group. The term "aryl-1-carbonyl" (for example, phenyl-cyclopropyl-1-carbon or phenyl-ethylcarbonyl and the like) represents an "arylalkyl" group as defined above having the indicated number of carbon atoms attached through of a carbonyl group. The term "alkylcarbonylalkyl" represents an "alkylcarbonyl" group attached through an "alkyl" group as defined above having the indicated number of carbon atoms. The term "arylalkyl carbon 1 alkyl" represents a group "1 to 1 carbon" linked through an alkyl group as defined above having the indicated number of carbon atoms. The term "alkylcarboxy" (for example, heptylcarboxy, cyclopropyl carboxy, 3-penty eny1 carboxy) represents an "alkylcarbonyl" group as defined above wherein the carbonyl is in turn linked through an oxygen bridge. The term "arylcarboxyalkyl" (e.g., phe 1 carboxymethyl 1) represents an "arylcarbonyl" group defined above wherein the carbonyl is in turn linked through an oxygen bridge to an alkyl chain having the indicated number of carbon atoms. carbon atoms. The term "arylalkylcarboxy" (for example, benzylcarboxy, phenol, citriccarboxy, and the like) represents a group "arylalkylcarboni 1 or" as defined above wherein the carbonyl is in turn linked through an oxygen bridge. The term "alkoxycarboxy" denotes an "alkylcarboxy" group bonded through an "alkyl" group as defined above having the indicated number of carbon atoms. The term "arylalkyl 1 ca rboxia 1 qui lo" represents an "arylalkylcarboxy" group linked via an "alkyl" group as defined above having the indicated number of carbon atoms. He . The term "alkylcarbonylamino" (eg, hexylcarbonylamino, cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) represents an "alkylcarbonyl" group as defined above wherein the carbonyl is in turn linked through the nitrogen atom of an amino group. The nitrogen atom can be replaced by itself with an alkyl or aryl group. The term "ar i laqui 1 carboni lamino" (for example, benzylcarbonylamino and the like) represents an "arylalkyl 1 carbonyl" group as defined above wherein the carbonyl is in turn linked through the nitrogen atom of a group Not me. The nitrogen atom can be replaced by itself with an alkyl or aryl group. The term "alkylcarboni laminoalkyl" represents an "alkylcarbonylamino" group linked through an "alkyl" group as defined above having the indicated number of carbon atoms. The nitrogen atom can itself be substituted with an alkyl or aryl group. The term "arylalkyl-1-carbonyl amino" represents an "arylalkylcarbonylamino" group bonded through an "alkyl" group as defined above having the indicated number of carbon atoms. The nitrogen atom can be replaced by itself with an alkyl or aryl group.

The term "Alkylcarbonylaminoalkylcarbonyl" represents a group to which the 1-carbonyl amino acid is attached through a carbonyl group. The nitrogen atom can be further substituted with an "alkyl" or "aryl" group. The term "aryl" represents monocyclic, polycyclic, unsubstituted heterocyclic aromatic and biaryl groups, mono-, di-ot-risubsides covalently bonded to any position on the ring capable of forming a stable covalent bond, certain preferred binding sites or binding are obvious to those skilled in the art (e.g., 3-indolyl, 4-imi zolyl). The aryl substituents are independently selected from the group consisting of halo, nitro, cyano, t-rihalomethyl, alkyl of 1 to 6 carbon atoms, aryl, aryl-C6-alkyl, hydroxy, COR5, alkyloxy from 1 to 6 carbon atoms, C 1 -Ca 1 -alkyl-1-oxyC6a-1-one, aryloxy, arylCi-C6alkyloxy, arylC6alkyl, Ci-C6alkyl, thio, alkylthio from 1 to 6 carbon atoms. carbon, Ci-C6alkylthio Ci-C 6a 1 a, arylthio, arylC? -C6alkylthio, arylC? -C6a 1 qu and 11 cycloC6a, cycloalkyl, NR8R9, alkylamino of 1 to 6 carbon atoms Ci-C6a 1 the inoCi-Cealqui lo, arylamino, arylC? -C6alkyl amino, arylCi-Cealkyl-aminoCi-Cgalkyl, di (arylC? -C6alkyl) aminoCi-Cealkyl, alkylcarbonyl of 1 to 6 carbon atoms, C? ~ Cea lqui read C -Calkyl, -CalkylCalkylCalkylcarbonyl, C -CalkylC6alkyl 1 -carbonylCi -Cealkyl, alkylcarboxylic acid of 1 to 6 carbon atoms, Ci-Cealkylcarboxy-Ci-Cgalkyl, arylC? -C6alkylcarboxy, arylC? C6alkylcarboxyCi-C6alkyl, carboxyCi-C-alkyloxy, alkylcarbonylamino of 1 to 6 carbon atoms, C6-C6alkylcarbonylaminoC? -C6alkyl, carnationnylNR7C? -C6alkylCOR ??, aI1CiC6alkylcarbonylamino, arylC? -C6alkylcarbonylaminoC? -C6alkyl, -CONR8R9, or -Ci -C6a lqui 1 CONR8R9; wherein R7, R8, R9, and RH are as defined above and the alkyl and aryl groups are optionally substituted as defined in the definition section; The definition of aryl includes but is not limited to phenyl, biphenyl, indenyl, fluorenyl, naphthyl (1-naphthyl, 2-naphthyl), pyrrolyl (2 -pi rroli lo), pyrazolyl (3-pyrazolyl), imidazolyl (1-imido zoli lo, 2-imidazolyl, 4-imide zoli lo, 5 -imide zol i 1 o), triazolyl (1, 2, 3 -1 ria zol- 1-i lo, 1, 2, 3 -1 ria zol -2 -ilo, 1, 2, 3-triazol-4-yl, 1, 2, 4-1 ri a zol-3-yl) oxazolyl (2 -oxa zolyl, 4-oxazolyl, 5 -oxa zol i 1 o), isoxazolyl (3-isoxa zolyl, 4-i soxa zol ilo, 5- i scxa zol ilo), thiazolyl (2-1 ia zolyl, 4-thiazolyl, 5-thiazolyl), thiophenyl (2-t iofeni lo, 3-thiophenyl, 4-thiophenyl, 5-t-phenyl phenyl), furanyl ( 2-furanyl, 3-furanyl, 4-furanyl, 5-furanyl), pyridyl (2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl), 5-tetrazolyl, pyrimidinyl (2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidine 1 or, 6-pi rimidini lo), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridinyl), quinolyl (2-quinolyl, 3-quinolyl, -quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl, 8 -quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoqui no 1 i 1), benzo [b] ] furani lo (2-benzo [b] furanyl, 3 -benz or [b] furani lo, 4-benzo [b] furanyl, 5 -benzo [b] furani lo, 6-benzo [b] furani lo, 7 - ben zo [b] furani 1 o), 2,3-dihydro-benzo [b] furanyl (2- (2,3-dihydro-benzo [b] furanyl), 3- (2,3-dihydro-benzo [b ] furanyl), 4- (2,3-dihydro-benzo-b) furanyl), 5- (2,3-dihydro-benzo-b) furanyl), 6- (2,3-dihydro-benzo-b) furani-lo), 7- (2,3-dihydro-benzo b] furanyl)), benzo [b] thiophenyl (2-benzo-b) thiophenyl, 3-benzo [b] thiophenyl, 4-benzo b] thiophenyl, 5 -be zo [b] t-phenoyl, 6-benzo b] thiophenyl, 7-benzo [b] thiophenyl), 2,3-dihydro-benzo [b] -thiophenyl (2- (2,3-dihydro-benzo [b] thiophenyl) , 3- (2,3-dihydro-benzo [b] -thiophenyl), 4 - (2,3-dihydro-benzo [b] thio-phenyl), 5- (2,3-dihydro-benzo [ b] -thiophenyl), 6- (2, 3-dihydro-benzo [b] thiophenyl), 7- (2,3-dihydro-benzo [b] -thiophenyl)), 4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl (2- (4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl), 3- (4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl), 4- (4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl), 5- (4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl), 6 - (. 4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl) ), 7- (4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl)), 4,5,6,7-tetrahydro-thieno [2, 3-c] pyridyl (4- (4,5) 6,7-tetrahydro-thieno [2,3-c] pyridyl), 5- (4,5,6,7-tetrahydro-thieno [2, 3-c] pyridyl), 6- (4, 5, 6, 7-tetr hydro-thieno [2, 3-c] pyridol), 7- (4, 5, 6, 7-tetrahydro-thieno [2, 3-c] pyridyl)), indol ilo (1 -indolyl, 2-indolyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 7-indolyl), isoindolyl (1-isoindolyl, 2-isoindolyl, 3-isoindolyl, 4-isoindolyl, 5-isoindolyl , 6-isoindol i lo, 7-isoindolyl), 1,3-dihydro-i soindolyl (1- (1,3-dihydro-isoindolyl), 2- (1,3-dihydro-isoindolyl), 3- (l, 3-dihydro-isoindolyl), 4- (1, 3-dihydro-isoindolyl), 5- (1,3-dihydro-1-syndiolyl), 6- (1, 3-dihydro-isoindolyl), 7- (1, 3-dihydro-isoindolyl)), indazole (1 -indazolyl, 3-indazolyl, 4-inda zolyl, 5-inda zo 1, 6-indazolyl, 7-inda zolyl) ), benzimido zol i lo (X-benzimidazolol, 2-benzimidazolol, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidozolol, benzimidazolyl) benzoxazolyl (1-benzoxazole, 2 - . 2-benz oxa zo 1 i 1 o), benzothiazolyl 1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl), carbazolyl (1-carbazolyl, 2- carbazyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz [b, f] a zepine (5H-dibenz [b, f] azepin-1-yl, 5H-dibenz [b, f] azepin -2-yl, 5H-dibenz [b, f] az epin-3-ylo, 5H-dibenz [b, f] azepin-4-yl, 5H-dibenz [b, f] azepin-5-yl), 10,11-dihydro-5H-dibenz [b, f] azepine (10,11-dihydro-5H-dibenz [b, f] azepin-1-yl, 10,11-dihydro-5H-dibenz [b, f ] azepin-2-yl, 10,11-dihydro-5H-dibenz [b, f] azepin-3-yl, 10,11-dihydro-5H-dibenz [b, f] azepin-4-yl, 10, ll -dihydro-5H-diben z [b, f] to zepin-5-yl), piperidinyl (2-piperidinyl, 3-piper idinyl, 4 -piper idini lo), pyrrolidinyl (1-pi rrolidini lo, 2 -pi rrolidini lo, 3-pi rrolidini 1 o), f eni Ipi ridyl (2-phenyl-pi r idi lo, 3-phenyl-pyridi lo, 4-phenylpi he l), phenyl p rimine (2-phenyl p ri i di ni 1 or, 4-phenyl-pyrimidinyl, 5-phenylimidimidinyl, 6-phenylpiidimide), pyridinyl pyridine, phenylpyride zinyl (3-phenylpiperidinyl, 4-phenylpiidazine) 5-phenylephine, inyl). The term "arylcarbonyl" (for example 2-thio phenylcarbonyl, 3-methoxycarbonyl, oxazolylcarbonyl represents an "aryl" group as defined above linked through a carbonyl group. the 1-carboni-1-yl group (eg, (2,3-dimethoxyphenyl) propylcarbonyl, (2-chloronaphthyl) pentenylcarbonyl, imide zol ilc, clopentylcarboni lo) represents an "arylalkyl" group as defined above wherein the group " alkyl is in turn bonded through a carbonyl The compounds of the present invention have asymmetric centers and can occur or be present as racemates, racemic mixtures, and as individual enantiomers or diastereomers, with all isomeric forms included in the present invention, as well as mixtures thereof - The pharmaceutically acceptable salts of the compounds of the formula 1, wherein a basic group or acid is present in the structure, also n are included within the scope of this invention. When an acidic substituent is present, such as -COOH, 5-tetra-zolyl or P (0) (OH) 2, the salt of calcium, ammonium, morpholino, sodium, potassium, barium and the like can be formed for use in the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acid salt such as hydrochloride, hydrobromide, phosphate, sulfate, trifluoroacetate, trichloroacet a to, acetate, oxalate, maleate, pyruvate, malonate, succinate, citrate, tartarate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethane sulfonate, picrate and the like, and includes acids related to the pharmaceutically acceptable salts listed in the Journal of Pharmaceutical Science, 66, 2 (1977) and incorporated herein by reference, can be used as the dosage form. Also, in the case of -COOH or -P (0) (0H) 2 which are present, the pharmaceutically acceptable esters can be used, for example, methyl, tere-butyl, pi va 1 or loxime ti lo, and the like, and these esters known in the art to modify the solubility or hydrolysis characteristics for use as prodrug or prolonged release formulations. In addition, some of the compounds of the present invention can form solvates with water or common organic solvents. Such solvates are included within the scope of the invention. The term "therapeutically effective amount" will mean that amount of drug or pharmaceutical agent that will produce the biological or medical response of a tissue, system, animal, or human that is being treated by a researcher, veterinarian, medical doctor or other.

PREFERRED MODALITIES OF THE INVENTION The compounds of Formula I are the preferred compounds of the invention Formula the wherein A is together with the double bond in the Formula indolyl, benzo [b] t iof eni lo, benzo [b] furani lo, indazolyl, benzo [b] i soxa zol i 1, benzimidazolyl, ben z thi a zolyl, benzoxazolyl, 4, 5, 6, 7-tet rahydro-thieno [2,3-b] pyridyl, 4,5,6,7-tetrahydro-t iron [2,3-c] pyridyl, 4,5 6,7-tetrahydro-t-ene [3,2-c] pyridyl, 4,5,6,7-tetrahydro-thieno [3,2- b] pyridyl, 7-dihydro-5H-t-ene [2] , 3-c] pyranyl or 4, 5, 6, 7-t and rahydro-, 7-et anon-thieno [2, 3-b] pyridyl; Ri is COR5, 0R6, CF3, nitro, cyano, S03H, S02NR7R8, PO (OH) 2, CH2P0 (OH) 2, CHFPO (OH) 2, CF2PO (OH) 2, C (= NH) NH2, NR7R8 or select from the following heterocycles with 5 elements: or Ri is wherein R.sub.2, R.sub.13, and R.sub.4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, R.sub.1 -Ce.sup.-one-one-one-one and the alkyl and aryl groups are optionally substituted; R2 is COR5, OR6, CF3, nitro, cyano, S03H, S02NR7R8, PO (OH) 2, CH2PO (OH) 2, CHFP0 (0H) 2, CF2P0 (0H) 2, C (= NH) NH2, NR7R8 or is selected from C? -C6alkyl-aminoC? -C6alkyl, arylCi-CealkylaminoCi-C-alkyl, di (arylCi- C6alkyl) aminoCi-Cdalkyl, alkylcarbonyl of 1 to 6 carbon atoms, C? -C6alkyl 1 carbonylC? C6alkyl, arICI? -C6alkylcarbonyl, arylC? -CalkylcarbonylCalkyl, alkylcarboxyl of 1 to 6 carbon atoms, CiCalkylcarboxyC -C6alkyl, arylcarboxy, arylCi-C-alkylcarboxy, arylC? -CdalkylcarboxyC? -C6alkyl , C 1 -C 6 alkylcarbonylamino, C 1 -C 6a 1 -calkyl 1 -laminoC 6 -Catoyl, carbonylNR 7 C 1 -C 6 alkylCORn, arylC 6 -Calkylcarbonylamino, arylC 6 -CalkylcarbonilaminoC 6 -Calkyl, CONR7R8, or C? -C6alkylCONR7R8 wherein the aryl and alkyl groups are optionally substituted and Rp is NR7R8, or C? -C6a lqui 1NR7R8; or R3 is where R? _2, R? , and R 4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, alkyl, and alkyl are optionally substituted; R 4 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, aryl, arylC 6 -Calkyl, NR 7 R 8, alkyloxy of 1 to 6 carbon atoms; wherein the alkyl and aryl groups are optionally substituted; R5 is hydroxy, alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cealkyl, CF3, NR7R8; wherein the alkyl and aryl groups are optionally substituted; Re is hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arcC? -C6a alkyl; wherein the alkyl and aryl groups are optionally substituted; R7 and R8 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, a rilC-C6a 1 qui 1, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylC? -C6a, 1-carbon 1 or, alkyl 1 carboxy of 1 to 6 carbon atoms or arylC? -C6a 1 qui 1 carboxy wherein the alkyl and aryl groups are optionally substituted; or R7 and R8 are together with the nitrogen to which they are linked forming a cyclic or -bicyclic system containing 3 to 11 carbon atoms and 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur, the ring system can be optionally substituted with at least one alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cealkyl, hydroxy, alkyloxy of 1 to 6 carbon atoms, arylCi-Cßalkyloxy, Ci-Cea lqui 1 oxyCj-C6alkyl, NR9R? 0 or Cj - C to 1 qui 1 amino -Ci -Ca 1 to 1, where R9 and Rio are independently selected from hydrogen, alkyl of 1 to 6 atoms of carbon, aryl, to rIlC-C6allo, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylCi-Cea 1 that read rboni lo, 1 to 1 cabox of 1 to 6 carbon atoms or arylC? -C6alkylcarboxi; wherein the alkyl and aryl groups are optionally substituted; or R7 and R8 are independently a red, 5-, 6- or 7-element, cyclic saturated or partially saturated, imide or lactam amine; In addition, the preferred compounds of the invention are the compounds of the formula wherein R1 6 and R? they are hydrogen. The invention in its broadest aspect will cover the following compounds: of Formula Ib: Formula Ib wherein A together with the double bond in Formula Ib is aryl; Ri is hydrogen, COR5, OR6, CF3, nitro, cyano, S03H, S02NR7R8, P0 (0H) 2, CH2PO (OH) 2, CHFP0 (0H) 2, CF2P0 (0H) 2, C (= NH) NH2, NR7R8 or it is selected from the following heterocycles with 5 elements: HN -S or R is wherein R 2, R 13, and R 4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylC 6 -C alkyl, and the alkyl and aryl groups are optionally substituted; R2 is C0R5, 0R6, CF3, nitro, cyano, S03H, S02NR7R8, P0 (0H) 2, CH2P0 (0H) 2, CHFP0 (0H) 2, CF2P0 (0H) 2, C (= NH) NH2, NR7R8 or is selected from the following heterocycles with 5 e 1 ement: HN -S X " R3, R1 and R17 are independently hydrogen, halo, nitro, cyano, thaltenenetium, alkyl of 1 to 6 carbon atoms, aryl, arylCi-C6-alkyl, hydroxy, oxo, carboxy, carboxy-Ci-Cealkyl, alkyloxycarbonyl of 1 to 6 carbon atoms, aryloxycarbonyl, arylCj-Cßalkyl loxycarbonyl, alkyloxy of 1 to 6 carbon atoms, C?-C6alkyl 1 oxyC?-C6a 1 qui lo, aryloxy, aryl X-Ceal qui loxi, arilCx- CealkyloxyCi-Cealkyl, thio, alkylthio of 1 to 6 carbon atoms, C? ~ C6a lqui 11 ioC? -C6alto what, arylthio, arylCx-C6alkylthio, to riCiC6a-1c? 11i oC? -Ceach l, 1, NR7R8, Ci-CealkylaminoCi-Cealkyl, arylCiCa lkylaminoCi-Cßal qui lo, di (arylC? -C6alkyl) aminoC? -C6alkyl, alkylcarbonyl of 1 to 6 carbon atoms, C -C6a 1 qui 1 ca rboni 1 - C ~ C6alkyl, arylC6a1, 1-carbonyl, arylCi-C6a lk-carboncarboniC-C6alkyl, 1-carboxylcarboxycarbon of 1 to 6 carbon atoms, Cj-C6a 1-carboxy Ci-C6 -alkyl, arylcarboxy, ary 1 carboxyC? -C6a, cycloalkyl, arylC? -C6-alkylcarboxy, arylC? -C6alkylcarboxyC? -C6alkyl, alkylcarbonylamino of 1 to 6 carbon atoms, C? -C6alkylcarbonylaminoC? -C6alkyl, -carbonylNR7C? C6alkylC0Rn, arylCL-C6a 1 qui 1 carboni lamino, arylCiCalkylcarbonylaminoC? -Calkyl, CONR7R8, or C? -C6alkylCONR7R8 wherein the aryl and alkyl groups are optionally substituted and Rp is NR7R8, or C1-C6alkylNR7R8; or R3 is wherein R.sub.2, R.sub.13, and R.sub.4 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, a.sub.1 -C.sub.6 -C.sub.1 to 1 and the alkyl and alkyl groups are optionally substituted; R4 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, aryl, arC1C6alkyl, NR7R8, alkyloxy of 1 to 6 carbon atoms; wherein the alkyl and aryl groups are optionally substituted; Rs is hydroxy, alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cealkyl, CF3, NR7R8; wherein the alkyl and aryl groups are optionally substituted; Re is hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylC? -C6alkyl; wherein the alkyl and aryl groups are optionally substituted; R7 and R8 are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-C-alkyl, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylCi-C6a 1 qui 1 carboni lo, alkylcarboxi of 1 to 6 carbon atoms or arylC? -C6alkyl 1 carboxy wherein the alkyl and aryl groups are optionally substituted; or R7 and R8 are together with the nitrogen to which they are linked forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system, containing from 3 to 14 carbon atoms and from 0 to 3 additional heteroatoms selected from the nitrogen, oxygen or sulfur, the ring system can be optionally substituted with at least one alkyl of from 1 to 6 carbon atoms, aryl, arylC6-C6alkyl, hydroxy, oxo, alkyloxy of 1 to 6 atoms of carbon, arcC? -C6alkyloxy, Ci-Cea 1 qui 1 oxyCi-C6alkyl, NR9R? 0 or Ci-Cea 1 qui lamino-C? -C6a lqui lo, where R9 and Rio are independently selected from hydrogen, alkyl 1 to 6 carbon atoms, aryl, aryl C1-C6alkyl, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylCi-Cealkyl 1 carbonyl, hydrocarboxyl of 1 to 6 carbon atoms or arylCi-Cgalkylcarboxyl; wherein the alkyl and aryl groups are optionally substituted; or R7 and R8 are independently a red, 5-, 6- or 7-element, cyclic saturated or partially saturated, imide or lactam amine; or a salt thereof with a pharmaceutically acceptable base or acid, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any autotransformations. Particular preferred compounds of the invention are those compounds of formula 1 wherein -Ri is 5-tetrazolyl, ie. or CQR5 and R2 is C0R5. In particular, the preferred compounds are those wherein R5 is OH and R4 is hydrogen.

The following compounds are preferred: 2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-benzo [b] thiophene-3-carboxylic acid; 2- (Oxalyl-amino) -6-oxo-4,5,6,7-tetrahydro-benzo [b] thiophene-3-carboxylic acid; 6-Benzoyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridin-3-carboxylic acid; 6-Benzyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 6-Methyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [2, 3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -6-phenethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; -Benzoyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [3,2-c] pyridine-3-carboxylic acid; -Benzyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [3,2-c] pyridin-3-carboxylic acid; -Methyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [3,2- c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -5-phenethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridine-3-carboxylic acid; 2- (Oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2 - (Oxal-ilinoamino) -, 5, 6, 7-t and rahydro-4,7-ethano-thieno [2,3-b] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -6-pyridin-2-ylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; Acid 2 - (oxa 1 i 1 -amino) -5 - (((4-oxo-chromene-4 H-2 -carbonyl) amino) methyl) -4,7-dihydro-5H-thieno [2, 3-c ] pyran-3-carboxylic; 6- (3-Methoxy-benzyl) -2 - (oxal-yl-amino) 4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 6- (Oxa 1 i 1 -amino) -1 H -indole-7-carboxy 1 i co; 6- (Oxalyl-amino) -lH-indole-5-carboxylic acid; 1- (3-methoxy-benzyl) -6- (oxalyl-amino) -1H-indole-5-carboxylic acid; 2- (Oxalyl-amino) -6-pyridin-3-ylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -6-pyridin-4-ylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalylamino) -5- (2'-spiro [1 ', 3'] dioxolan) -6,7-dihydro-4H-benzo- [b] thiophene-3-carboxylic acid; 3- [4- (3-Morpholin-4-yl-propionyl) piperazin-1-ylmethyl] -6- (oxalyl-amino) -lH-indole-5-carboxylic acid; 2 - (Oxalyl-amino) -6-quinolin-2-ylmethyl-1,4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] thiopyran-3-carboxylic acid; 2- (Oxalylamino) -6-oxo-4,7-dihydro-5H-thieno [2,3-c] thiopyran-3-carboxylic acid; 2 - (Oxalylamino) -6,6-dioxo-4,7-dihydro-5H-thieno [2, 3-c] thiopyran-3-carboxylic acid; 2- (Oxalyl-amino) -9H-thieno [2,3-c] chromen-3-carboxylic acid; 2 - ((2-H-tetrazole-5-carbonyl) amino-4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; N- (3- (2H-tetrazol-5-yl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) oxalamic acid; 6-Benzyl 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyridin-3,6-di-carboxylic acid ester; 6-Ethyl 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyridin-3,6-dicarboxylic acid ester; 6-Acetyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2, 3-c] pyridin-3-carboxylic acid; 2- (Oxalyl-amino) -6-phenylcarbamoylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; - (1, 3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3- acid carboxylic; - (Benzoylamino-methyl) -2- (oxalyl-amino) acid 4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; Acid 5 -ben z oi loxi e t i 1 - 2 - (oxa 1 i 1 -amino) -4,7-dihydro-5 H -thieno [2, 3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (1-oxo-l, 3-dihydro-5-isoindol-2-ylmethyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 1- (2- (4-Methyl-piperazin-1-yl) -2-oxo-ethyl) -6- (oxalyl-amino) -lH-indole-7-carboxylic acid; -0 N- (4-carboxymethyl-4,5,6,7-tetrahydrobenzo [b] thiophen-2-yl) -oxalamic acid;N- (4-carboxymethylene-4,5,6,7-tetrahydro-5-benzo [b] thiophen-2-yl) -oxalamic acid; N- (4-carboxymethyl-4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) -oxalamic acid; 0 N- (- ca rboxime t i len-, 7-dihydro-5 H -thieno [2, 3-c] pyran-2-yl) -oxalamic acid; N- (4- (2H-tetrazol-5-ylmethyl) -4,5,6,7-tetrahydro-benzo [b] thiophen-2-yl) -oxalamic acid; N- (4- (2H-tetrazol-5-ylmethyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) -oxalamic acid; 2- (Oxalyl-amino) -5- ((3-phenoxy-benzoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((3,5-Dimethoxy-benzoylamino) -methyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((3,5-bis-trifluoromethyl-benzoylamino) -ethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((Cyclohexanecarbonyl-amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((3-dimethylamino-ben zoi 1 amino) -me th il) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 - acid rboxíico ca; - ((4-Acetylamino-benzoylamino) -methyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; Acid 5 - ((2 - ci cl open t -2 - in i 1 -a ce ti 1 amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3- c] pyran-3-carboxylic; - ((2-Acetylamino-benzoylamino) -methyl) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((3-Methoxy-benzoylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid i; co; - ((4-Dimethylamino-benzoylamino) -methyl) -2- (oxaii 1-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((4-phenoxy-benzoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((4-Acetoxy-benzoylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; Acid 5 - (but -2-ene i 1 amino-me ti 1) - 2 - (oxa 1 i 1 -amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-ca rboxí lico; 2- (Oxalylamino) -5- ((4-oxo-4-phenyl-butyrylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((5-oxo-hexanoylamino) -ethyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 4-Carboxymethyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-benzo [b] thienophen-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((2-t-iof-2-yl-acetylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (((lH-Indole-2-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (((1H-indol-3-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 acid -carboxylic; - (((lH-Indole-5-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((3-pyridin-3-yl-acryloylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((4-oxo-4-phenyl-but-2-enoylamino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- acid carboxylic; - ((2- (4-Benzyloxy-phenoxy) -acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((4-oxo-4H-chromen-3-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran- 3-carboxylic; - (((5-Benzyloxy-1H-indole-2-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3-carboxylic; 2- (Oxalyl-amino) -5- ((3-thiophen-2-yl-acryloylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((4-oxo-chromen-4H-3-ca-rboni-1) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3-carboxylic; 2- (Oxalyl-amino) -5 - ((3-phenyl-propionilamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pran-3-carboxylic acid; - (((furan-2-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (((Naphthalene-2-carbonyl) -amino) -methyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2 - (Oxa 1 i 1 -amino) -5 - ((2-phenoxy-acetylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (phenylacetylamino-methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2- (3,4-Dimethoxy-phenyl) -acetylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-acid carboxylic; - ((2- (4-Ethoxy-phenyl) -acetylamino) -methyl) 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((3-phenyl-acryloylamino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pi r an- 3 - caboxy 1 i acid co; Acid 5 - ((3 - (3,5-dimethoxy-f-en-1) acryloylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- caboxic acid; Acid 2 - (oxa 1 i 1 -amino) - 5 - (((5-oxo-pi r ro li din- 2 ca rboni 1) -amino) -methyl) -4,7-dihydro-5H-thieno [2 , 3-c] pyran-3-carboxylic acid; - (((furan-3-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((thiophene-2-ca rbon i 1 amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((pyrazine-2-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((((l-oxy-pyridine-2-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- acid carboxylic; Acid 2 - (oxa 1 i -amino) - 5 - (((pi ri din-2-carboni 1) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran -3-carboxylic; 2- (Oxalyl-amino) -5- (((pyridine-3-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-ca-carboxylic acid; - ((2- (3,5-b? S-trifluoromethyl-f-enyl) -acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-] c] pyran-3-carboxylic; - ((3-Benzenesulfonyl-propionylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-t-ene [2, 3-c] pyran-3-carboxylic acid; - ((3- (3, 5-di f luoro-feni 1) acryloylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran -3-carboxylic acid; 2- (Oxalylamino) -5 - ((4-oxo-pent-2-enylamino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] p'í ran-3 - acid ca rb ox í 1 ico; - ((3 - (1,3-Dioxo-1,3-dihydr-o-i-soindol-2-yl) -propionylamino) -methyl) -2- (oxalyl-amino) -4,7-d -hydro- 5 H -thieno [2, 3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((6-oxo-heptanoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2- (4-Dimethylamino-phenyl) -acetylamino) methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (((Benzo (1,3) dioxol-5-carbonyl) -amino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3-carboxylic; - ((2-Acetylamino-3-phenyl-propionylamino) methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2-Acetoxy-benzoylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2 - (Oxalyl-amino) -5- ((2-oxo-3-phenyl-propionylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2-Benzoylamino-acetylamino) -methyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5 - ((4-oxo-pentanoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((3-furan-2-yl-acryloylamino) -methyl) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2-Acetylamino-acetylamino) -methyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((2-phenylsulfanyl acetylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; Acid 5 - ((2-benz i 1 s ul fani 1 - a cet i 1 amino) -me ti 1) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2, 3 -c ] pyran-3-carboxylic; - ((2- (lH-indol-3-yl) -2-oxo-acetylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; - ((3- (1H-Indol-3-yl) -2-ox? 'Propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3 c] pyran-3-carboxylic; - ((3- (2-nitrophenyl) -2-oxo-propionylamino) -methyl-2- (oxalyl-amino) -4,7-dihXdro-5H-thieno [2, 3-c] acid pyran-3-ca rboil; - ((2-Acetylamino-3-phenyl-acryloylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (((1-Cetyl-pyrrolidin-2-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran- 3-carboxylic; Acid 5 - ((2 - (1,3-dioxo-1,3-dihydro-i oindo 1 -2 -yl) -3- (1H-imidazol-4-yl) -propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((4 - (3,4-dimethoxy-f-enyl) -2-oxo-but-3-eneylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid 2, 3-c] pyran-3-carboxylic acid; - ((3-lH-benzoimidazol-2-yl-propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - ((2- (1,3-dioxo-l, 3-dihydro-isoindol-2'-yl) -butyrylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic acid; - ((2-Acetylamino-propionylamino) -methyl) 2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2-Acetyl-1-amino-4-methyl-1-amino-1-butyrylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3 -c] pyran-3-carboxylic acid; - ((2 - (1,3-Dioxo-1,3-dihydro-i-soindol-2-yl) -4-methyl-pentanoylamino) -methyl) -2- (oxalyl-amino) -4-7 acid dihydro-5H-thieno [2, 3-c] pyran-3-caboxic acid; Acid 5 - ((2-α-Cetylamino-3-methyl-1 -but iri lamí) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-tiepo [2, 3-c] pyran-3-carboxylic; - ((2- (1,3-Dioxo-l, 3-dihydro-isoindol-2-yl) -3-phenyl-propionylamino-propionylamino) -methyl) -2- (oxalyl-amino) -4- -dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - ((3-furan-3-yl-acryloylamino) -methyl) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; Acid 5 - ((2-indan-2-i 1 -acetylamino) -met i 1) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 -carboxylic; - (((9,10-dioxo-9,10-dihydro-anthracene-2 carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; Acid 5 - ((2 - (naphta 1 en-1-yloxy) -acetylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2, 3 c] pyran-3-carboxylic; 2- (Oxalyl-amino) -5- (((4-oxo-4H-chromen-2-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran acid -3-carboxylic acid; 2- (Oxalyl-amino) -5 - ((3-oxo-indan-l-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - ((2- (1,3-Dioxo-1,3-dihydro-iso-indol-2-yl) -propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-caboxic acid; 7- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 acid -carboxylic; 7- (Acetylamino-methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5 (((3-oxo-indan-l-carbonyl) amino) methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - (2,4-Dioxo-thiazolidin-3-ylmethyl) -2 '(oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (5,6-Dichloro-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3 -c] pyran-3-carboxylic acid; - (1,3-Dioxo-l, 3 / 4,5,6,7-hexahydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2] , 3-c] pyran-3-carboxylic acid; 2 - (Oxalyl-amino) -5- (1, 1, 3-trioxo-1,3-dihydro-lH-benzo [d] isothiazol-2-ylmethyl) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic acid; - [(4-Methoxy-benzenesulfonylamino) -methyl) 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; N- (6-hydroxy-3-hydroxymethyl-4,5,6,7-tetrahydro-benzo [b] thiophen-2-yl) -oxalamic acid; 2 - (Oxal-il-amino) -6- (2'-spiro [1 ', 3'] dioxolan) -6,7-dihydro-4H-benzo [b] thiophene-3-carboxylic acid; - (2-Methyl-4-oxo-4H-quinazolin-3-ylmethyl) 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (5-Chloro-l, 3-dioxo-6-sulfamoyl-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2] , 3-c] pyran-3-carboxylic acid; Acid 5 - (5,7-dioxo-5,7-dihydro-pi rolo [3,4 b] pyridin-6-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [ 2, 3-c] pyran-3-carboxylic acid; - (1, 3-Dioxo-1,3-dihydro-pyrrolo [3, 4 c] pyridin-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - (5,7-di-oxo-5,7-dihydro-pyrrol [3, 4 • b] pyrazin-6-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H- acid thieno [2, 3-c] pyran-3-carboxylic acid; - (5-Nitro-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; - (1, 3-dioxo-3, -dihydro-lH-isoquinolin-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 -carboxylic; - (4,6-Dioxo-4,6-dihydro-thieno [2, 3 c] pyrrol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - (4,6-Dioxo-4H, 6H-thieno [3,4-c] pyrrol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; - (4,6-Dioxo-2,6-dihydro-4H-pyrrolo [3,4 c] pyrazol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid 2, 3-c] pyran-3-carboxylic acid; Acid 5 - (4,6-di oxo-4,6-dihydro-dihydro-3-dihydro-3-dihydro-3-dihydro-4-dihydro-4H-dihydro-4H-dihydro-5H-) thieno [2, 3-c] pyran-3-carboxylic acid; - (2-Acetylamino-4,6-dioxo-4, β-dihydro-pyrrolo [3, 4-d] thiazol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H acid -thien [2, 3-c] pyran-3-carboxylic acid; - (5-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] acid ] pyran-3-carboxylic; - (5-methoxy-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic; - (4-Hydroxy-1,3-dioxo-1,3-dihydr? 'Isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-] acid c] pyran-3-carboxylic; - (4-methoxy-1,3-dioxo-1,3-dihydr? 'Isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-d -hydro-5H-thieno acid [2, 3 -c] pyran-3-carboxylic acid; Acid 5 - (4-nitro-1,3-dioxo-1,3-dihydro-i soindol • 2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; Ac Xdo 5- (4-acetyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 carboxylic; - (2,6-dioxo-4-trifluoromethoxyphenyl) -1- piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2 r 3-c] acid ] pyran-3-carboxylic; - (4-Methanesulfonyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - (5-Methylcarbamoyl-l, 3-dioxo-l, 3-dihydr? 'Isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3 -c] pyran-3-carboxylic acid; - (5-ethylcarbamoyl-l, 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] acid ] pyran-3-carboalonic; - (5-Propicarbamo i 1 - 1,3-di-oxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid , 3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (1-thioxo-1,3-dihydro-isoindol-2-ylmethyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (4-Dimethylcarbamoyl-2,6-dioxo-piperazin-l-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (4-Methylcarbamoyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; - (2,6-Dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; - (4-Carbamoylmethyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; Acid 5 - (4-carboxymethyl-2-6-dioxo-p iper azi n-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran -3-carboxylic acid; - (3,5-Dioxo-2,3-dihydro-5H-benzo [f] [1,4] oxazepin-4-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H- acid thieno [2, 3-c] pyran-3-carboxylic acid; - (2-Acetylamino-5, 7-dioxo-5, 7-dihydro-pyrrolo [3, 4-d] pyrimidin-6-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H acid -thien [2, 3-c] pyran-3-carboxylic acid; - (4- (4-Acetylamino-benzenesulfonyl) -2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3 -c] piran-3-ca rboxí lico; - (4- (Methoxy-methyl-carbamoyl) -2,6-di-oxo-piperidin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3- c] pyran-3-carboxylic; PHARMACOLOGICAL METHODS The compounds are evaluated for biological activity with. a truncated form of PTPIB (corresponding to the first 321 amino acids), which was expressed in E. coli and purified to apparent homogeneity using published procedures well known to those skilled in the art. The reactions of the enzyme were performed using standard conditions essentially as described by Burke et al. (Bi o ch emi s t ry 35; 15989-15996 (1996)). The test conditions are as follows. The appropriate concentrations of the compounds of the invention are added to the reaction mixture containing different concentrations of the substrate, p-nitrophenyl phosphate (range: 0.16 to 10 mM - concentration of the final assay). The buffer solution used was 100 mM sodium acetate at pH 5.5, 50 M sodium chloride, 0.1% bovine serum albumin (w / v) and 5 mM dithiothreitol (total volume 100 ml). The reaction was initiated by the addition of the enzyme and plated on my plates at 25 ° C for 60 minutes. The reactions were suspended or interrupted by the addition of NaOH. The activity of the enzyme was determined by measuring the absorbance at 405 nm with appropriate corrections for the absorbance at 405 nm of the compounds and p-nitrophenyl phosphate. The data are analyzed using an appropriate non-linear regression to the kinetic models of the classic Michaelis Menten enzyme. Inhibition is expressed as Kx values in μM. The results of the representative experiments are shown in Table 1.

Table 1 Inhibition of classical PTPIB by the compounds of the invention In addition, the compounds are evaluated for biological activity in terms of their effect as PTPa inhibitors in essentially the same way as described for the inhibition of PTPIB. Derivatives of their activity as previously evaluated the compounds of the invention may be useful in the treatment of diseases selected from the group consisting of type I diabetes, type II diabetes, tolerance of glucose deterioration, insulin resistance and obesity. In addition, derived from their activity as evaluated above, the compounds of the invention may be useful in the treatment of diseases selected from the group consisting of immune dysfunctions including immunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma. , osteoporosis, primate disorders including cancer and psoriasis, diseases with decreased or increased synthesis or hormonal growth effects, diseases with decreased or increased synthesis of hormones that regulate the release of / or response to hormonal growth , brain diseases including Alzheimer's disease schizophrenia, infectious diseases.

SYNTHESIS OF THE COMPOUNDS In accordance with one aspect of the invention, the compounds of the invention are prepared as illustrated in the following reaction scheme: Method A Allowing an aryl or substituted heteroaryl (I) to react with an acid chloride of the formula (II), wherein A, R1; R2, R3, R4, Ri6 and Ri7 are defined as above.

Mé t o d o B By allowing a carboxylic acid (I), a primary amine (II) and an aldehyde (III) to react with an isocyanide (IV) wherein R? 2, Ri3, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, to RiCi-Cea lqu i 1 or as defined above and the alkyl and aryl groups are optionally substituted as defined above; or R? 2, R13, Rp, and R15 are independently selected from where Y indicates the point of attachment for R? _2, R13, R14, and R15 and A, Ri, R2, and R4, are as defined above. In a preferred method, the Ugi reaction of the fourth component described above can be performed by attaching any of the components to a solid support. Therefore, the synthesis can be done in a style of bonding chemistry.

Method C Allowing an amine (I) and a substituted 4,5-dihydr or -7 H-1 ieno [2, 3-c] pir an (II) to react under basic conditions (for example K2C03, in N, -dime t ilf ormami da or methyl ethyl ketone) or under Mitsunobu conditions (Oyó Mitsunobu, Syn thesis, (1981) 1-28) to yield (III) where X is OH, OS02Me or halo, and Rl r R2, R, R7 and R8 are defined previously.

The general procedure for the Preparation of the Esters of Ace t oxime ti 1 or (C. Schultz et al, The Journal of Biological Chemistry, 1993, 268, 6316-6322.): A carboxylic acid (1 equivalent) was suspended in acetonitrile dry (2 ml per 0.1 mmol). Diisopropyl amine (3.0 equivalents) was added followed by bromomethyl acetate (1.5 equivalents). The mixture was stirred under nitrogen overnight at room temperature. The acetonitrile was removed under reduced pressure to yield an oil which was diluted in ethyl acetate and washed with water (3 x). The organic layer was dried over anhydrous magnesium sulfate. Filtration followed by removal of the solvent under reduced pressure produced a crude oil. The product was purified by column chromatography on silica gel, using an appropriate solvent system. The present invention also has the objective of providing topical, oral and parenteral pharmaceutical formulations suitable for use in the new methods of the treatment of the present invention. The compounds of the present invention can be administered orally as tablets, aqueous or oily suspensions, pills, troches, powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavoring agents, coloring agents and preserving agents to produce the excellent and pharmaceutically acceptable preparations. The tablets contain the active ingredient in a mixture with pharmaceutically acceptable non-toxic excipients which are suitable for the production of the tablets. These excipients may be, for example, (1) inert diluents, such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating and disintegrating agents, such as corn starch or alginic acid; (3) binding agents, such as starch, gelatin or acacia; and (4) lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets can be covered or uncovered by known techniques to retard disintegration and absorption in the gastrointestinal tract and therefore provide a sustained action over a long period. For example, a time-delaying material such as glycerol monostearate or glycerol distearate may be employed. The cover or coating can also be made using the techniques described in US Pat. Nos. 4,256,108; 4,160,452; and 4,265,874 to form controlled release osmotic therapeutic tablets. Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of a soft gelatin capsule wherein the active ingredient is mixed with water or in an oily medium, such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions usually contain the active materials in a mixture with excipients suitable for the production of aqueous suspension. Such excipients may be (1) suspending agent such as sodium carboxymethylcellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and acacia gum; (2) dispersing or soaking agents which may be (a) naturally occurring phosphatide such as lecithin; (b) a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; (c) a condensation product of ethylene oxide with a long-chain aliphatic alcohol, for example, heptadecaethyleneoxycetanol; (d) a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or (e) a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example, po-oxy oxy-1 in sorbitan. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to known methods using those dispersing or soaking agents and suspending agents which are mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenterally diluent or solvent acceptable, for example, as a solution in 1, 3 -butadiene or 1. Among the vehicles and acceptable solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, established, sterile oils are conventionally employed as a solvent or medium to be suspended. For this purpose, any soft established oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as acetic acid or oleic acid find use in the preparation of injectants. The Compounds of the invention can also be administered in the form of suppositories by rectal administration. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The compounds of the present invention can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multimeric vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phospholipid 1 -co1 ine. For topical use are employed, creams, ointments, jellies, solutions or suspensions, etc., which contain the compounds of Formula 1. The dosage levels of the compounds of the present invention are in the order of about 0.5 mg to about 100. mg per kilogram of body weight, with a preferred dosage range between about 20 mg to about 50 mg per kilogram of body weight per day (from about 25 mg to about 5 g per patient per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dose will vary depending upon the patient being treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain 5 mg to 1 g of an active compound with an appropriate and convenient amount of the carrier material which may vary from about 5 to about 95 percent of the total composition. The unique dosage forms will generally contain between about 5 mg to about 500 mg of the active ingredient. It will be understood, however, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, gender, diet, time of administration, route of administration. the administration, rate of excretion, combination of the drug and the severity of the particular disease to be submitted to therapy. The necessary dosage will be individualized by the doctor.

EXAMPLES The process for preparing the compounds of Formula 1 and the preparations containing them are further illustrated in the following examples, which, however, were not constructed to limit the invention. Hereinafter, TLC is thin layer chromatography, CDC13 is dechloric chloroform, CD3OD is methanol t et r adeutio and DMSO-d6 is dimethylsulfoxide hexadeu t e rio. The structures of the compounds are confirmed by either elemental or NMR analysis, where the peaks assigned to characteristic protons in the title compounds are present where appropriate. 1H NMR shifts (dp) are given in parts per million (ppm) lower field of t etry as the internal reference standard. M.p. : is the melting point and is provided in ° C and is not corrected. Column chromatography was performed using the technique described by W.C. Still et a l. , J. Org. Ch em. 4: 2923 (1978) on Merck 60 silica gel (Art. 9385). The HPLC analyzes are performed using a 5μm C x 4 x 250 mm column eluted with several mixtures of water and acetonitrile, flow = 1 ml / min, as described in the experimental section. The Wang resin is polystyrene with an ether linker of 4-hydroxymethyl-1-phenol. The compounds used as a starting material are either known compounds or compounds which can be easily prepared by per se known method.

EXAMPLE 1 Monosodium salt of 6-Benzo-i-2- (oxa-1-amino-4-yl) -4,5,6,7-tetrahydro-thieno [2, 3-c] iridin-3-carboxylic acid A mixture of N-benz oí 1 - 4 -pipe r i dona (20.0 g, 0.1 mol), ethyl cyanoacetate (10.9 ml, 0.1 mol), ammonium acetate (2.0 g) and acetic acid (6 ml) in benzene (100 ml) was heated at reflux temperature in a reaction flask. of 3 necks equipped with a Dean-Stark water trap for 1 h. The cooled reaction mixture was diluted with ethyl acetate (100 ml), washed with water (3 x 100 ml), saturated aqueous sodium chloride (80 ml), dried (MgSO) filtered and evaporated in vacuo produce the quantitative yield of the ethyl ester of (l-benzoyl-piperidin-4-ylidene) -cyanoacetic acid as a slow-crystallization oil. A mixture of benzo-1-pipe-ri din-4-phenylidene (10.0 g, 0.034 mol), sulfur (1.13 g, 0.035 mol) and morpholine (6.5 ml) in ethanol (35 ml) was heated to 50 *. "* C for 2 h and was stirred at room temperature overnight. The precipitate was separated by filtration and washed with 96% ethanol (3 x 50 ml), diethyl ether (3 x 50 ml) and dried in vacuo which yielded 9.27 g (84%) of the ethyl ester of the product. 2-amino-6-benzoyl-4,5,6,7-tetrahydro-thieno [2, 3-c] pyridine acid 3-caboxylate as a solid. To a stirred solution of the ethyl ester of 4, 5, 6, 7 -et rahi-thienyl [2, 3-c] pi r idin-3-carboxylic acid (5.0 g, 0.015 mol), triethylamine ( 4.21 ml, 0.03 mol) in dry tetrahydrofuran (30 ml) at 0 ° C was added dropwise a solution of ethyl oxalyl chloride (1.9 ml, 0.017 mol) in dry tetrahydrofuran (20 ml). The resulting reaction mixture was stirred at room temperature for 18 h, poured into ice water (300 ml) and extracted with ethyl acetate (3 x 100 ml). The combined organic extracts were washed with saturated aqueous sodium chloride (100 ml), dried (MgSO), filtered and evaporated in vacuo yielding 4.2 g (84%) of the 6-benzoyl-2-ethyl ester ( ethoxyoxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid as a crystallization oil. To a solution of the ethyl ester of [3, 3-c] pi r idin-3-carboxylic acid (4.2 g, 9.76 mmol) in ethanol (100 ml) was added a solution of sodium hydroxide (0.9 g, 21.46 g. mmol) in water (100 ml). The resulting reaction mixture was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the residue was dissolved in water (100 ml) and washed with ethyl acetate (2 x 100 ml). To the aqueous phase, concentrated hydrochloric acid was added at pH = 1 and the precipitate was filtered off and washed with water (2 x 50 ml), diethyl ether (2 x 30 ml) and dried in vacuo at 50 ° C producing 2.9 g (79%) of the title compound as a solid. P.f. : Master r fo: Calculated for C? 7H? 3N206S? Na ?, 1 x H 2 O; C, 49.28%; H, 3.65%; N, 6.76%. Found: C, 49.31%; H, 3.86%; N, 6.53%. By a similar procedure as described in Example 1 the following compounds have been prepared.

EXAMPLE 2 2- (Oxalyl-amino) -4,5,6,7,7-tetrahydro-benzo [b] thiophene-3-carboxylic acid P. f. : 230-231 ° C Calculated for C11H11NO5S; C, 49.07%; H, 4.12%; N, 5.20% Found C, 49.87%; H, 4.37%; N, 5.06% EXAMPLE 3 6-Benzyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid Calculated for C? 7H? 6N205S, 1.75 H2O; C, 52.10%; H, 5.01%; N, 7.15%. Found: C, 52.11%; H, 4.81%; N, 7.01%.

EXAMPLE 4 6-Methyl-2- (oxalyl-amino) 5,6,7-tetrahydro-thieno [2, 3-c] pyridine-3-carboxylic acid: P.f .: > 250 ° C Calculated for CnH? 2N 05S, 0.6 H20; C, 44.77%; H, 4.51%; N, 9.49%. Found C, 44.54%; H, 4.17%; N, 9.21%.

EXAMPLE 5 Na ' Monosodium salt of 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid: P.f. : > 250 ° C Calculated for CioHsNxOeSNa, 0.75 x H 2 O; C, 39.16%; H, 3.12%; N, 4.57%. Found C, 39.29%; H, 3.67%; N, 4.41%.

EXAMPLE 6 2- (Oxalyl-amino) -6-phenethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid Calculated for C? 8H? 8N205S, 1 x H 2 O; C, 55.09%; H, 5.14%; N, 7.14%. Found: C, 55.47%; H, 5.04%; N, 7.07%.

EXAMPLE 7 2- (Oxalyl-ammonium) -4,5,6,7-tetrahydro-4,7-ethano-thieno [2,3-b] pyridine-3-carboxylic acid: Calculated for C? 2H? 2N205S, 0.75 x H20; C, 46.52%; H, 4.39%; N, 9.04%. Found C, 46.48%; H, 4.79%; N, 8.87%.

EXAMPLE 8 2- (Oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid hydrochloride: Triethyl ester of 4-oxo-1-piperidin carboxylic acid was used as the starting material. The Boc group was removed using 25% trifluoroacetic acid in dichloromethane. P.f. : > 250 ° C Calculated for C? 0H10N2O5S, 1 HCl, 0.5 x H20; C, 38.35%; H, 4.34%; N, 8.64%. Found: C, 38.04%; H, 3.83%; N, 8.87%.

EXAMPLE 9 2- (Oxalyl-amino) -6-pyridin-2-ylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridin-3-carboxylic acid To a mixture of trifluoroacetic acid salt of 2- (ethoxyoxalylamino) -4,5,6,7-tetrahydro-thienyl [2, 3-c] pi ridin-3-carboxylic acid ethyl ester (1.5 g, 3.40 mmol, prepared as described in Example 8), potassium carbonate (2.4 g, 17.1 mmo 1), potassium iodide (100 mg) in acetone (40 ml) was added 2-picolyl chloride hydrochloride (0.61 g, 3.7 mmol) . The resulting mixture was stirred at reflux temperature for 18 h, filtered and evaporated in vacuo. The mixture was triturated with diethyl ether and the solid was filtered off and purified on silica gel (300 ml) using a mixture of ethyl acetate / ethanol / triethylamine (3: 1: 0.4) as eluent. The pure fractions were collected and the eluent was evaporated in vacuo yielding 650 mg (39%) of triethylammonium salt of 2- (ethoxyoxalylamino) -6-pyridin-2-ylmethyl-4, 5, 6, 7 - tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid as a solid. To a solution of the above triethylammonium salt (650 mg, 1.40 mmol) in ethanol (15 ml) was added IN aqueous sodium hydroxide (4.1 ml, 4.1 mmol) followed by water (15 ml). The resulting reaction mixture was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo and the Xduo was dissolved in water (20 ml) and washed with diethyl ether (2 X 10 ml). To the aqueous phase, IN hydrochloric acid was added to pH = 1 and the aqueous phase was evaporated in vacuo. The residue was suspended in a mixture of 2-propanol / water (1: 1, 40 ml), stirred for 1 h, the solid was filtered off and washed with 2-propanol (2 X 15 ml) and dried in vacuo at 50 ° C yielding 181 mg (38%) of the title compound c ru do. The crude product (181 mg) was dissolved in a mixture of water (10 ml) and 5N sodium hydroxide. (10 ml) and washed with diethyl ether (2 X 10 ml). The aqueous phase was acidified to pH = 3 with IN hydrochloric acid and the precipitate was separated by filtration and washed with water (3 X 20 ml), was cured in vacuo at 50 ° C for 1 * 8 h in which 51 mg (11%) of the title compound was provided as a solid. P.f. : 238-244X Calculated for C? 6H15N3? 5S, 2.5 x H2 O; C, 47.29%; H, 4.96%; N, 10.34%. Found: C, 47.43%; H, 4.84%; N, 10.00%. By a similar procedure as described in Example 9 the following compounds were prepared.

EXAMPLE 10 Acid 6 - (3 -me t-oxy-be nci 1) -2 - (oxalylamino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-ca rb ox i 1 i co: P.f. : 233-237 ° C Calculated for C? 8H? 8N206S, 1 x H 2 O; C, 52.93%; H, 4.94%; N, 6.86%. Found C, 52.79%; H, 4.99%; N, 6.42%.

EXAMPLE 11 Cl orhydr a t o of 2 - (or x to 1 il-am i n o) _- 6-pyridin-3-ylmethyl-4,5,6,7-tetrahydro-thieno [2, 3 c] pyridine-3-carboxylic acid: P. f. : 234-238 ° C Calculated for C? 6Hi5N305S, 1 x HCl, 0.5 x H 2 O; C, 47.24%; H, 4.21%; N, 10.33%. Found: C, 47.35%; H, 4.10%; N, 10.35%.

EXAMPLE 12 2- (Oxalyl-amino) -6-quinolin-2-ylmethyl-4,5,6,6-tetrahydroxy-ene [2,3-c] pyridine-3-carboxylic acid: __ P. f. : > 250 ° C Calculated for C2oH 7N305S, 1 x H 2 O; C, 55.95%; H, 4.22%; N, 9.61%. Found C, 55.94%; H, 4.46%; N, 9.78%.

EXAMPLE 13 2 - (Oxy-1-amino) -6-pyridin-4-ylmethyl-4,5,6,7-tetrahydro-thieno [2, 3 c] pyridine-3-carboxylic acid hydrochloride: P.f. : 230-235 ° C Calculated for C? 6H? 5N305S, 1 x HCl, 1 x H20; C, 46.21%; H, 4.36%; N, 10.10%. Found: C, 45.82%; H, 4.42%; N, 10.02%.

EXAMPLE 14 Monosodium salt of 6- (oxalyl-amino) -1H-indole-7-carboxylic acid To a stirred solution of 6-amino-1 H-ind or 1-7-carboxylic acid ethyl ester (1.5 g, 7.3 mmol, prepared as described in J. Org. Chem. 61, 1155-1158 (1996)), triethylamine (1.5 ml, 11.0 mmol) and dry tetrahydrofuran (100 ml) at 0 ° C were added dropwise a solution of ethyl oxalyl chloride (980 μl, 88.0 mmol) in dry tetrahydrofuran (10 ml). The resulting reaction mixture was stirred at room temperature for 2 h. it was poured into ice water (300 ml) and the precipitate was filtered off and dried in vacuo at 50 ° C yielding 2.25 g (100%) of the ethyl ester of 6- (ethoxyoxalylamino) -lH-indole-7-ethyl ester. -carboxylic like an oil. To a solution of the ethyl ester of 1H-i-1-hydroxy-1-carboxylic acid before (2.0 g, 6.6"0 mmol) in water (30 ml) The resulting reaction mixture was stirred at room temperature for 20 minutes. The volatiles were evaporated in vacuo and the hydrochloric acid IN was added to the residual aqueous phase at pH = 1. " The precipitate was separated by filtration and washed with water (2 X 50 ml), diethyl ether (2 X 30 ml) and dried at 50 ° C yielding 1.34 g 82%) of the title compound as a solid. P.f. : > 250 ° C Calculated for CnH7N205Na, 1.5 x H 2 O; C, 44.46%; H, 3.39%; N, 9.43%. Found C, 44.31%; H, 3.34%; N, 9.00%.

By a similar procedure as described in Example 14 the following compound was prepared.

EXAMPLE 15 Monosodium salt of 6- (oxalyl-amino) -1H-indole-5-carboxylic acid The ethyl ester of 6-amino-1H-indole-5-carboxylic acid was prepared as described in J. Org. Ch em. 61, 1155-1158 (1996)). P.f. : > 250 ° C Calculated for CnH7N205Na, 1.5 x H2O; C, 44.46%; H, 3.39%; N, 9.43%. Found: C, 44.44%; H, 3.68%; N, 9.00%.

EXAMPLE 16 Monosodium salt of 3 - [4 - (3-morphin-4-yl-1-propionyl) -piperazin-1-ylmethyl] -6- (oxal-yl-amino) -lH-indole-5-carboxylic acid To a solution cooled with ice of 37% aqueous formaldehyde (2.7 g, 33.0 mmol) in acetic acid (8 ml) was added dropwise a solution of the methyl ester of the piperazidic acid. 1 -carboxy 1 ico (2.7 g, 15 mmol). After stirring for 15 min. A solution of 6- (et oxo oxa 1 i 1 -amino) -1H-indole-5-carboxylic acid (4.0 g, 13.0 mmol) in a mixture of acetic acid (80 ml) and tetrahydrofuran (80 ml) was added. ml) and the resulting reaction mixture was stirred for 18 h. at room temperature. The volatiles were evaporated in vacuo and water (100 ml) was added to the residue. The aqueous phase was extracted with ethyl acetate (2 x 100 ml), the combined organic extracts were washed with water (2 x 100 ml), saturated aqueous ammonium chloride (1 x 80 ml), dried (MgSO), filtered and evaporated in vacuo. The residue was triturated with diethyl ether (50 ml) and the precipitate was filtered off and washed with diethyl ether., dried in vacuo at 50 ° C in which 3.4 g (51%) of the 3- (4-tert-butoxycarbonyl-piperazin-1-ylmethyl) -6- (ethoxy oxa) ethyl ester were produced. 1-ami no) -1H-indole-5-caboxy i i co as a solid. To a solution of the ethyl ester of 6- (ethoxyoxalylamino) -lH-indole-5-carboxylic acid in dichloromethane (20 ml) was added trifluoroacetic acid (20 ml) at room temperature. The resulting mixture was stirred for 1 h, the volatiles were evaporated in vacuo and water (50 ml) was added to the residue and the resulting mixture was stirred for 20. The precipitate was filtered off and washed with water (50 ml. ), diethyl ether (50 ml) and dried in vacuo at 50 ° C in which 3.6 g (100%) of trifluoroacetic acid salt of 6- (ethoxyoxalylamino) -3-piperazine- ethyl ester was produced. li lme ti 1-1 H- indo 1 -5-ca rbox i 1 co as a solid.

To an ice-cooled mixture of the above piperazine (3.0 g, 5.81 mmol) in dichloromethane (100 ml) and triethylamine (2.5 ml) was added dropwise a mixture of chlorochloroxychloride (0.6 ml, 6.39 g. mmol) in dichloromethane (10 ml). The resulting mixture was stirred for 1 h at room temperature, washed with water (50 ml), dried (MgSO), filtered and evaporated in vacuo yielding 1.8 g (6-6.8%) of the ethyl ester of 3 - (4-) acid. a cr i loi 1 -p ipe ra z in -1-ylmethyl) -6- (ethoxyoxalylamino) -lH-indole-5-carboxylic acid as an oil. To a solution of the above mixture (0.5 g, 1.1 mmol) in ethanol (50 ml) was added morpholine (0.24 g, 2.74 mmol). The resulting mixture was stirred at reflux temperature for 18 h and the volatiles were evaporated in vacuo.The residue was dissolved in water (50 ml), the pH was adjusted to 2 with 1 N hydrochloric acid and the resulting mixture was washed with water. ethyl acetate (2 x 50 ml) The aqueous phase was neutralized with IN sodium hydroxide, the precipitate was separated by filtration, washed with water and dried in vacuo at 50 ° C for 3 h. produced 0.3 g (50%) of 6- (ethoxyoxalylamino) -3- [4- (3-morpholin-4-yl-propionyl) -piperazin-1-ylmethyl] -lH-indol-5- ethyl ester carboxylic acid as a solid To a solution of the ethyl ester of lH-indole-5-carboxylic acid (0.2 g, 0.37 mmol), in ethanol (5 ml) was added sodium hydroxide (45 mg, 1.10 mmol) in Water (15 ml) The resulting reaction mixture was stirred at room temperature for 18 h, the pH was adjusted to 1 by the addition of IN hydrochloric acid, the aqueous phase was washed with ethyl acetate (2 x 25 m). l) and the pH was adjusted to 5 by the addition of IN sodium hydroxide, followed by the addition of dichloromethane (25 ml). The precipitate was filtered off and washed with water (50 ml) and dried in vacuo at 50 ° C yielding 30 mg (11%) of the title compound as a solid. P.f. : > 250 ° C LC-MS (E +) M / Z 488 EXAMPLE 17 Ac gone 1- (3-methoxy-benzyl) -6- (oxalyl-amino) -1 H-indole-5-carboxylic acid To a solution of the ethyl ester of 6-amino-1H-indo 1 -5-ca rboxyl-1-co (1.0 g, 3.30 mmol, prepared as described in J. Org Ch., 61, 115-1158 (1996 )) in dry N, N-dimethylformamide (40 ml) was added sodium hydride (0.28 g, 7.3 mmol, 60% in mineral oil). The reaction mixture was stirred for 1.5 h and a solution of 3-methyl t-oxybenzyl chloride (0.5 ml, 3.6 mmol) in dry N-dimet and formamide (2.5 ml) was added dropwise. The resulting reaction mixture was stirred for 1.5 h, poured into water (300 ml) and washed with diethyl ether (3 x 100 ml). The undissolved matter was separated by filtration and the aqueous phase was acidified to pH = 4 by the addition of IN hydrochloric acid. The precipitate was separated by filtration and washed with water, dried in vacuo at 50 ° C yielding 400 mg (29%) of 6- (ethoxyoxalylamino) -1- (3-methoxy-benzyl) ethyl ester. ) - 1H-indo 1 -5-carboxy li co as a solid.

To a solution of the ethyl ester of lH-indole-5-carboxylic acid (0.3 g, 0.7 mmol) in ethanol (10 ml) was added 1N sodium hydroxide (2.1 ml, 2.1 mmol) and water (10 ml). The resulting reaction mixture was stirred at room temperature for 18 h. The volatiles were evaporated in vacuo, the pH was adjusted to 2 by the addition of IN hydrochloric acid, the precipitate was filtered off and washed with water, dried in vacuo at 50 ° C yielding 230 mg (89%) of the compue The product is a solid. P.f. : 222-226 ° C Calculated for C19H? £ N206, 0.4 x H20; C, 60.77%; H, 4.51%; N, 7.46%. Found: C, 60.96%; H, 4.44%; N, 7.28%. By a similar procedure as described in Example 1 the following compound was prepared.

EXAMPLE 18 2- (Oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] thiopyran-3-carboxylic acid: Calculated for C? 0HgN? 5S2; C, "41.80%, H, 3.16%, N, 4.88%, Found: C, 41.97%, H, 3.20%, N, 4.69%.

EXAMPLE 19 Monosodium salt of 2- (oxalyl-amino) -9H-thieno [2, 3-c] chromen-3-carboxylic acid To a solution of 4-chromanone (20 g, 0.14 mol), ethyl cyanoacetate (16.8 g, 0.15 mol) and ammonium acetate (11.4 g, 0.15 mol) in benzene (500 ml) was added acetic acid (5 ml) , the resulting reaction mixture was heated at reflux temperature for 18 h and the water formed was collected in a Dean-Stark water trap. An additional portion of ammonium acetate (10 g, 0.13 mol) was added and heating at reflux temperature was continued for an additional 8 h. The volatiles were evaporated in vacuo, to the residue water (500 ml) was added and the aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined organic extracts were washed with water (2 x 100 ml), saturated aqueous sodium chloride (100 ml), dried (MgSO 4), filtered and evaporated in vacuo or yielding a mixture of 1: 1 of starting material without change and ethyl ester of chroman-4-i-lead-cyano-acetic acid as an oil. To a solution of the crude product in ethanol (250 ml) was added sulfur (2.5 g, 0.08 mol) and morpholine (15 ml). The resulting reaction mixture was stirred at 50 ° C for 4 h and cooled to room temperature and filtered. The volatiles were evaporated in vacuo yielding 30, g of the crude product. The product was divided into two portions, one of which was semi-purified on silica gel (900 ml) using a mixture of ethyl acetate / heptane (1: 3). The semi-pure fractions were collected and the solvent evaporated in vacuo yielding a crude oil which was dissolved in diethyl ether (80 ml) and crystallized by the addition of heptane (125 ml). The precipitate was separated by filtration, washed with heptane and dried in vacuo at 50 ° C for 18 h yielding 8.9 g (24%) of the ethyl ester of 2-amino-9H-thieno [2, 3-c] - Chromen- 3- carboxy 1 ico as a sun gone. To a stirred solution of the ethyl ester of 2-amino-6H-thiol ene [2, 3-c] cr ornen-3-carboxylic acid (2.9 g, 10.53 mmol), triethylamine (3 ml) in dry tetrahydrofuran (100 ml) at 0 ° C a solution of ethyl oxalyl chloride (1.6 g, 11.6 mmol) in dry tetrahydrofuran (20 ml) was added dropwise. The resulting reaction mixture was stirred at room temperature for 1.5 h. it was poured into ice-cold water (200 ml) and the precipitate was filtered off and dried in vacuo at 50 ° C. under 2.6 g (66%) of the ethyl ester of 2- (ethoxyoxali- amino) -9H-thieno [2, 3-c] chromen-3-carboxylic acid as a solid To a solution of the above ethyl ester (1.5 g, 4.0 mmol) in ethanol (25 ml) was added sodium hydroxide (480 mg , 12 mmol) and water (50 ml) The resulting reaction mixture was stirred at room temperature for 42 hrs Water (100 ml) was added and the mixture was washed with diethyl ether (100 ml) The aqueous phase was acidified by the addition of concentrated hydrochloric acid to pH = 1, the precipitate was filtered off, washed with water and dried in vacuo at 50 ° C for 6 h, yielding 0.6 g (47%) of the compound of 1 title as a solid Pf: 227-228 ° C Calculated for d4H9N06SNa, 0.5 H 2 O; C, 48.01%; H, 2.59%; N, 4.00% Found: C, 48.39%; H, 2.93%; N, 3.93% .

EXAMPLE 20 2- ((2-H-tetrazole-5-carbonyl) -amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid: A mixture of oxalyl chloride (0.8 g, 6.31 mmol) in acetonitrile (1) was added dropwise to a mixture of N, N-dimethy1-formamide (1.6 ml) and acetonitrile (5 ml) cooled to -20 ° C. ml). The resulting mixture was stirred for 15 min. and dipotassium salt of tetrazole-5-carboxylic acid (1 g, 5.25 mmol, prepared as described in J. Me.Chem.E. 29, 538-549 (1986)) and the mixture was added. The resulting mixture was stirred for an additional 20 min. To the mixture was added dropwise a solution of the methyl ester of 2-amino-4,5-dihydro-7H-thieno [2,3-c] pyran-3-carboxylic acid ester (1.3 g, 5.25 mmol), pyridine (2.2 ml) and acetonitrile (2.5 ml) for 10 min. The reaction mixture was allowed to reach room temperature where it was then heated to reflux temperature for 0.5 h. The cooled reaction mixture was poured into water (100 ml) and the pH adjusted to 1 by the addition of concentrated hydrochloric acid. The precipitate was separated by filtration, washed with heptane and dried in vacuo at 50 ° C for 18 h, yielding 1.3 g (70%) of the methyl ester of the 2- (1H-) acid. tetrazole-5-carbonyl) -amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid as a solid.

The above tertiary ester (0.6 g, 1.71 mmol) was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) was added. The resulting mixture was stirred for 40 min. at room temperature. The volatiles were evaporated in vacuo and to the residue was added diethyl ether (50 ml), water (25 ml) and IN sodium hydroxide (2 ml). The phases were separated and the aqueous phase was washed with diethyl ether (50 ml) and the pH adjusted to 1 by the addition of concentrated hydrochloric acid. The precipitate was separated by filtration, washed with water (25 ml) and dried in vacuo at 50 ° for 18 h in which 190 mg (38%) of the title compound was produced as a solid. P.f. : > 250 ° C Calculated for C? 0H9N5? 4S, 0.25 x H20; C, 40.07%; H, 3.19%; N, 23.36%. Found: C, 40.39%; H, 3.18%; N, 22.92%.

EXAMPLE 21 Na N- (3- (2-tetrazol-5-yl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) oxalamic acid disodium salt: The ethyl ester of 2-amino-4,5-dihydro-7H-thieno [2, 3-c] pi-3-carboxylic acid (26 g, 0.114 mol) was dissolved in formamide (200 ml) and the The resulting mixture was heated at reflux temperature for 1.5 h. After cooling to room temperature the precipitate was filtered off, washed with water (2 x 80 ml) and dried in vacuo at 50 ° C for 18 h for 1 ember, and 10.0 g (42%) of 5,6-dihydro-8H-pyran [', 3': 4,5] thieno [2,3-d] pyrimidin-4-one as a solid. To the phosphorus oxychloride (70 ml) was added the above-mentioned pi-im-n-1a (7.0 g, 0.04 mol) and N, N-d ime t i 1 an i i na (0.2 ml). The resulting mixture was heated at reflux temperature for 2 h, cooled and poured into ice water (700 ml). The precipitate was separated by filtration, suspended in a mixture of ethyl acetate (400 ml) and water (250 ml) and stirred for 15 min. The aqueous phase was separated and the organic phase was washed with saturated aqueous sodium chloride (100 ml), dried (MgSO 4), filtered and evaporated in vacuo yielding 5.2 g. (68%) of the 4-chloro-5,6-dihydride-8 H-pyran [4 ', 3': 4,5] thieno [2,3-d] pyrimidine as a solid. To a hot solution of the previous thieno-pyrimidine (4.5 g, 0.02 mol) in ethanol (40 ml) was added dropwise a solution of hydrazine hydrate (10.0 ml) in ethanol (20 ml). The resulting solution was heated to reflux temperature for 2 h, cooled to room temperature, the precipitate was removed by filtration, washed with ethanol (20 ml) and dried in va cuo at 50 ° C for 1.5 h producing 3.2 g. (73%) of the 5,6-dihydro-8H-pyran [4 ', 3': 4,5] thieno [2,3-d] pyrimidin-4-yl hydrazine as a solid. To a solution of the above hydrazine (3.0 g, 0.014 mol) in 50% aqueous acetic acid (100 ml) cooled in an ice bath was added dropwise a solution of sodium nitrite (1.0 g, 0.015 mol) in water (10 ml). The reaction mixture was stirred for 2 h, the precipitate was filtered off, washed with water (25 ml) and dried in vacuo at 50 X; for 1 h yielding 3.0 g (95%) of the 10, 11-dihydro-8H-pyran [4 ', 3': 4, 5] thieno [3,2-e] tetrazolo [5, 1-c] pyrimidine as a solid. To a solution of the above tetrazole (2.5 g, 0.011 mol) in dioxane (30 ml), IN sodium hydroxide (25 ml) was added dropwise. The reaction mixture was stirred for 3 h, poured into ice water (100 ml) and the pH adjusted to 4 by the addition of acetic acid. The precipitate was separated by filtration, washed with water (25 ml) and dried -vw at 50 ° C for 18 h producing 2.2 g (82%) of the N- (3- (2H-1 et ra zo 1 - 5 - i 1) -4,7-dihydro-5H-t ieno [2, 3 -c] pi ran-2-i 1) formamide as a solid. The above formamide (0.6 g, 2.7 mmol) was dissolved in dry tetrahydrofuran (50 ml) and triethylamine (1 ml) was added. To the cooled reaction mixture in an ice bath was added dropwise a solution of ethyl oxalyl chloride (0.4 g, 2.96 mmol) in dry tetrahydrofuran (5 ml). The resulting reaction mixture was stirred for 2 h at room temperature, the volatiles were evaporated in vacuo. To the residue was added water (50 ml), diethyl ether (50 ml) and IN hydrochloric acid at pH = 2 and a small filtrate was removed by filtration. The organic phase was separated, dried (Na 2 SO 4), filtered and evaporated in vacuo. The residue (0.4 g) was suspended in dichloromethane (20 ml) and stirred for 1 h, the solid matter was separated by filtration and dried in vacuo at 50 ° C yielding 0.16 g (18%) of the ethyl ester of the acid. N- (3- (2H-tetrazol-5-yl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) oxalamic acid as a solid. To a solution of the ethyl ester of the above oxalamic acid (0.16 g, 0.49 mmol) in ethanol (15 ml) was added 1N sodium hydroxide (1.0 ml, 1.01 mmol). The resulting reaction mixture was stirred at room temperature for 2 h. The precipitate was filtered off and washed with ethanol (10 ml), dried in vacuo at 50 ° C for 48 h, yielding 140 mg (83%) of the title compound as a solid. P.f. : >; 250 ° C Calculated for C? 0H9N5O4SNa2, 3 x H 2 O; C, 30.54%; H, 3.33%; N, 17.81%. Found: C, 30.70%; H, 3.35%; N, 17.49%. By a similar procedure as described in Example 1 the following compounds were prepared.

EXAMPLE 22 6-Benzyl Ester of 2 - (oxa-1-yl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyridin-3, 6-di-caboxy 1 i co:, __ P. f. : > 250 ° C Calculated for C? 8Hi6N207S; C, 53.46%; H, 3.99%; N, 6.93% Found C, 53.44%; H, 4.15%; N, 6.69% EXAMPLE 23 6-Ethyl 2- (oxalyl-amino) -4,7-dihydro-5H-t-ene [2, 3-c] pyridin-3,6-dicarboxylic acid ester: Calculated for C .3 H 4 N20- S; C, 45.61%; H, 4.12%; N, 8.18%. Enco rad! C, 45.71%; H, 4.31%; N, 7.86%.

EXAMPLE 24 . Ct! 6 - a ce 1 - 2 - (oxalyl-amino) -4, 5, 6, 7 - a dro-t ene "" 2, 3-c] p pd n-3 carb or x 1 co P.f .: 2¿2-244X Calculated for C.:li.;K;C,S, 0.25 x H2 O; Z, 5.50-; h, 3.98-; N, 8.84. Found, 45.6 -; h, 3.9"7 &N; 6.51 *.

Oxalyl-amino ") - 6-fe? Lcarbamo? Lmet? 1,4,6,6,7-tetrahydro-t? Ene [2, 3 c]? Ridin-3-carboxyl? Co: P.T. : 244-246X - Calculated for C: BH -N2OCS, 1 x H2C; _ C, 51.30%; H, 4.54%; N, 9.97%. Found: C, 51.08; H, 4.52 ?; N, 9.63%.

AX PLO 26 11 e 1) -2- (oxalyl-amino) -4,7-d? Hydro-5H-t i- &no [2, 3-c] pr? Dm-3-carbcx? L? Co: _, _ ^? To a pezcia of benzyloxycetaldehyde (8.3 g, 0.06 mol) e ceño (80 ml) was added l- .e or -3-tr? Met? Is? I lox? -l, 3-butadiene (10.6 g, C6rol). The reaction mixture was stirred with rrrrogen for 15 rr. _ p. , cooled to "C" "" C and 0.5 M zinc chloride (55 ml, 0.03 mol) was added dropwise to the solution. The reaction mixture was allowed to warm to ambient temperature for 16 h and evaporated in vacuo. The resulting oil was diluted with ethyl acetate (100 ml), washed with hydrochloric acid-IN (3 x 50), saturated scdio bicarbonate (3 x 50 ml), salt (3 x 50 ml), dried ( MgSO 4) and Xn vacuo was evaporated. The resulting oil was subjected to flash chromatography using ethyl acetate / hexanes (1: 2) as a solvent. The pure fractions were collected by evaporating in vacuo 7.1 g (X 0%) of the benzyloxy-methyl-2,3-dihydro-pyran-ID 4-oira as an oil. : H NMR [400 MHz, CDC13) d 7.39-7.31 (m, 6 HJ -, 5.42 (dd, J = 6, 1 Hz, 1 H), 4.61 (d, "J = 3 Hz, 1 H), 4.5 * 7 (rp, 1 H), 3.70 (m, 2 H), 2.74"(dd, JX Hz, 14 Hz, 1H 2.41 (ddd, J = 17 Hz, 2 Hz, ? Cl La 2, 3 - d 1 n idrc-pira r. - 4 - previous one (7.1 g, 5.032 mol) and 10% palladium on charcoal (0.4 g) in ethyl acetate (50 ml) were placed in a shaker 'd. Doraba Parr and hydrogenated at 3 Ü ~ psi. The reaction mixture was shaken for 2 h, at which time the TLC analysis (methanol / d, chloromethane 1: 9) indicated that the reaction was complete. The reaction mixture was filtered through a pad of Ceiite and the oltiles evaporated in vacuo. The residue was chromatographed on an overhead column using ethyl acetate under 1%. The pure fractions were combined to produce, after evaporation, a vacuole 3.C-g (75%) of the 2-hydroxyethyl-tetrahydro-pyra. -4-ona cerno or oil. - H NM XOO MHz, CDC13) d 4.36- .29 (m, i: -: ', 3. "~" "** - 3.6c ím, 3HX 3.61-3.54 (m, 1H) / 2.65-2.43 (go ., 2H 2.34-2.27 (m, 2 H), 2.04 (bs, Ih, The previous tetrahydro-phan-4-one (1.90 g, C.015 mol), tert-butyl cyanoacetate (2.7 g, 0.019 mol), sulfur (0.51 g, 0.016 mol) and rr _ 0. C 3 mo they were dissolved in absolute strength v 20 ml), and heated to 50 ° C. The reaction mixture was evaporated, evaporated in vacuo, and then elevated in acetic acid (X 5 C ml), washed with water ( 2 x 50 ml), salt m was [2 x 5 C ml and dried (MgSO 4). The solvent was evaporated in vacuo and X d or was subjected to flash column chromatography using ethyl acetate / hexa (1: 1). ) as the eluent The pure fractions were collected yielding after evaporation in vacuo 3.7 g (90%) of the ester ter c-bu t t 1 i co of 2-aminc-5-hydroxymethyl-4,7-d hydro -5H -thien [2, 3-c] pyran-3-carboxyl? Co as a solid .: HNR (400 MHz, CDC13) d 4.64 (s, 2 H), 3. BX3.É "* (m, 3 H), 2.7" 7-2.72 (rp, 1 H), 2.5 * 7-2.53 (rp, 2 r.? 1.54, .... The ester t er c-bu t 1 i co of co-oxidic acid (3.0 g, 0.015 mol), phthalimide (2.10 g, 0.014 mol) and triphenylphosphine XS 0.014) were dissolved in tetra iarofuranc secc '60 rr. X and cooled to C ° C to a nitrogen atmosphere. It was added dropwise at 0 ° C to z odi caboxy 1 a or diisopropyl I A IX 2. 1 rl, 0.C1 rrcX and the solution is stirred overnight, heating slowly to room temperature. The volatiles were supported in vacuo and the remaining solid was dissolved in ethyl acetate (60 ml). The organic phase was washed with brine (2 x 50 ml), dried (MgSO 4) and added in vacuo. The mixture was subjected to column chromatography and initiated by elution with a mixture of ethyl acetate / hexanes (1: 3). Once the product is eluted, the eluent mixture is added to ethyl acetate / Xexan (1: 2). The pure fractions were collected, producing after evaporation in 2.90 g (4%) of the tert-bical ester of 2-amino-5 (1, 3-dioxo-1,3-dihydro). -isoindol-2-ylmethyl) -4,7-dihydro-5H-t ienc "" 2, 3-c] pir an-3-caboxy 1 i co as a solid: H NMR (400 MHz, CDC13) d 7.87-7.85 (m, 2 H, ".93-7.71 n," 2Hi, 5.94 (bs, 2 H), 4759 (d, J = - IX Hz, 1H), 4.52 (d, J = 14 Hz , 1H), 4.0-3.98 Xm, 2 H), 3.83-3X9 (m, 1 H), 2.87 (d, J = 17 H z, -1 HX 1.58 (dd, J = 17 H ?, 9 Hz, 1H ), 1.50 (s, The tert-butyl ester of 4-ddro-5K-tie or [2, 3-c] pyran-3-carboxylic acid (0.5 mmo in dichloromethane 5 ml) was added triethylamine (0.33 ml, 2.4 mmol) and Steyr acid-tert-butyl imidazol-1-yl-oxo-acetic acid (0.47 g, 2.4 mmol) under nitrogen. The reaction mixture was allowed to stir at r.c. temperature for 18 hours. The volatiles were added to the mixture and the residue was dissolved only in ethyl acetate (20 ml). The organic phase was washed with 1% hydrochloric acid (2 x 10 ml), brine (2 x 10 ml), dried (MgSO./) The organic phase was evaporated in vacuo yielding 0.64 g (99%) of the tert. -butylic acid 2- (tert-butoxyoxalyl-ammo) -5- (1,3-d? oxo-l, 3-? ~ "- - - ri.-sc? ool-2-imet? l? -4, 7-d dro-5h- x = - "., 3-c] pira n-3-carncxíl? Co as a solid.: H NMR (400 MHz, CDC13) d 12.48 (s, 1H, I ? ZC, 8- S6 (, 2HX X "X - O" ^ 2 (r, 2H), - ~? A> = 5 Hz, ~ -uX 4.65,, J = = l 9 hz, Go A 4. C7-3.90 (m, 2H), 3.88-3.80 (m, 1H), 2.97 ^ a '~ =: t H =, 1HX 2.68 (dd, J = 17 Hz, 9 Hz, 1H), 1.58 (s, 9H ), 1.54 (s, 9H) The di-erc-bu t ii ii co ester above (2.8 g, 5.16 mmoi) was dissolved in a mixture of acid X.ucroacét ice ydc 1 cr orne ta no tl: 5) (36 ml) The reaction was stirred at room temperature by r- - precipitates, separated by filtration, treated with ether, dried in vacuo, 5% which was 1.26 g (57%) of the od the guy eats a solid. _ P.f. : 245.2-245.6 ° C -H NMR (300 MHz, 3MS0-d? D 12.32 (s, 1H, 95 d, 7 = 70 Hz, 1 H), 4.62 (d, J = 20 Hz, 1 H), 3.96-3.69 (m, 3 H), 3. 01 (d, J = 18 Hz, 1H), 2.60 (dd, J = 18 Hz, "9 Hz, 1H). Calculated for C? GH: 4N2? 6S; C, 53.02%; H, 3.28%; N, 6.51%. Found; C, 53.01%; H, 3.31%; N, 6.41%.

EXAMPLE 27 Aci d- 5- (benzoyl ino-methyl) -2- (oxalyl-amino) - dihydro-5H-ti in o [2, 3-c] pyran-3-c a rb ox XI ico The ester tert -bu t í 1 co of 2- (tert-butoxioxalylamino) -5- (1,3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -4,7-dihydro- 5H-ti-etro [2, 3-c] pi-n-3-oxo-organic (0.33 q, 0.60 m ol) was dissolved in an ethanol solution (2 ml) and dichloromethane (3 ml). Hydrazine (28 μl, 0.9 mmol) was added and the reaction was stirred under nitrogen at room temperature for 24 h. The analysis indicated that the initial material was still present. An additional portion of hydrazm (28 μl, 0.9 mmcl) was added and the reaction was stirred at room temperature for another 16 h, then at 45 ° C for 5 h. The mixture was concentrated in vacuo, redissolved in dichloromethane and the i sclubie material was removed by filtration. The filtrate was collected and concentrated in vacuo yielding the ester of the acid 5 -aminome 111 -2 - >; t er c - b ^? toxoxa 111 -am ino) -4,7-d? h? dro-5H-1 ene [2, 3-c] pyran-3-ca rb ox i 11 co as a solide, the c a was performed at tra of the next step sn additional purification. The erc-bu 1-co-ester of 5H-1 acid in crude [3, 3-c] p-ran-3-carboxylic acid (3.25 g, 0.60 mmol) was suspended in a mixture of dichloromethane and acetonitrile. (1: 1, 5 ml). Tpetilapr is added. to X.25 ml, 1.8 mmol) was added by hydrotreater of 1-drox? -benzotpazol X.IO g, 0.72 mmol, and l- (3-dimet and laminopropyl) -3-et-1-hydrochloride rimodi iodide (0.14 g, CX2 mmol) as solids. The heterogeneous reaction mixture was stirred at room temperature for 2 days, after which the mixture was homogenized. The solvents were evaporated and the residue dissolved in dicluchane and then added with 1 M aqueous hydrochloric acid, then with saturated sodium bicarbonate. The organic phase was dried 1 a; S C, was concentrated and concentrated in vacuo p r odu c in a sc ity which was purified by a t ra g r a f i a n t i n g. t a n e a using a mixture of ethyl acetate and hexanes (1: 1) as eluent. The pure fractions were collected and evaporated ir. -v act producing 50 mg (16% during two passes of the ester rc-but í 1 co of the acid 5- ref:; Xat: -. C-re :: l-2- (tere-cu toxiax to 111 -2"*: 3c; -4, 7-? N dro-5H-t eno [2, 3-c] p? Ran-3-earfccxilieo co o a solid - b P XOG Kh :, C DC 13 d 12.46 (s, 1H), (at 2FX 7.51-7.42 (m, 3H), 6.72 P "5 J = / 1H), 4.74 (d, J = IX, ¿Q5-3.9? * m / 1 H 1, 3.86-3.78 (m, 1H), 3.45-3.38, go, lh, 2. 7 (d, J = 19 H z ~, 1H), ^. c? aa 'J = 1S H =' 5 Hz, 1HX 1.61 (s, 9H), benzciiai iro-netil-tieno [2, 3-c] p? ran -: o r -i 'pg, 2.2 B r-cl) was treated with acid or o ce or co-d or rome t a n o 2 O (2 ml) for 4 h. The volatiles were evaporated in vacuo and poured twice with di-1 orromene, forming a precipitate which was separated on dried, yielding 30 mg (95%) of the compound of the product as a solid. XH NMR (400 MHz, DMS0-d) d 12.31 (s, 1 H), S .63 (t, J = 4 Hz, 1 HX 7.86! D, J = HX, 2 H), 7.51-7.43 (rr., 3H, X 4.80 (d, J = 17 Hz, 1H) , 4. 64 (d, J = 17 Hz, 1H), 3.82 (m, 1H), 3.44 (m, 2K 2.95 (d, J = 18, 1H), 2.52 (dd, J = 18 Hz, 9 Hz, 1 K '. LC / MS [- H 403.39, HPLC (254.4 nm,: 2.99 s, 84%.

EXAMPLE 28 Acid 5 - b e n z < 1 exempts - X or aXi? -_ ami no) - 4, 7 -d? Hydro-5H-thieno iran- 3 -carboxylic The tert-bu tic ester of 2-amins ^ -5-hydroxylmethyl-4,7-dihydro-5H-thieno [2, 3-c] pi-3-caboxylic acid ( 0.23 g, 0.87 mmol), benzoic acid (0.10 g, 0.96 mmol) and triethylamine 0. 23 ml, 1.7 mmo or 1) dissolve. in dichloromethane (4 ml) and stirred under nitrogen. Hydrochloride of 1 - (3-d ime t il ami nop r opi 1) - 3 - e t i 1 ca rbodi imi da (0.17 g, (0.12 g, 0.96 mmol) as solids. The reaction mixture was stirred at room temperature for 2 days, after which the solvents were quenched in water. The crude mixture was dissolved in ethyl acetate and washed with 1K hydrochloric acid, saturated sodium sulfate, brine and dried (Na2SO4). The solvent is added to the water, yielding a solvent. The yellow qe was purified by in vitro chromatography using a mixture of ethyl acetate and hexanes (1: 2) as eluent.The pure fractions were collected and aporadated in vacuo yielding 0.X2 g (70%) of the tert-butyl ester of 2-arrino-5-benzoyl-Iaximet l-4,7-dihydra-5H-teo 2,3-c] pyran-3-cartoic acid as a solid: H NMR (400 MHz, CDC13 ) d 8.06 (d, J = 7 Hz, ZHX .5 t, J = * "" * Hz, 1H), 7742 (t, J = 7 Hz, 2 H, 4.64 's, 2 H 4.44 (d, J = 5 Hz, 2 H), 4.03-3.97 (m, IH), 2.88 (d, J = 18 Hz, i H), 2.64 (dd, J = 1 ^ Hz, 10 Hz, 1H), 1.50 (s, 9hX The ester carboxylic ester of the above carboxylic acid (0.18 g, 0.45 mmol) dissolved in dry tetrahydrofuran (5 X, is aai or trietilarma (0.18 m 1, 1.4 rrcl) and ester ter c-bu ti 1 i of the acid 1 to 1-i-1-oxo-acetic acid 0.26 g, X mmol) under nitrogen. The t; Z. C- to the reaction was stirred "" "at temp * e ra ura to" '_' ^ _ -i for 3 r. The volatiles were evaporated i n and to c and the remaining soliao was reconstituted in ethyl acetate (10 ml). The organic layer was washed with 1% hydrochloric acid (2 x 10 ml), brine '2 x 1 C ml), dried, NaOH, the solven was filtered and dried. The oil is purified by chromatography and starched with a mixture of ethyl acetate and ethyl acetate, 1: 2, n non-eluent producing the -e-ster 0.20 gi 50 *.) 90% of the acid tertiary ester of benzo-11-oxime 111-2- (ter ct -toyl-allyl-araino-?, 7-a? N? Dro-5H-t? Ene [2, 3 -c "p? rar-3-carbox_l? co as a solid. 1H NMR (400 MHz, CDC13) d 8.07 (d, J = Hz, 2H), 7.56 (t, J = 7 Hz, 1H), 7.44 (t, J = "7 Hz, 2H), 4.85 (d, J = 15 Hz, 1K), 4. - (d, J = 15 Hz, 1H), 4.49 (d, J = 5 Hz, 2 H), 4.03-3.99 (m, 1H), 2.99 (d, J = 17 Hz, 1H), 2.72 (dd, J = 17 Hz, 11 Hz, 1 H), 1.58 (s, 9 H), 1.60 (s, 9H). • Ester di-tert-bt í 1 ico _ ant er 1 cr XX5 g, 0.29 mmol) was dissolved in a solution of 20% of the trifluoric acid in dichloromethane (3 ml), immediately the solution developed a dark to dark color which quickly became red The reaction was stirred for 1.5 hours at ambient temperature and the volatiles were evaporated in vacuo yielding a brown solid which was washed twice with diethyl ether and water and separated by filtration. - m vacuo, yielding __30 mg (25%) of the title compound as an odor. : H NMR (400 MHz, DMS0-de) d 12.40 (s, 1K), 7.98 (d, J = 7 Hz, 2H), 7.67 (t, J = 7 Hz, 1H), "7.54 (t, J = 7 Hz, 2 H), 4.83 (d, J = 15 Hz, 1 H), .70 (d, J = 15 hz, 1 H), 4.44 (d, J = 5 Hz, H), 4.02-3.99 (rr ., 1 H,, 2.99 (d, J = 16 Hz, 1 H), .70 (dd, J = 16 Hz, 9 Hz, 1 H) - LC / MS [MH 404.05.

HPLC 254.4 nm 1 b 90 EXAMPLE 29 Acid 2 - (or xa li X-amino) -5- (1-oxo-l, 3-d ih id r_q ^ soindol-2-ylmethyl) -4,7-dihydro-5H-thieno [2, 3 ' c pt. rar -3-carbox I? Cp _, ^.

To a solution of the tert-butyl ester of 2-amino-5- (1,3-dioxo-l, 3-dihydro-β-somodol-2-methyl) -4,7-dihydro-5H-thieno [2] 3-C] p-n-3-caboxy 11 (0.308 g, 0.74 mmol) in absolute ethanol (5 ml) was added hydrazine (47 μl, 1.48 mmol.) The reaction was stirred at 80 ° C for 4 hours. and then at room temperature for another 12 hours, precipitate was separated by filtration and the fi nitra was concentrated in vacuo.

The oily residue was added d i c 1 or r ame t (15 ml) and the precipitate formed was separated by 1 x ation. The filtrate was concentrated in vacuo to give 0.19 g (90%) of the tert-butyl ester of 2-amino-5-aminomethyl-4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid. as a solid. ** H NMR (400 MHz, CDCl 3) d 5.91 (bs, 2H), 4.62 (s, 2H), 3.64-3.60 (m, 1H), 2.92-2.84 (m, 2 H), 2.80-2.75 (m 1 H), 2.52-2.45 (m, 1 H) ", 1.53 (s, 9 H) icarboxylic aldehyde (52 mg, C 36 mmol) was dissolved in a mixture of acetopitrile an idro (2 ml) and acetic acid (44 μl, 0.72 mmol.) 2-amino-5-arr.incmethyl-4-tert-butyl ester, * 7-dihydrc-5H-thieno [2,3-c] pyran-3- carcc ilicc (2.11 g, 0.36 mmol) was added and the reaction was stirred for 20 minutes at room temperature, volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate (25 mL). organic mixture was washed with saturated sediment bicarbonate (5 ml), 1% hydrochloric acid (5-1), brine (5 ml), dried (N2SO4), filtered and evaporated,? The residue was purified by vertical chromatography using a gradient from 15 ethyl acetate / dicylamine or 17% ethyl acetate. / .-, - i oremeta or as eluent producing 45 -: f-tert-butyl ester of 2- to ino-5- (1-oxo-l, 3-dihydro-isoindol-2-ylmethyl) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic acid as a solid. : H NMR (400 MHz, CDC13) d 7.85 (d, J = 7 Hz, 1H), 7.53 (t, J = 7 Hz, 1H), 7.47-7.43 (m, 2H), 4.68 (d, J = 17 Hz, 1H), 4.58-4.51 (m, 3H), 3.99 (dd, J = 14 Hz, 3 Hz, 1H), 3.93-3.89 (m, 1 H), 3.66-3.61 (m, 1 H), 2.88 (d, J = 17 H z, 1 H), 2.55 (dd, J = 17 Hz, 1 Hz, 1H), 1.52 (s, 9H). To a solution of the tert-butyl ester of 2-amino-5- (1-oxo-l, 3-dihydro-isoindyl-2-ymethyl) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carbolic (45 mg, 1.1 mmol) in anhydrous dichloromethane (4 ml) was added imidazol-1-yl-oxoacetic acid tert-butyl ester (73 mg, 3.3 mmoi) and triethylamine (17 μl, 1.1 mmol). The reaction was stirred under nitrogen at room temperature for 5 h. The solvent was evaporated in vacuo and the material was dissolved in jg 1 io acetate (20 mX.) The organic solution was washed with CSN hydrochloric acid (3 ml), saturated scdic bicarbonate (3 ml). brine (5 ml), dried (N to S O 4), filtered and the solvent was evaporated in vacuo The residue was purified by chroma reaction using dichloromethane (100%) followed by 17% ethyl acetate. / di Cl or ore as eluents yielding 54 mg (91% ") of the tert-butyl ester of 2- (tert-b-oxaxyazoline) -5- (1-oxo-l, 3-dih? dro-? somdol-2-ylmethyl) - 4,7-dihydro-5H-t-ene [2, 3-c] pyran-3-carboxylic acid as solide, or NMR XCC MHz, CDC13) d 12.5 C (s, 1H), - .5"? id, J = 8 Hz, 1 H), 7.53 (t, J = 7 Hz, 1 H), 7.4 ~? - 7.43 (m, 2 H), 4.81-4.65 (m, 3H), 4.53 (d, J = 17 Hz, 1H), 4.01 (dd, J = 14 Hz, 3 Hz, 1H), 3.9 C-3.89 ( m, 1 H •, 3.69-3.62 (m, 1 H), 2.97 (dj = X3- -H z, H), 2.63 (dd, J = 17 Hz, 11 Hz, 1H), 1. XX 's, 9 H), 1.56 (s, 9 HX PCI-MS [M + H] 529.5 The tertric acid ester of DUtOXIO i _ amino) -5- (1-oxo-l, 3-d? hydro-isci dcl-2-? imet? l) -4, "-d: h? dro -5H-t? Ene [2, 3-cj? R n-3-carbcxico (52 mg, 0.098 mmol) was treated with a solution of 50% trifluoroacetic acid / dichloromethane (3 ml) for 4.5 h ambient temperature. The volatiles were added in vacuo and the residue was extracted or expelled three times with dichloromethane (10 ml).; c o. filtration and washed with dichloromethane or yielding 28 mg (70%) of the title compound as a solid. 1 H NMR (400 Mhz, DMSO-dc) d 12.32 (s, 1 H), 7.69 (d, J = 8 Hz, 1H), 7.61-7.59 (m, 2H), 7.51-7.45 (m, 1H), 4.81 (d, J = 15 Hz, 1H), 4.65 (d, J = 15 Hz, 1H), 4.60 (s, 2H), 3.95-3.92 (m, 1H, 3X5 (d, J = 5 Hz, 2 H , 2.94 (X, J = 16 Hz, 1 K, 2.56 (dd, J = 16 Hz, 10 Hz, 1HX APCI-MS [M + H] X 417.3 HPLC, 254.4 nm): 3.079 s (100%) EXAMPLE 30 oxa - a m. i n: -? X, 7-tetrahydro- It acid 2- (ethoxy? oxai? 1 ^ amino) -6-oxo-, 6, "-tetra hiarc-ber.zo [b] t? ofen-3-carboxyl? co Z g, C.C13 mol) was dissolved in a mixture of 40 μl), ethanol '2 C ml) and tetrahydrofuran (20 ml) at room temperature. To the resulting mixture was added sodium hydroxide I * (20.24 ml, 20.24 mmol). The resulting reaction mixture was stirred at room temperature for 27 h, the pH was adjusted to 3 by the addition of concentrated hydrochloric acid. The precipitate is S TDa by filtration and water was washed x 15 ml), diethyl ether (2 x 15 ml) and dried in vacuo at -50 ° C yielding 1.96 g (73%) of the title of 1 title as a solid. . P.f. : > 230 ° C Calculated for C; X5"NO; C, re.64%; H, 3.3C%; N, 4.94% Found: C, 46.97%; H, 3.30%; N, 5.80%. Similar procedure as described in Example 1, the following compounds have been prepared.

EXAMPLE 31 4-carboxymethyl-2-oxalyl-amino) -4,6,7-tetrahydro-benzo [b] thiophene-3-carboxylic acid 2-Carbomethoxymethylcyclohexanone was prepared in the same manner as described in J. Am. Chem. Soc. 81, 3955-3959 (1959) for 2- carbetoxy-ethylcyclohexanone. P.f. : > 250 ° C Calculated for 0.75 x H2 O; C, 35.61%; H_, 4.29%; N, 4.11%. Found: Z, 4 X9 *; H, 4.02%; N, 4.08%.

EXAMPLE 32 A c i aX 2 - (oxa li 1-am? O) -6-oxo-4, 7-dihydro-5H-1 ene [2, 3 - c t i or 11 r - 3 - ca rbox í 1 i co s_:. - The 1 - or xo - 2, 3, 5, 6 - e t r a h i d r o - 4 H - t i op i r a n - 4 - one was prepared as described in J. Org. Chem. 27, 282-284 (1962). P.f. : > 250 ° C Calculated for C :: H = N 06S;, 0.2 x N a C 1; C, 38.13%; H, 2.88%; N, 4.45%. Find C, 37.98%; H, 2.82%; N, 4.29%.

EXAMPLE 33 'r.osodi of i d; - (oxa 1 il _ m o) - 6, 6 - - 5c, H- 11 e n o [2, 3-c] t? op? ran-3- The 1, 1-d-oxido-2,3,5,6-tetrahydro-4H-t? Cpyran-4-one was prepared as described in J. OrgX r.e / p. 60, 1665-1673 (1995). P.f. : > 25C ° C Calc side for C..Ke: 0-S; Ka., 1 x H 2 O; , 33.43%; H, 2.81%; N, 3.90-. Found: Z, 33.43-; H, 2X8%; r:, 2X6X Per a similar precedence as in the Example 27, the following will be prearranged.

EXAMPLE 34 cid; 2- (oxalyl-amino) -5 (• oxc-cromene-H-3-carbonyl) amino) methyl) -4,7-dihydro-5H-thieno [2, 3-clpir. -3-carboxylic __ ^. JS_ - • H NMR (400 MHz, DM S O - d £) dl2.32 (s H * > = H 9.03 (s, 1 H), 8.19 (d d, J = "" 8 Hz, 2 Hz, 1H), 7.90 (dt, J = 8 Hz, 2 Hz, 1H), 7.78 (d, J = 8 Hz, 1H), 7.60 (t, J = 8 Hz, 1H ), 4.88 (d, J = 15 Hz, 1 H), 4.70 (d, J = 15 Hz, 1 H * -, 3.83-3 9. Rr., I H 3 2-3.66 (m, 1 H), 3.55-3.48 (rr., I K), 2.95 { D, J = 15 Hz, 1H), 2.60 (give J = 15 Hz, 6 H z, 1 H). - LC / MS [M-H] X 4"" *** 1.4 HPLC (254.4 m: 3. 105 s, 94?.

AX PLO 35 2-Oxalyl amino acid) - (((4-oxo-c_r omen o - 4 H - 2 - i; a mjin o) metiX X, _ '-_ d ih idro -_5 K - 11 ene 3- j P- ra -3-carboxy.

-H NMR (400 MHz, DMSO-d6) d 12.32 (s, 1H), 9.33 (t, J = 4 Hz, 1H), 8.05 (d, J = 8 Hz, 1 H), 7.8 (t, J = 8 Hz, 1H), 7.76 (d, J = 8 Hz,: HT ".53, -, Z = 8 Hz, 1H), 6.84 (s, IHT, 4.83 (a, J = 15 Hz, 1H), 4.66 (d, J = 15 Hz, 1H), 3.83-3.84 (m, 1H), 3.56-3.45 (m, 2H), 2.98 (d, J Xe h, 1 HX 2.63-2.52 (m, 1H, partially obscured by D S O.) LC / MS [MH] 471.4 HPLC (254.4 nm;: 2886 s, 95%.

EXAMPLE 36 .i "... ^ _. - ((3-furan-3-yl-acrylolamino) -methyl) -2- (oxalyl-arrinc '-4,7-dihydro-5H-t-ene [2, 3-c-pyran-3 - c arb oxi I ico - 1 H NMR (400 MHz, DMSO-d 6) d 12.32 (s, 1 H), 8.20 (t, J = 5 Hz, 1 H), 7.99 (s, 1 H), 7.71 (s, 1 H), 7.33 (d, J = 15 Hz, 1H), 6.68 vs, H), 6.42 at J = 15 Hz, 1 H), 4.81 (d, J = _ 15 Hz, 1H), 4.65 (d, J = 15 Hz, 1H), 3.74 -3.67 (m, 1H), 3.44-3.34 (m, 2 H), 2.91 (d, J = 17 Hz, 1H), 2.53 aa, Zr., Partialme rrt e obscured by DMSO). LC / MS [-H] ": 419.4 HPLC, 254.4 ni): 2.822 s, 91%.

EXAMPLE 37 - . 5 - ((3-furar.C i 1 or 11 a m i n o) -me? Ilj -2 l x - a m i n o.}. - 4,? -5H-thieno [2, 3-c] pyran-carboxylic acid H NMR (400 MHz, DMSO-d6) d 12.32 (s, 1H), 8.37 (t, 1H), 7.77 (s, 1H), 7.23 (d, J = 15 Hz, 1 H), 6.76 (d, J = 3 Hz, 1 H), 6.S * 7 (dd, J = 3 Hz, 2 Hz, 1H), 6.50 (d, J = 15 Hz, 1 H), 4.81 (d, J = 15 Hz, 1 H), 4.65 (d, J = 15 Hz, 1 H), 3.74-3.67 (m, 1 H), 3.48-3.32 (m, 2 H) , 2.91 (d, J = 17 Hz, 1H ', 2.53 Xd, 1 H, partially replaced by DMSO). [M-H] * "": 419.3 HPLC (254.4 nm): 2.815 s, 86%.

EXAMPLE 3 Acid? - oxaiylamino) -5 ((("3-oxo-indan-l carbo n? l) am? no) met l) -4,7-dh? dro-5H-t? ene [2, 3-c ] piran-3-carboxyl co _, -E - H NMP (4GC MHz, DMSO-de) d 12.32 (s, r 8.81 (DS,:. H), -.74-7.62 (m, 3H), 7.47 (t, = ~ 7 Hz, 1 H), 4.83 (d, J = 15 Hz, 1H), 4.67 (d, J = 15 Hz, 1 H), 4.29 (t, J = 5 Hz, 1H), 3.41-3.25 'm, 3H), 2.91 ( d, J = 15 Hz, 1 HX 7 2 X - (d, J = 5 Hz, 2H), 2.58-2.51 (m, 1 H, partially obscured by DMSO) LC / MS [M-HJX: 457.5 HPLC ( 254.4 nm): 2.634 s, 97% By a similar procedure as described in Example 26 the following compound was prepared.

AX PLO 39 Acid 5- (2, 4 - d i or x or -_ t i a z o 1 i d i n - 3 -i X m e t X) 2 (cxalyl-a ino) -4, * 7-dihydro-5H-thieno [2, 3-c] pyran-3-cg rboxylic _. " - -: H NMR (400 MHz, CD; OD and DMSO-d¿) d 4.88 irr "2 H), 3.97-3.89 (m, 3H), 3.72-3.69 (m, 2 H), 3.08" (m , 1 H), 3.02 (m, 1 H), MS (ESI (-)): 39.9 HPLC (254.4 nm): 2.67, s, 100%.

By a similar procedure as described in Example 1 the following c omp u have been prepared.

EXAMPLE 40 oxalyl-amino) -5- (2'-_a: air.i? - 4_H-ben TC [b t? ofen-3-carboxylic acid P. f. : 232-Z34GC C lculated pair C .3 H .3 N C - S, 1 x H; C; C, 45.22%; H, 4.38 X N, 4.06%. Found: C, 45.24%; H, 4.39%; ¡? 3.98%. By a similar procedure as was written in Exercise 27, the following com ponents have been revised.

EXAMPLE 41 - ((3,5-dimethoxy? -benzo? Lamino-me 11 (oxalyl-aitino * 1-4,7-d? H? Dro-5H-thieno [2, 3-c.] Pira n- 3 - ca rbox í 11 co _ _ 10 -H NMR (400 MHz, DMSO-dc) d 12.31 (s, 1H 8.63 (t, J = 5 Hz, 1H), 7.02 (s, 2 H), 6.62 's , 1H 4.80 (d, J = 15 Hz, Ih), 4.64 (d, J = 15 Hz, 1H), 3.82-3.79 (m, 1H), 3.77 (s, 6H), ID 3.47-3.45 (m, 2H, 2.94 (d, J = 17 Hz, 1H), 2.53 (dd, J = 17 Hz, 11 Hz, 1H) LC / MS [MH] X 463.4 HPLC (254.4 r.rX : 3.161 s, 93%.

EXAMPLE 42 ? • "" > 5- (5,6-Dichloro-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3 -c]? iran-3-carboxylic acid - To a solution of 2-hi d or x ime i 1 -tetrahydro-pyran-4-one (625 mg, 4.81 mmol) in u. A mixture of pyridine (778 μl, 9.62 m ol) and chloroform (6.0 ral) at 0 ° C under nitrogen was slowly added with 4-butyrobene sulfo níls chloride (1.60 g, 7.22 mmo 1). The mixture was allowed to warm to room temperature and was stirred for 3 h. Chloroform (30 ml) was added, the solution was washed with 2.0 N hydrochloric acid (3 x 10 ml), 5% N HCO 3 (3 x 10 ml) and water (3 x 10 ml). The mixture was dried (Na 2 SO 4), filtered and the solvent was evaporated in vacuo. The residue or solide was purified by column chromatography on silica gel using a gradient of icicromethane: hexane: ethyl acetate ( 1: 1: 0 a as uyen e The pure fractions were collected and the vials were vaporized in and producing Q.98 - g (65%) of the ester 4 -oxo-t et ra idro -pir an - 2-Ie t I ii co of the acid 4-nitro-pe cen s 1 ón i co as a solid.

: H NMR (400 MHz, CDC13) d 2.37 (d, 2H, J = 7.8 Hz), 2.57 (m, 1H), 3.63 (m, 1 H), 3.89 (m, 1 H), 4.20-4.26 (m , 3H), 8.14 (dd, 2 K, Z = C, c 'H z, J = 9 Hz), 8.42 (-dd, 2H, J = 0. 6 Hz, J = 9 Hz), MS m / z: 315.3 m + 4-oxo-tetrahydrc-pyran-2-imethyl ester of 4-nitro-benzenesulfonic acid • * or C. S g, 1.59 m or 1), ethylene glycol (986 mg, 15.9 p-tolue sulfonic acid (61 mg, 0.32 mc) was refluxed in benzene (20 ml) or as The solvent was removed in vacuo to yield a solid. 5 was dissolved in dichloromethane (30 ml) and successively washed with saturated aqueous sodium bicarbonate solution (2 x 5 ml) and aq (2 x 5 ml) .The organic phase was dried (N a). The SC was removed and D 1 n was eliminated, producing __582 mg of the ester 1, 4, 8-tric-xa-spiro [4.51 dec-7- 1 i cc - of the c o-be ncens u 1 f ón i co n solide. 4, im, 2 H), 3.96 (m, 4 H), '4.15 (m, 2H), 8.12 (dd, 2H, J = 1.5 Hz, J = 9.0 Hz), 8.40 (dd, 4H, J = 1.5 Hz, J = 9.0 Hz). MS m / z: 359.3.

The 3, 4-dichlorophthalimide (90.2 mg, 0.42 mmoi) was dissolved in N, N-dimethylformamide (2.0 at room temperature), sodium hydride (17 mg, 0.42 mmol) was added under nitrogen, and ester 1.4 was added. , 8-tri oxa-e spi ro [4.5] of c-7-methylmethoic acid of 4-nitric acids (100 mg, 0.28 mmol) and the mixture was heated at 140 ° C for 3 h. After cooling to room temperature, the reaction mixture was added to ice water (5 ml) and the mixture was extracted with ethyl acetate (3 x 15 ml) The combined ethyl acetate extracts were washed with hydrochloric acid 1.0 N '2 x 5 ml), water (2 x "5 ml), saturated sodium bicarbonate (2 x 5 ml) and water (2 x 5 ml). After drying (N to 2 S 04) followed by filtration, the solvent was removed in vacuo yielding 97 mg 194%) of 5,6-dichloro-2- (1, 4, 8-trioxa-esp? Ro [4.5 Dec-7-? -methyl) -iso ind or 1 -1,3-dion as a solid.

- H NMR (400 MHz, CDC13) d 1.60 (m, 2 H), 1.78 (m, 2 H), 3.54 (m, 1 H), 3.64 (m, 1 H), 3.88 (m, 2 H), 3.95 (m , 4H), 7.95 (d, 2H, J = 3 Hz). MS m / z: 373.7 (M +). The . 5,6-Di-chloro-2 - (1,4,8-t-rioa-spiro [4.5] dec-7-ylmethyl) -isoindole-1,3-dione (87 mg, 0.23 mmol) was dissolved in tetrahydrofuran ( 2.5 ml). 1.0 N hydrochloric acid (1.0 ml) was added to the solution and the mixture was added at 75 o- for 20 h. The heterogeneous mixture was evaporated, and the resulting solid was dissolved in ethyl alcohol (10 ml) and washed with water (3 x 2 l.) The gaseous layer was dried (M g S 0), filtered and dried. the solvent was evaporated in vacuo yielding 62.1 mg (81%) of the 5,6-di-chloro-2 - (4- or xo -tetxah-dro-p-ran-2-ylmethyl) -? soindol- 1,3-dione as a solid: H NMR 400 MHz, CDC13) d 2.31-2.41 (m, 2HX, 2.48 (t, 1 H, J = 2.0 Hz), 2.62 (m, 1H), 3.60 (, 1 H), 3X2 (m, 1 H), 3.99 (m, 2H), 4.29 rr., 1 H), 7.96 { D, 2 H, Z = 2.7 H z). MS m / z: 331.1 i + ¡ j-, to 5,6-dichloro-2- (4-oxo-tetrahydro-p-ran-2-ylmethyl) -iso? ndol-l, 3-dione (60 mg, 0.18 mmoi) was stirred with tere cyanoacetate -butyl (33.5 mg, 0.24 mmol), elemental sulfur (6.44 mg, 0.20 mmoi) and morpholine (32.4 μl, 0.37 mmol) in ethanol for 20 h at 50 ° C. The volatiles were evaporated in vacuo and the resulting solid was dissolved in dichloromethane (30 ml) and washed with a a '2 x 10 ml). The organic phase was dried MgSO 4, filtered and the solvent was evaporated O-1 vacuo. The residue (111 mg) was purified by TLC v- or T- (Kieselgel 60F25, Imm) using one of hexane and ethyl acetate (1: 1) as the entity. The pure compound was obtained after 1 to e-vaceration to solve and i n vacuo producing 28 m 32%) of the tert-butyl ester of the acid 2-ai-5- 5,6-d? Chlorc-l, 3-d? Oxs-l, 3-d? H? Dro-iscm dcl-2 -? lmet? i; -4, -dí? Dro-5H-t? Eno [2, 3 - e} p go ar.-3-carboxyl? C? as a solid. ~ 1 H NMR (400 Hz, C DC 1:.) D 1.5 (s, 9 H), 1.90 (r, 1 H i, 3.35 (m, 2 H 2.60 (m, 2 H), 2.90 (, 1 H), 4.62 (m, IHj, \ 95 (d, 2H, J = 1.8 Hz) MS m / z 483.3 'r -., 427 (rr-57). 'r. a mixture to the tert-butyl ester of the acide 2-amm o-5-, 5, 6-d? cioro-l, 3-d? oxo-l, 3 -a i n a. soindcl-2-? imet? l) -, 7-d? h? dro-5H-thieno [2,3-c] pyran-3-carboxy? co (27.5 g, 0.057 mmol), tert.-butylic acid ester imidazol-1-yl-oxoacetic acid (55.8 mg, 0.29 m oi and triethylamine (16 μl, 0.114 mmcl) in tetrahydrofuran (2 ml) was stirred at room temperature for 20 h. The volatiles were evaporated in vacuo and the resulting syrup it was dissolved in a dichloromethane (15 ml) and washed with water (3 x 3 ml), the organic phase was dried (MgSO 4), filtered and the solvent was evaporated in vacuo. duo '35 .7 rr.g * was purified by preparative TLC iKelselgei 60F; ~ _, 0.5 mm) using a mixture of p.exar.c and ethyl acetate (8: 2- as euyen e.

After isolation, 8.5 mg (24%) of 2- (tert-butoxyoxalylamino) -5- (5,6-dichloro-l, 3-dihydro-soindol-2-iimet) tert-butyl ester was obtained. l) -4, "7-dihydro-5H-thieno [2,3-c] iran-3-carboxylic acid, 1 HNR (400 Hz, CDC13) d 1.58 s, 18H), 2.68 (m, 1H), 2.97- 3.C2 (m, 1H), 3.82 (m, 1H), 63-4.65 (m, 1 H, 4. -4 m H) 7.97 d,, J = 2.1 H z). M S m / z 611.4 (-) 2- (tert-Butoxioxalylamino) -5- (5,6-dichloro-l, 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -4-7- tert -butyl ester d? h? dro-5H-t? ene [2,3-c] p? ran-3-carboxylic acid (3.5 mg, 5.7 x 10-3 mmol) was dissolved in 20% trifluoroacetic acid in dichloromethane (1.0 ml. ) and stir for 2 h at room temperature. The volatiles were evaporated in vacuo at 1 p rodu 2. 7 mg (95%) of the tablet computer as a solide. "H NMR (400 MHz, CD3OD) d 2.66 (m, 1H), 3.10 (m, 1H), 3.80 (m, 1 H), 3.98 (m, 2H), 4.66 i, 1 H 4 [K i f 1 K MS m / z 498.3 (M-). ^ GJ The following compounds were prepared in a similar manner as described in? Je lc 42.

AX PLO 43 A. c i d o - (1,3-di-oxo-1,3,3,6-hexahydro-isolndol-2-ylmethyl) -2- (oxalyl-amino) -4, ~ > -dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid 2- (1, 4, 8-trioxa-spiro [4.5] dec - * 7 -ylmethyl) -4,5,6,7-tetrahydro-isoindol-1,3-dione 73.X mg (62%) as a oil. : H NMR (400 MHz, CDC13) d 1.42-1.58 (m, 2H), 2.24 (m, 2H), 2.62 (m, 2 H), 3.10 (m, 2H), 3.5X (m, 2H), 3.71 (m, 3 H), 3.94 (m, 6 H), 5.9 (m, 2 H). 2 - . 2 - '4-exc-tetra? Dro-p? Ran-2? Methyl) - r ^ r' - i tetra n? Dro-? Sc? Ndol-1, 3-dione ~ 5T5 mg (92%) as a solid. -: H NMR (400 MHz, CDC13) d 0.86 (m, 2H), 1.64 (m, 2H), 2.22 (rp, 1H), 2.34 (m, 2H), 2.61 (, 3 H), 3.13 (m, 2 H), 3 9 (m, 1 H), 3795 (m, 1 H), 4.28 (m, 1 H), 5. 2 (, 2 H).

The ester t er c-bu ti 1 i co of the acid 2-am no -5- 1, 3-d? O ol, 2, 4, 5, 6, "" "-h xahiaro-i or in dol-2 -ethyl-4, 7-dinidro-5H-tie not [2, 3 -X-n-3-carboxylic acid was obtained as a solid from purification by preparative TLC (Kieselgel 60F25Í, Imm. , hexane: ethyl acetate, 1: 1) (36 mg, 471) .lH NMR (400 MHz, CDC13) d 1.53 (s, 9H), 2.22 (m, 2H), 2.62 (m, 2H), 2.83 ( m, 1 K), 3.11 (m, 2H), 3.56 (m, 1H), 3.83 (m, 2H), 4.50 (m, 2H), 5.89 (m, 2H), MS m / z 419.5 (M +), 363.4 (M-57).

The tert-butyl ester of 2 (tert-butoxyoxalylamino) -5- (1,3-dioxo- 1, 3, 4, 5, 6, 7-hexahydro-? Soindol-2-ylmethyl) -4, 7-dihydrc-5H-thieno [2, 3-c] pyran-3-carboxylic acid was obtained after preparative TLC (Kieselgel 6OF254, 0.5mm, hexane: ethyl acetate, 8: 2). : H NMR (400 MHz, CDC15) d 1.60 (s, 18H), 2.2 (m, 2 H 1, 2.9 (, 3 H, 3.14 (m, 2 H), 3.90 (rp, 2 H >, 4.11 , rr., 1 rX, 4.63 (m, 1 H), 4.7 m, I ri), 5.91 (m, 2 HX MS m / z 545.4 (M-), 489.4 (M-57). t F "i1 c ompu of the title was __ abuv__ as a solid (17.2 mg, quantitative yield).

A NMR (400 MHz, CD3OD) d 2.28 (m, 2H), 2.55 (m, 2H), 2.97 (m, 2H), 3.31 (m, 2H), 3.56-3.93 (m, 3H), 4.70 (m, 2H), 5.91 (m, 2H). MS m / z 433.3 (M-).

EXAMPLE 44 A e XR ± c 2- ioxaiii-amino) 1, 1, 3-trio? Ol, 3-dih id ro-lH-oenzoId] isothiazol-2-ylmethyl) -4,7-dih? D ^ o-5H- thieno [2, 3-c] pyran-3-carboxylic__ "H NMR (400 MHz, CD3OD) 8-09-7.8 (m, 4H), 4.85-4.67 (m, 3 H), 4.21-4.12 m, 1H), 4.02-3.9Í" (m, 1H), 3.11 -3.06 (m, 1H), 2.90-2.80 (m, 1H). ' MS (ESI (-)): 465. HPLC (254.4 nm): 231, s, 99%.

AX PLO 45 Act '• me t cxX-benzenesulfonylamino) -methyl] -2- (q_x allyl-ammo) -4,7-dihydro-5H-tiep o_ [2,? P - 3-carboxy To a solution of the tert-butyl ester of the etciac 2-am? No-5-arr? Nomet-l-4, ~ "'- dih? Dro-5H-t? Enc [2,3-c] p? Ran- 3-carboxylic acid (101 mgX 0.35 mmol) in dichloromethane (1 ml) was added pyridine (32 μl, 0.39 mmol) and 4-me t-oxobenzenesulfonyl chloride (82 mg, 0.39 mm or 1). it was diluted with dichloromethane? 2 l) and subjected to preparative TLC (1: 1 hexanes / ethyl acetate) yielding 10 mg X- of the tertiary ester of the acid 2-amino-? - ((-4-ethoxy-benzene sulfcn? lammo) -metii) -4, 7 -aihi dr o -5K-11 e n'o 2,3-c] p? ran-3-carboxylic acid as a solid.

A NMR (400 MHz, CDC13) d 7.82 (d, J = 9 Hz, 2H), 6.93 (d, J = 9 Hz, 2H), 5.3 (bs, 2 H) ', 4.57 8s, 2H), 3.84 ( s, 3H), 3.72 (m, 1H), 3.10- 3.06 (m, 1H), 2.95-2.87 (m, 1H), 2.69 2.6 m 1H), 2.41-2.32 (m, 1H), 1.47 (s, 9H) ). MS: APCI (-): 453 [M-H].

To a solution of the ester te rc- use of 2-amino-5- ((4-methoxy-benzenesulfonylamino) -methyl) -4,7-dihydro-5H- .thieno [2,3-c] pyran-3 acid. carboxylic acid (8 mg, 0.017 mmol) in dichloromethane (1 ml) was added t-ethylamine (μl, 0.051 mmol), and tert-butyl ester of imidated zo-1-l-1-oxo-acetic acid (10 mg). 0.51 mmol). and was stirred at room temperature for 16 h. The volatiles were removed and a dichloromethane (2-ml) was added to the residue. The solution was purified by preparative TLC (10% methanol / 90% dichloromethane) yielding 10 mg (100%) of the 2- (tert-buxyoxalylamino) -5- ((4-methoxy-benzenesulfor) tert-butyl ester. ilami c) -methi) -4,7-dihydro-5 H -thie not [2, 3-c] ira n-3-carboxylic acid as a solid.

: H NMR (40C MHz, CDC13) d 7.83 (d, J = 9 Hz, 2HJ, 6.93 (d, J = 9 Hz, 2 H), 4.68 (m, 2 H), 3.85 (s, 3H), 3.7 (m, 3 H), 3.29-3.22 (m, 1 H), 2.80-2.75 (m, 1H), 2.53-2.43 (m, 1H), 1.56 (s, 18 H) MS: APCI (+): 582.8 [M + H], 527 (-1 tBu). 2- (tert-butoxyoxal-amino) -5- ((4-methoxy-be n-sulfo nylammo) -methyl) -4,7-dihydro-5H-t? E? Ic tert -butyl ester. 2,3-c] p-3-carboxylic acid (10 mg, 0.017 g) was added to a solution of 25% tpfl eroacetic acid in dichloromethane (2 ml) The reaction mixture was stirred at room temperature for 2 h , at this time, the solvent was removed in vacuo.The residue was precipitated by the addition of diethyl ether and washed two times with diethyl ether yielding after drying or 2 mg (25%) of the compound of the title X. solid 1 H NMP X 00 Hz, X; CD d 7.78 (d, J = 9 H z, 2 H), 7.02 (d, J = 9 Hz, 2 H), 4.76-4.63 {m, r ^ i '3.84 (s, 3H), 3X5 (m, 1H), 3.50-3.47 (m, 2H), 2.89-2.83 (m, 1H), 2.52-2.42 (, 1H). M S: A P C I (-): 4"" "* 1 [M + H]; EXAMPLE 46 Aci N- (6-hydroxy? -3-hydroxymethyl-4, 5, 6, 7-tetrahydro-benzo [b] thiophen-2-yl) -oxalamic acid The tert-butyl ester of 2- (ethoxyoxalylamino) -6- (2'-escrrc [1 *, 3 '"aio eiari -6, 7-d? N? Dro-4H-oen c [P] 11 of en-3-carbox i 11 co (20 g, 0.05 mol) was dissolved in a mixture of (1: 4) trifiuoroacetic acid and dichloromethane (200 ml) which contains water (1 ml) at 0 ° C. C. The reaction mixture was stirred at 0 ° C for 1 h and at room temperature for 2 N. The volatiles were evaporated in vacuo and the solid residue was triturated with ethyl ether (2 x 100 ml) and dried in vacuo yielding 15.08 g (100%) of the acid 2-e: ox: cxal: Xa ",: po '-6-cxc-4, 5, 6," "-tetrahydro-ber. Zo [b] t? Ofer. -3 -carbo ill co as a solid.

To a mixture of ethanoi (50 ml) and dichloromethane (50 ml) was added 2- (ethoxyoxalylamino) -6-oxo-4,5,6,7-tetrahydro-ben zo [b] thiof en- 3 - ca rbox 1 i co (2.0 g, 6.43 mmol) followed by sodium borohydride (124 mg, pellets). The resulting mixture was stirred at room temperature for 1 h and an additional sodium borohydride pellet was added. After stirring for a further 4 h the reaction mixture was rapidly cooled by adding a mixture of water (100 ml) and formic acid (100 ml) at 0 ° C. The aqueous phase was extracted with ethyl acetate (2 x 100 ml) and the combined organic phases were washed with brine (100 ml), dried Na 2 SO 4, filtered and evaporated in vacuo yielding 860 mg (43%) of the compound. sto the title as a solid. After standing for 18 h the aqueous phase was filtered and the filter cake was washed with water (2 x 15 ml), diethyl ether (2 x 15 ml) and dried in vacuo yielding an additional portion of 710 mg ( 48%) of the title compound as a solid, calculated for C: 1H13N;? 5S :, 0.5 x H 2 O; C, 47.14%; H, 5.C3%; N, 5.00%.

C, 47.19%; H, 5.00%; N, 4.94%. The following compound was prepared in a similar manner as described in Example EXAMPLE 47 Aci. 2- (oxalyl-amino) -6- (2'-e spix or J "1 ', 3'] di oxol or '-6,7-dinidro- 4 H -ben or [b] t? Ofen-3- carbohydrate P.f. : > 250 ° C Calculated for C: 3 H: 5 N O - S; C, 47.70%; H, 4.00%; N, X28 Found: Z, 47.93%; H, 4.09; N, 4.27 EXAMPLE 48 Aciao 6-h? Drox? -2- (oxalyl-ammo) -4, 5, 6 / - tetx ridrc-Denzo JX > ] _t i e Xe n-3-carbox? l? co The ethyl ester of 2-io-ete-icxalil-ammd) -6- (2'-spiro [i ', 3' j aioxoianX -6, 7-dm? Dro-4H-oer. Zc [bjt? Ofen-3- Carboxylic acid (8.7 g, 22.7 mmol) was dissolved in a cooled mixture in a 25% ice bath of tpfluoroacetic acid in dico-rumomethane (100 ml) and water (0.5 ml) was added. The reaction mixture was stirred at 0 ° C for 2 h at room temperature for 48 hrs. The volatiles were evaporated to vacuo and the residue was isolated, 1 C 3 ml and evaporated m vac or '2 eces). . The solid residue was washed with diethyl ether (80 ml) and vacuoed at 50 ° C., yielding 6.68 g (83-) of the ethyl ester of aciao 2- (x-oxoxalyl-ammo) -6-oxo-4,5,6. , 7- tetran-aro-benzoLD t? Cfen-3-carboxyl? Co as a sci.

To a solution of the ethyl ester of 2- (ethoxyoxallylamino) -6-oxo-4,5,6,7-tetrahydroxy-2-carboxylic acid (2, 2-carboxylic acid). g, 5.8S mmole) in a mixture of di-methyl ether (40 ml) and ethanol (40 ml) was added sodium borohydride (64 mg, 1.77 mmoi). The reaction mixture was stirred at room temperature for 64 h, additional sodium borohydride (22.3 mg, 0.59 mmol) was added and stirring was continued for a further 18 h. Two more portions of sodium borohydride (23 mg and 15 mg 'were added over the next 6 h of stirring.) To the reaction mixture was added saturated ammonium-cooled ice (50 ml) and the resulting mixture was added to the reaction mixture. extracted with ethyl acetate (3 x 50 ml) The combined organic extracts were dried (Na 2 SO 4), filtered and evaporated in vacuo, the ids were dissolved two times ethyl acetate (100 ml) and evaporated. The residue was washed with diethyl ether (80 ml) and dried in vacuo at 50 ° C yielding 1.46 g (75%) of the ethyl ester of 2-ethoxyoxalylamino) -6-h? draxi-4, 5, 6, 7-tetra? ara ~ benzo [b] thiophen-3-arbaxyl as a solid 1.35 g of this material was subjected to column chromatography (silica gel) using a mixture of ethyl acetate and heptane (1: 1) as eluent. The pure fractions were collected and the solvent was evaporated in vacuo yielding 0.9 g of the ethyl ester of 2- (ethoxyoxalylamino) -6- iarexy-4,5,6,7-tetrahydro-benzo [b] thiophene- 3-Cayboxyl pure as a solid. X NMR (300 MHz, CDC13) d 1.42 (m, 6H), 1.85 (ir, 2H), 2.02 (m, H), 2X1 (dd, 1H), 2.85 im, 1H), 3.00 (m, 2H 4.19 ( bs, 1H), 4.40 (dq, 4 H), 12.45 (bs, 1H, NHCO).

To a solution of the above di ethyl ester (0.3 g, 0.88 mmol) in water (10 ml) was added sodium hydroxide IN (3.1 ml, 3.08 m or i). The resulting reaction mixture was stirred at room temperature for 16 h. The aqueous phase was acidified by the addition of concentrated hydrochloric acid to pH = 1 and the reaction mixture was evaporated in vacuo to 1/2 of the original volume. The precipitate was separated by filtration, washed with a small portion of diethyl ether and vacuumed at 50 ° C for 16 h, yielding 130 mg '52) of the title compound as just one.

P.f. : amorphous NMR (300 MHz, DMSO-d¿) d 1.63 (m, 1H), 1. 86 (m, 1H), 2.5 (m, 1H, partially obscured by DMSO), 2.71 (m, 1H), 2.86 (m, 2H), 3.91 (m, 1H), 4.87 (bs? 1 H), 12.35 (bs, 1H, N HCO). The following compound was prepared in a similar manner as described in Example 27.

M P LO 49 A c i do 5- (2-met? L-4-oxp-4H-quinazolin-3-ylmethyl) -2 -? Sx allyl-amino '-4f * 7-dihydro-5H-t? eno [2, 3-c ix n-3-carboxylic acid - H NMP (300 MHz, DMSO-de) d 12.32 (s, H, 8.10 (d,. = 8 Hz, 1 H, 7.80 t, J = 7 H z, H), X 59 (d,. = 8 Hz, 1 H), 7.49 (t, Xj = 7 Hz, HX 4.78 (d, i Ol z, 1H), 4.53 (d, J = 15 hz, 1 H), 4.39 [d, Z = 15 Hz, 1HX, 4.21 (dd, J = 15 Hz, 9 Hz, 1H) , 4.00-3.94 (m, i H), 3.05 (d, Z 17 Hz, 1H), 2.74-2.65 (m, 1H, partially obscured by the nearest smglete), 2.68 (s, 3 H). 13C NMR (ICO.6 MHz, DMSO-d6) d 167X, 162.8, 161.6, 157.6, 156.1, 148.3, 1 6.9, 136X, 130.5, 127.9, 127.8, 126.5, 121.4, 115.0, 74.4, 65.9, 49.8, 31.4, 25.0. [- H: 4 .1 hPLC (254.4 nm): 2.631 s, 81%.

EXAMPLE 50 Acide * "? -, • xe-d -hydrc ^ soi no 1 - 2 - 11 to 111" i -2- (oxalyl-ammo) -4,7-d? H? Oro-5H-thienc [2, 3-c] pira n-3-carboxylol. _ Acetal of diethyl f t a 1 imi doe with a value of 00 g, 0.38 nci and 1 N hydrochloric acid (600 ml) is mixed, stirred at reflux temperature for 5 min. or until a homogeneous solution is obtained. The reaction mixture was cooled and the precipitate was separated by filtration and dried in vacuo or at 50 ° C. for 16 h in which 63.3 g (88%) of the phthalimido-acetaldehyde was extracted as a solid. H NMR (300 MHz, CDC13) d 4.58 (s, 2H), 7.76-7.78 (m, '2H), 7.90-7.92 (m, 2H), 9.67 (s, 1H). To a mixture of f t a 1 imidoa ce t a 1 de h i do (64 g, 0.34 mol) and t ra ns-1-methoxy-3 - (tri-ethylsilyloxy) -1,3-butadiene (81.5 g, 0.38 mol) in benzene (600 ml) was stirred for 15 min. b or itrogen, a 45% solution of a diethyl ether complex zinc chloride in dichloromethane (55.5 ml, 0.17 mol) was added dropwise at 0 ° C. The reaction was allowed to warm to room temperature overnight. To the reaction mixture was added water (500 ml) and the resulting mixture was extracted with ethyl acetate (200 ml). The organic extract was washed off with X.O N hydrochloric acid (2 x 200 ml) and brine (200 ml). The organic phase was dried (aq), filtered and the solvent was evaporated to a solution which crystallized slowly (98 g). ethyl acetate and diethyl ether (400 ml, "1: 1) and the resulting precipitate was separated by filtration, washed with a small portion of diethyl ether and dried at 50 ° C in 1 h yielding 59.8 g (69%) of 2-4-4-cxe-3, 4-dihydro-2H-pi ra n-2-i 1me ti 1) -isoindole-1,3-dione as a solid. The filtrate was evaporated in-to-c and the residue was purified by column chromatography on silica gel (1 L) leaving a mixture of ethyl acetate and or -; as eluent. The pure fractions were collected and the solvent was evaporated in vacuo or almost to dryness, the solid was separated by filtration and dried in vacuo * at 5_07C j? Qj: 16 h producing an additional 15 g. -. { 4-oxo-3,4-di-idro-2H-pyran-2-ylmethyl) -isaindol-1,3-dio ate a solid. : H NMR XOO MHz, CDCX! d -2.61 (d, 2H), 3. 85 (dd, 1H), 4.18 (dd, 1H), 4.76 (m, 1H), 5.43 ai, 1H), 7.28 (d, 1 H), 7.69-7.77 (m, 2 H) 7 7.84-X 88 ( m, 2 H). The 2- (4-oxo-3,4-dihydro-2H-pyran-2-ylmethi'-isoindoi-i, 3-dione (13 g, 0.051 mol) was dissolved in ethyl acetate (250 ml) and placed in a Parr vessel, 10% Pd / C (1.5 g) was carefully added and the mixture was shaken under 30 psi hydrogen pressure for 6.5 h (Parr apparatus). Filtration followed by evaporation of ethyl acetate in which produced 11.5 g of crude 2-, 4-cxc-tetrahydro-pyrene, -2-ylmethyl) -isoindole-1,3-dione pure enough for the next step. The pure analytical compound could be obtained by • purification of a small sample (250 Xg) by column chromatography on silica gel, using a mixture of hexane / ethyl acetate as a gradient (from 100/0 to 50/50). The pure fractions were collected and the solvent evperated in vacuo, 142"mg_JJ5.5%) dj" 1 to 2 - (4-axc-tetrahydro-pyran-2-ylmethyl) -isoindole -1,3-dione , as a solid: H NMR (400 MHz, CDC13) d 2.30-2, _68 (m, 4H), 3.62 (m, 1H), 3X4 (m, 1H), 4.00 (m, 2H), 7X5 (m , 2 H), 7.88"'(m, 2 H). To a mixture of 2- 4-oxo-tetr ahydro-pyran-2-ylmethyl) -isoir.dol-1, 3-dione "(18.7 g, 0.072 mol), tert-butyl acetate or tert-butyl acetate (11.2 g) , CC: * 9 mol, elemental sulfur (2.5 g, 0.09 mol) in ethanol, morpholine (20 ml) was added and the resulting mixture was stirred at 50 ° C. for 3 h. The cooled reaction mixture was filtered and The volatiles were evaporated in vacuo. The residue was added with water (200 ml) and 100 ml of diethyl ether.A precipitate was separated by filtration and dried in vacuo at 50 ° C_produced with 9.1 g (30%) of the ether. s-2-amino-5- (1-tert-butyl) acid, 3-dioxo-l, 3-dihydro-iso-ndol-2-ylmethyl) -4, -d? Hydro-5H-thieno [2, 3-c] pyran-3-carb-xylic acid as a solid. The filtrate was extracted with ethyl acetate (2 x 150 i) and washed with brine (100 ml), dried (Na: S0), filtered and the solvent evaporated in vacuo. The residue (20 μg) was purified by column chromatography on silica gel (1 L) using a mixture of hexane and 11Xo acetate (1: 2) as the eluent. The pure fractions were extracted and the solvent was evaporated in vacuo, the residue was washed with diethyl ether and the scliac was separated by filtration and dried in vacuo at 50 ° C yielding an additional 2.2 g of the tert-ester. -build of 2-amino-5- (I, 3-dioxo-l, 3-dihydro-isoindol-2-ime thi 1) -4, "-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid as a solid. The filtrate was evaporated in vacuo yielding almost 10.2 g pure (34%) of the ter-ester of 2-amino-7- (1,3-d-oxo-1,3-dihydro-isomodol-2-ylmethyl) -4, 7-dihydro-5H-t? Eo [2,3-c] p? Ran-3-carboxylic acid as an oil. "H NMR (300 MHz, CDC13) d 1.50 (s, 9H), 2. 5 ? - 2.63 (m, 1 H), 2.84-2.90 (m, 1H), 3.79 (q, 1 H), 3.96-4.04 (m, 2H), 4.48-4.62 (m, 2H), 5.91 (bs, 2 H, NX), 7.70 (m, 2H), 7.84 (m, 2H). Tertiary butyl ester of 2-amino-7- 1, 5-a? Exc-I, 3-d? Htdro-iso? R acid. doi-2-ylmethyl) - "4, -di-idro-5K-thieno [2, 3-c] pyran-3-carboxylic acid -H NMR (300 MHz, CDC13) d 1.50 (s, 9H), 2. T-2 .90 im, 2H), 3.6"-3X7 (m, 2 H), 4.02-4.15 (r, 2 H), 4.90 m, 1 H, 6.04 (bs, 2 H, N HZ), 7.70 ( , 2 H), .84 (m, 2 H) A mixture of tert-butyl ester of 2-amino-7- (1,3-dicxo-1,3-dihydro-isoindol-2-? et? l) -4, "'-dihydro-SH-thieno [2, 3-c] pyran-3-carboyl (10.2 g, 0.25 mol), tere-cutiic acid ester irr.i da zo 1 - 1 - i 1 -oxo - a cé ti co '"*" .2 g, 0.037 mol, in dry tetrahydrofuran (150 i was stirred at room temperature for 4 h An additional portion of the latter was c-bu ti 1 i co of the imida zo acid 1 - 1 - i 1 Oxoacetic acid 2.0 0.01 mol) was added and the resulting mixture was stirred for 16 h at room temperature. The precipitate was separated by filtration and washed with small portions of diethyl ether and dried in vacuo yielding 3.5 g (26%) of the tert-byl ester of 2 - (ter c-bu t oxi oxa 111-amino) - - (go 3-dioxo-1,3-dihydro-isoindol-2-yl-methyl) -4, -d? hydro-5H-t? ene [2,3-c] pyran-3-carboxylic acid as a solid . The filtrate was evaporated in vacuo and the residue was added to a (100 ml) and ethyl acetate (100 ml). The precipitate was filtered off and dried in vacuo or at 50 ° C affording an additional 0.8 g (6%) of 2- (tert-butoxyoxalylamino) -7- (I, 3-) tert-butyl ester. dioxo-l, 3-dihydro-? somdol-2-ylmethyl) -4,7-d? hydro-5H-t? ene [2, 3-c] p? ran-3-carboxylic acid as a solid. l NMP-300 MHz, CDC13) d 1.60 (s, 9H), 1.62 (s, 9H ", 2.79-2.97 (m, 2H) ~, 3.73 (m, 1 H), 3.83-3.88 (dd, 1 H ), 4.0 * 7-4.16 (m, 2H), 5.09 (m, 1H), 7.71 (m, 2H), 7.85 (m, 2 H), 12.55 (bs, 1 H, N HC O).

The tert-butyl ester of 2- (tert-butoxyoxalylamino) -7- (1,3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -4,7-dihydro-5H-ti in or [2,3-c] pyran-3-carboxylic acid (0.8 g, 1.47 5 mmoi) above was added to a solution of 25% trifluoroacetic acid in dichloromethane and 3 C ml). The reaction mixture was stirred at room temperature for 6 h, during this time, the solvent was removed in vacuo. The residue is .0 precipitated by the addition of diethyl ether, separated by filtration and dried in vacuo at 50 ° C yielding 0.5 g (79%) of the title cund as a solid. P.f. : > 250 ° C. 5 Calculated for C: 9H14N; 05S, 0.5 x H 2 O; C, 51.94%; H, 3.44%; N, 6.38%. Found: Z, 52.02%; H, 3.37%; N, 6.48%.

EMPLO 51 Sa nosodica del ido - (aeethylamino-amino'1-2-dioxalylamino) -4,7-d? Hydro-5H-thieno [2, 3-c] aryar. -3-carboxylic _L_ To a mixture of the tert-butyl ester of the acid or 2-amino-7- (1,3-dioxo-l, 3-dihydro-iso-ndol-2-ylmethyl) -4,7-dihydro-5H-thieno [2 , 3-c] pyran-3-carboxylic acid (6.0 g, C.014 mol) in ethanol (100 m hydrazine hydrate (1.4 ml, C. CU? The reaction mixture was refluxed for 1 h, cooled and the precipitate was separated by filtration. The filtrate was evaporated i n - = cuo and to the residue s < water (100 ml) was added and the resulting mixture was extracted with dichloryl ether (2 x 100 ml). The combined organic extracts were washed with brine (100 ml), dried (N to S 0 X, filtered and the solvent evaporated in vacuo yielding 2.9% (71%) of the 2-amino acid tert-butyl ester. 7-a.momethyl-4, "-di-hydrc-5 H -thieno [2, 3-c] pyran-3-ca ee: -: ial as an oil: H NMR (3 C 0 MHz, C DC 13 ) d 1.55 (s, 9 H), 2. - 2 - Z .9 - (, 4 H, 3.69-3.78 im, 1 H), 4.13 (m, 1 rX, 4.50 (m, 1 H, 6.09 (bs , 2H, t? Ofen-N * í2).

To a solution cooled with ice water of the o-ami no- / - aminomethyl-4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid tert-butyl ester (1.5 g, 5.27 mmol ) and triethylamine (1.5 ml) in dichloromethane (50 ml) was added dropwise acetyl chloride (0.46 g)5.80 mmoi). The reaction mixture was allowed to reach room temperature and was stirred by an additional C.sub.S h. The reaction mixture was washed with aq (2 x 25 ml), dried (2 OO), filtered and the solvent evaporated in vacuo. The residue was purified by column chromatography on silica gel (1 L) using first ethyl acetate and then on a mixture of ethyl acetate and ethanol (20: 1) as eluents. The pure fractions were collected, and the solvent was evaporated in vacuo or yielding 0.3 g (17%) of the acid terebute of 7- (acetylamine or -methyl) -2-ammo-4,7-dih. ? -5H-thieno [2,3-c] pyran-3-carboxylic acid as a solid. : H NMR (300 MHz, CDC13) d 1.56 (s, 9H), 1.99 (s, 3 H), 2 7 (X, 2 H), 3.19 (m, 1H), 3.67-2.79 (m, 2H), 4.09-4 6 (m, 1H), 4.63 (m, 1H), 5.91 (bs, 1H), 6.10 (s, 2H).

To a mixture of the tert-butyl ester and 11 cc of 7- (acetyl-methyl-methyl!) -2-amino-4,7-dihydro-5H-t-ene [2, 3-c] pyra-3 - carboxy 1 i co (0.3 g, 0.92 mmcl) in dry tetrahydrofuran (40 ml) was added dropwise a mixture of the tert-butyl ester of the acid midazol-1-yl-oxo-acetic acid (0.22 g, 1.10 mmol) in dry tetrahydrofuran (5 ml). The mixture was stirred at room temperature for 3 h. The volatiles were evaporated in vacuo and the residue was dissolved in ethyl acetate (100 ml) and washed with water (50 ml) and brine (50 ml), the organic phase was dried (Na 2 SO 4), filtered The residue was evaporated in vacuo and the residue was stirred with a mixture of diisopropyl ether (5 ml) and diethyl ether (5 ml) The precipitate was filtered off and the filtrate was evaporated by evaporation. which yields 0.25 g (60%) of the tert-butyl ester of the acid 7 - (α-tetyl-1-amino-methyl-1-yl-2 -'-tert-xutcxioxalil-arpir.) c "-4, 7-d? hydro-5H -t? ec [2,3-c] p? ran-3-cardo Iiico as an oil.: H NMR X00 Hz, CDC15) d 1.64 (s, 9 H), 1.65 * s, 9 H), 2. C2 (s, 3 H), 2.87 (m, 2H), 3.29 rr, 1 H ", 3.74 (p, 1 H ', 3.89' ddd, 1H), 4.18 (m, 1K), 4.78 (m, 1H) , 5.93 (bs, 1H, NtfCOMe), 12.5 's, 1H, "Kh'COCOOh 1.

The terc-b ester uses the acid * "*" - (acetylamino-mstyl) -2- (tert-butoxioxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid (0.2 g, 0.44 mmol) was added to a solution of 25% trifluoroacetic acid in diclcromethane (20 ml). The reaction mixture was stirred at room temperature for 4 h, during which time the solvent was removed in vacuo, the residue was precipitated by the addition of diethyl ether, filtered off and dried at 5 ° C. ° C proatelendo 0.11 _g _ _ ("" "3%) of 1 tit compound as a solid. . _. _ - - _ Calculated for C, 3K;; 0-S; Na :, 0.5 x H-O; C, 41.83%; H, 3.78%; N, 7.50%. Found: 1 R; H, 4.08; , 7.6 1: H MPN (30C MHz, DMSO-d £) d 1.87 (s, 3H), .82 Os, 2HX 3.19 (m, 1H), 3.51 (m, 1 H), "3.67 m, I.- : ', 4.0- (m, 1 HX, 4.6 im, 1 H), 8.14 (t, : -:,,, 12.3 s,: H,;. * "Í: OCOOH;." ~~ EXAMPLE 52 To the erc-buyl ester of 2-amino-5- (1,3-dioxo-l, 3-dihydro-isoindol-2-yl-1-yl) -4,7-dihydrc-5H-thieno [2, 3 -c] pyran-3-carboyl (4.5 g, 0.011 mol) dissolved in dixX (3C ml), sodium bicarbonate (1.0 g, 0.011 mol) dissolved in water (16 El) was added, the mixture The reaction mixture was cooled to 0 ° C and 9-fluorenylmethyl croformate (3.0 g, 0.012 mcl) was added.After stirring for 5 minutes the reaction mixture was warmed to room temperature and vigorously stirred for 16 h. The organic phase was separated and washed with brine (10 ml), the aqueous phase was extracted with dichloromethane (2 x 20 ml) and the combined organic phases were dried (MgSO.sub.4), filtered and evaporated in vacuo to yield an orange solid. which was purified by flash chromatography using dichloromethane as eluant.The pure fractions were collected and evaporated in vacuo yielding 5.6 g (81%) of the tert-butyl ester of 5- (1, 3-dioxo-l, 3-dihydro-β-syndiol-2-ylmethyl) -2-i ^ (9H-fluoren-9-ylmexycarbonylamino) -4,7-dihydro-5H-thieno [2, 3 -c] pyran-3-carboxylic acid as a solid. : H NMR (400 MHz, CDC13) d 10.60 (bs, 1H), 7.87-7.84 (m,? H •, ~. ~ B (d, J = 8 Hz, 2 H) X 3 - 0 X7Ü (m, 2H), 7.60 (d, J = 8 Hz, 2H), 7.39 (t, J = 8 Hz, 2H), 7.30 (t, J = 8 Hz, 2 H), 4.74 ^ (d, J = 14 Hz, 1H), 4.62 (d, J = 14 Hz, 1H), 4.48 (d, J = 7 Hz, 2H), 4.27; t, J = 7 Hz, 1H), 4.05-4.00 < m, 2H), 3.86-3.80 (m, 1H), 2.92 (d, J = 17 Hz, 1 K), 2.6 (dd, J = 1, 9 Hz, I H), 1.52 (s, XH).

LC / M f '+ qi 49 The thieno [2, 3-c] pyran protected by F-moc above (5.5 g, 8.6 mmol) was added at 0 ° C to a solution of 20% trifluoroacetic acid in dichloromethane (30 ml). The reaction was stirred for 4 h at room temperature. The volatiles were evaporated in vacuo and the residue was precipitated with diethyl ether, filtered off and dried, which yielded 4.2 g (85%) of the acid, 3-aoxo-1, 3-dihydrate. -isoindol-2-ylmethyl) -2- (9K-fiuoren-9-ylmethoxycarbonyl) -4,7-dih? arc-5H-t? er. or [2, 3-c] pyran-3-carboxylic acid as solid ur 1 HNP, 4 CC Hz, DM SO - de) d 10.22 (brs, i KX ".83 (d, J = 5 Hz, 2 H), 7.88-7.82 (m, 4H), ".66 id, J = 5 Hz, 2 H ,,, 7.40 (t, J = 5 Hz, 2H), 7. 3 J = 5 H- 2 H 4.68-4.4 (m, 4H), 4.34 3. 9 C - 3.81 m, 2H), 3.72-3.67 2.87 (m r iHj, 2.51 (m, 1 H). to ream Kanq .5 mmo 1) was added, and the mixture was lowered to nitrogen, 5 ml of cypiiethylamine X was added, followed by sulfenyl chloride (2.25 ml. 29 mmol X The reaction was stirred at 0 ° C for 0.5 h, then at room temperature for another 0.5 h The resin was filtered off and washed with dichloromethane (2 x 30 ml), N-methylpyrrolidinone (20 ml) and again with _. -ketomethane (Z xx 3 '- * 0' "> mn-i, ') i.' EFl *" resin methanesulfonyl ester 'Wanq was dried in vacuo for 2 h and used directly in The next step is the methanesulfonyl ester of the above Wang resin and 5- (1,3-dioxc-l, 3-dihydro-? -isoin-2-ylmethyl) -2- XH-fluoren-9-ylmethoxy acid. -carbonylamino) -4,7-d? -hydro-5H-thieno [2,3-c] pyran-3-carboxylic acid (4.85 g, 8.4 mmol) was added N-methylpyrridinone (45 ml). of cesium "(2.2 g, 6.7 mmol)" and the reaction was stirred under nitrogen for 16 h and then at 80 ° C for 36 h. or at room temperature, the resin was separated by filtration, washed with water, methanol, and then repeated, and dried in vacuo for 2 h, yielding the ester of the Wang resin of the 5- (1,3-d? Oxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (9H-fi cren-9-ylmethoxy? -carbonylamino) -4,7-dihydro-5H-thieno [ 2, 3-c] pyra n-3-carboxylic acid. The ester of the above Wang resin (4.85 g) was stirred in a 20% pipepdine solution in tetrahydrofuran (20 ml) for 45 minutes. The resin was then separated by flushing, washed with tetrahydrofuran (2 x 20 i), methanol (2 x 20 ml), and dichloromethane (3 x 20 ml) and dried in vacuo for 3 h producing the ester of the 2-m acid Wang resin. and not X, 3-dioxo-l, 3-dihydro-isoindol-2-y1met-11) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carbclic. The ester of the above Wang resin (4.85 g ") was suspended in a mixture of aiciorcmethane (50 ml) and triethylamine (3.0 ml), tert-butyl ester of imidazoyl-1-yl-oxoacetic acid ( 4.2 g, 0.021 moi) lower nitrogen and the mixture was stirred at room temperature for 16 h.The resin was separated by filtration, washed with methanol (30 i then dichloromethane (30 ml) and this process was repeated twice. The resin was dried in vacuo for several hours yielding the ester of the Wang resin of 2- (tert-butoxyoxalyl-aminc'-5- (l, 3-dioxo-l, 3-dihydro-isoindol-2- l l- t i I) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid A small sample of the ester from the previous Wang resin was treated with 20% trifluoroacetic acid in dichloromethane (3 ml) per 1 h The resin was filtered off Cn and the filtrate was concentrated in vacuo, the residue was evaporated twice from di c 1 or t yielding 32 mg of a solid, which gave: H NMR and MS ccr.s sien tes with the co-synthesized-in e epp lo 26. The loading of the resin ang was determined to be 0.6 mmol7g. The ester of the above Wang resin (3.0 g, 1.8 mmol) was suspended in dichloromethane (25 ml) .- hydrazine (0.14 ml, 4.5 mmol) was added and the reaction was stirred under nitrogen at ambient temperature for 24 h. The resin was filtered off and washed several times, alternating between methanol and dichloromethane.

Xitrado gathered "and concentrated to perform £ C mg of a solid. The reaction was determined Incomplete starch by the analysis of the ubrredient, at this time the resin was again put in dichloromethane (15-) and treated with hirazine (50 μl) for an additional 16 h. The resin was separated by filtration and washed as before, yielding an additional 30 mg of the by-product from the filtrate. At this point the reaction was judged to be complete and the resin was dried in vacuo for 3 h, yielding 2.67 g of the ester-from the resin in Wang of 5-ami-omet-l-2- (tert-butoxyoxalil) -amino) -4,7-dihydro-5H-i ene [2, 3-c] pi ra n-3-ca rbox í 1 i co. The resin gave a positive mnhydrin test for the ami as. The ester of the ang anne resin (2.6"7 g) was suspended in a mixture of e xahydrofuran and dichloromethane (1: 1, 90 ml) and distributed to the OntoBloc (80 cavities, 0.02 mmol per cavity). The blocks were drained, meanwhile, 80 carboxylic acids were weighed in individual bottles (0.044 mmol per bottle), a solution of l- (3-d? Meth? Laminoprop? I).-3-etiicarbod ?? m? Da (0.85 g, Four . 4 mmol), hydrate of 1-hr idr oxy-ben z or t r i a zol (0.6 g, 4.4 mmol), and triethylamine (1.1 mL, 8.0 mmol) was prepared in N, N-d? Methylformamide (100 mL). This solution was added to each bottle (1 ml per bottle) and then the contents of each bottle were transferred to an OntoBlock cavity (occasionally the bottles were sonicated to achieve complete solubility). The blocks were then shaken for 2 days. After this time the blocks were drained and washed using methane! and dichloromethane. The blocks were then placed in a vacuum desiccator for 2 h, after which 1 ml of a solution of the im-butyl ester of im idazoi-1-ii-oxo-acetic acid (di-or-methyl ether 0.2 M) was added. added to each cavity. The blocks were then shaken for 16 h. Again the blocks were washed using the above method. After washing, 1 ml of a solution of 20% t -fluoroacetic acid in dichloromethane was added to each well and allowed to stand for 45 minutes. The blocks were drained and the filtrates collected in a micro tillating plate. The cavities were treated with about 075 ml of acetic acid solution at 20% strength in d or 1 and the liquid was collected again. The volatiles were evaporated i_n vacuo, yielding 80 -compounds as solids in the microtitre plate. The plate was analyzed by Mass Spectrometry in which 6 6 of the cavities showed the current product as the molecular ion. The average percentage of the peak area of the HPLC at 220 nm.

X is the point of union fifteen twenty 10 15 20 25 10 fifteen twenty It is noted that in relation to this date the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention. Having described the invention as above, the content of the following is claimed as property

Claims (109)

1. A compound of Formula 1 Formula 1 characterized in that A is together with the double bond in Formula 1 indolyl, benzo [b] thiophenyl, benzo [b] furani lo, indazolyl, benzo [b] is oxazolyl or, benzimidazolyl, benz thia zolyl or, benzoxazolyl, 9H- t ieno [2, 3-c] chromenyl, 4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl, 4,5,6,7-tetrahydro-thieno [2,3-b] pyridyl, 4,5 , 6,7-tetrahydro-thieno [2, 3-c] pyridyl, 4,5,6,7-tetrahydro-thieno [3,2-c] pyridyl, 4,5,6,7-tetrahydro-thieno [3 , 2-b] pyridyl, 4,7-dihydro-5H-thieno [2,3-c] pyranyl, 4,7-dihydro-5H-thieno [2,3-c] thiopyranyl, 4,7-dihydro-5H -thien [2,3-c] thiopyranyl-6-oxide, 4,7-dihydro-5H-thieno [2,3-c] t iopir ani 1 - 6, 6-dioxyde or 4, 5, 6, 7 - te rahydro-4, 7-ethanone-thieno [2, 3-b] pyridyl; Ri is hydrogen, COR5, ORe, CF3, nitro, cyano, SO3H, S02NR7R8, PO (OH) 2, CH2PO (OH) 2, CHFPO (OH) 2, CF2PO (OH) 2, C (= NH) NH2 NRvRs or is selected from the following heterocycles with 5 elements: 0 IM-S HN NC o R j e s wherein R12, R3, and R14 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-C-alkyl, and the alkyl and aryl groups are optionally substituted; R2 is COR5, ORe, CF3, nitro, cyano, SO3H, SO2NR7R8, PO (OH) 2, CH2PO (OH) 2, CHFPO (OH) 2, CF2PO. (OH) 2, C (= NH) NH2, NR7R8 or is selected from the following heterocycles with 5 elements: .N N, N o »- OH S- ^ OH HN * V0H HN" 5- and * SH HN '** - R3, Ri6 and R17 are independently hydrogen, halo, nitro, cyano, thalte omet i lo, alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cß-alkyl, hydroxy, oxo, carboxy, carboxy-Ci-C-alkyl, alkyloxycarbonyl of 1 to 6 carbon atoms, aryloxycarbonyl, arylCi Cea lkyloxycarbonyl, alkyloxy of 1 to 6 carbon atoms, Ci-C-alkyloxyCi-Cealkyl, aryloxy, aryCi-C-alkyloxy, arylCi-CealkyloxyCi-Cealkyl, thio, alkylthio of 1 to 6 carbon atoms, Ci-CealkylthioCi-Csalkyl, arylthio, arylCi-C-alkylthio, aryCi-Csal i 11Ci-Cßa 1 qui 1, NR7R8, Ci-CsalkylaminoCi-Cealkyl, arylCi C Calkyl aminoCi-Cßal qui lo, di (arylCiCa1 alkyl) aminoCi-Cβa lkyl, alkylcarbonyl of 1 to 6 carbon atoms, C i-Cea 1 qu i 1 ca rboni 1 -Ci-Cealkyl, ar il Ci- Ceal 1-cabonyl, arylCiCalkylcarbonyl, Ci-Cealkyl, 1-carboxycarbon with 1 to 6 carbon atoms, Ci-C and 1-Ci-carboxy-alkyl, arylcarboxy, arylcarboxy, Carboxylic acid, alkylcarbonylamino of 1 to 6 carbon atoms, Ci-Cßalkyl carboni laminoCi-Ceal quil or, -carbonylNR7C? -C6alkylCORn, arylCi - Cea lqui lea rboni lamino, arilCi- Cßalqui 1 ca rboni laminoCi-Ceal qui 1, CONR7R8, or Ci-CealquilCONR7R8 where the aryl and alkyl groups are optionally substituted and Rn is NR7R8, or C? -C6alkylNR7R8; or R3 is Or? »Xr < wherein R.sub.2, R.sub.13, and R.sub.14 are independently hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-C-alkyl, and the alkyl and aryl groups are optionally substituted; R 4 is hydrogen, hydroxy, alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cßalkyl, NR Rs, alkyloxy of 1 to 6 carbon atoms; wherein the alkyl and aryl groups are optionally substituted; R 5 is hydroxy, alkyl of 1 to 6 carbon atoms, aryl, ar i lCi-Cßalkyl, alkyloxy of 1 to 6 carbon atoms, Ci-Cealkyl-oxyCi-C-alkyloxy, aryloxy, arylCi-Cßal qui 1 oxy, CF3, NR7R8; wherein the alkyl and aryl groups are optionally substituted; R6 is hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-C-alkyl; wherein the alkyl and aryl groups are optionally substituted; R7 and Re are independently selected from hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cealkyl or, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylCi-Cealqui 1 carbonyl, alkyl carboxyl of 1 to 6 carbon atoms or arylCi-Cealqui Icarboxi wherein the alkyl and aryl groups are optionally substituted; or R and Rs are together with the nitrogen to which they are linked forming a saturated, partially saturated or aromatic cyclic, bicyclic or tricyclic ring system, containing from 3 to 14 carbon atoms and from 0 to 3 additional selected heteroatoms Starting from nitrogen, oxygen or sulfur, the ring system can optionally be substituted with at least one alkyl of 1 to 6 carbon atoms, aryl, arylCi-Cßal qui lo, hydroxy, oxo, alkyloxy of 1 to 6 carbon atoms, arylC-C6alkyloxy, Ci-Cea 1 quiCyloCi-Cdalkyl, NR9R10 or Ci-Csal which is not Ci-Cea 1, wherein Rg and Rio are independently selected from hydrogen, alkyl from 1 to 6 ' carbon atoms, aryl, arylCi-Cßalkyl or, alkylcarbonyl of 1 to 6 carbon atoms, arylcarbonyl, arylCi-Cealkylcarbonyl, 1-carboxykyl of 1 to 6 carbon atoms or arCiCi-Cßalqui Icarboxi; wherein the alkyl and aryl groups are optionally substituted; or R7 and Rs are independently a red, 5-, 6- or 7-element amine, saturated or partially saturated cyclic, imide or lactam; or a salt thereof with a pharmaceutically acceptable base or acid, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any tautomeric forms.

2. A compound according to the rei indication 1, characterized in that A is indolyl.

3. A compound according to claim 2, characterized in that Ri and R2 are CORs and R4 is hydrogen; where Rs is defined as above. -

4. A compound according to claim 2, characterized in that Ri is 5-tetrazolyl and R2 is CORs; wherein R5 is defined as above.

5. A compound according to claim 2, characterized in that Ri and R2 are COOH and R is hydrogen.

6. A compound according to claim 1, characterized in that A is benzo [b] thiophenyl.

7. A compound according to claim 6, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

8. A compound according to claim 6, characterized in that Ri is 5-tetrazolyl and R2 is COR5; wherein R5 is defined as above.

9. A compound according to claim 6, characterized in that Ri and R2 are COOH and R4 is hydrogen.

10. A compound according to claim 1, characterized in that A is benzo [b] furanyl.

11. A compound according to the rei indication 10, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

12. A compound according to claim 10, characterized in that Ri is 5-tetrazolyl and R2 is COR5; wherein R5 is defined as above.

13. A compound according to claim 10, characterized in that Ri and R2 are COOH and R is hydrogen.

14. A compound according to claim 1, characterized in that A is indazolyl.

15. A compound according to claim 14, characterized in that Ri and R2 are CORs and R4 is hydrogen; where Rs is defined as above.

16. A compound according to claim 14, characterized in that Ri is 5-tetrazolyl and R2 is COR5; wherein R5 is defined as above.

17. A compound according to claim 14, characterized in that Ri and R2 are COOH and R4 is hydrogen.

18. A compound according to claim 1, characterized in that A is benzo [b] i s oxa zol i 1 o.

19. A compound according to claim 18, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

20. A compound according to claim 18, characterized in that Ri is 5-tetrazolyl and R2 is CORs, wherein R5 is defined as above.

21. A compound according to claim 18, characterized in that Ri and R2 are COOH and R is hydrogen.

22. A compound according to the rei indication 1, characterized in that A is benzimidazolyl.

23. A compound according to claim 22, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

24. A compound according to claim 22, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is defined as above.

25. A compound according to claim 22, characterized in that Ri and R2 are COOH and R4 is hydrogen.

26. A compound according to the rei indication 1, characterized in that A is benzthiazolyl.

27. A compound according to the rei indication 26, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

28. A compound according to the rei indication 26, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is defined as above.

29. A compound according to claim 26, characterized in that Ri and R2 are COOH and R4 is hydrogen.

30. A compound according to claim 1, characterized in that A is benzoxazolyl.

31. A compound according to claim 30, characterized in that Ri and R2 are CORs and R4 is hydrogen; where Rs is defined as above.

32. A compound according to claim 30, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is defined as before.

33. A compound according to claim 30, characterized in that Ri and R2 are COOH and R4 is hydrogen.

34. A compound according to the rei indication 1, characterized in that A is 4, 5, 6, 7-tetrahydro-thieno [2, 3-b] pyridyl.

35. A compound according to claim 34, characterized in that Ri and R2 are CORs and R4 is hydrogen; where Rs is defined as above.

36. A compound according to claim 34, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is defined as above.

37. A compound according to claim 34, characterized in that Ri and R2 are COOH and R4 is hydrogen.

38. A compound according to claim 1, characterized in that A is 4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl.

39. A compound according to claim 38, characterized in that Ri and R2 are CORs and R4 is hydrogen; where Rs is defined as above.

40. A compound according to the rei indication 38, characterized in that Ri is 5-tetxazolyl and R2 is CORs; where Rs is defined as above.

41. A compound according to claim 38, characterized in that Ri and R2 are COOH and R4 is hydrogen.

42. A compound according to claim 1, characterized in that A is 4, 5, 6, 7-tetrahydro-thieno [3,2-c] pyridyl.

43. A compound according to claim 42, characterized in that Ri and R2 are CORs and R is hydrogen; wherein R5 is defined as above.

44. A compound according to claim 42, characterized in that Ri is 5-tetrazolyl and R2 is CORs; wherein R5 is defined as above.

45. A compound according to claim 42, characterized in that Ri and R2 are COOH and R4 is hydrogen.

46. A compound according to claim 1, characterized in that A is 4,5,6,7-tetrahydro-thieno [3,2-b] pyridyl.

47. A compound according to claim 46, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

48. A compound according to claim 46, characterized in that Ri is 5-tetrazolyl and R2 is COR5; where Rs is defined as above.

49. A compound according to claim 46, characterized in that Ri and R2 are COOH and R4 is hydrogen.

50. A compound according to claim 1, characterized in that A is 4,7-dihydro-5H-thieno [2, 3-c] pyranyl.

51. A compound according to claim 50, characterized in that Ri and R2 are COR5 and R4 is hydrogen; wherein R5 is defined as above.

52. A compound according to claim 50, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is defined as above.

53. A compound according to the rei indication 50, characterized in that R2 is CORs or 5-tetrazolyl; where Rs is defined as above.

54. A compound according to the rei indication 50, characterized in that Ri and R2 are COOH and R is hydrogen.

55. A compound according to claim 52, characterized in that R3 is alkyl of 1 to 6 carbon atoms; wherein the alkyl group is optionally substituted.

56. A compound according to claim 50, characterized in that Ri is 5-tetrazolyl, R2 is COOH, R4 is hydrogen and R3 is alkyl of 1 to 6 carbon atoms; wherein the alkyl group is optionally substituted.

- 57. A compound according to claim 55, characterized in that R3 is placed in position 5.

- 58. A compound according to claim 55, characterized in that R3 is placed in position 7.

59. A compound according to the rei indication 56, characterized in that R3 is placed in position 5.

60. A compound according to claim 56, characterized in that R3 is placed in position 7.

61. A compound according to claim 50, characterized in that Ri and R2 are COOH, R4 is hydrogen and R3 is alkyl of 1 to 6 carbon atoms; wherein the alkyl group is optionally substituted.

62. A compound according to claim 50, characterized in that R3 is -CH2-NR? R? wherein R7 and Rs are as defined above.

63. A compound according to claim 51, characterized in that R3 is -CH2-NR7R8, * wherein R7 and Rs are as defined above.

64. A compound according to claim 62, characterized in that R3 is placed in the position 5.

65. A compound according to claim 62, characterized in that R3 is placed in the position 7.

66. A compound according to claim 63, characterized in that R3 is placed in position 5.

67. A compound according to the rei indication 63, characterized in that R3 is placed in the position 7.

68. A compound according to claim 62, characterized in that R3 is placed in the position 5.

69. A compound according to claim 61, characterized in that R3 is placed in the position 7.

70. A compound according to the rei indication 1, characterized in that A is 4, 5, 6, 7-tetrahydro-4,7-ethanone-thieno [2,3-b] pyridyl.

71. A compound according to claim 70, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

72. A compound according to claim 70, characterized in that Ri is 5-tetrazolyl and R2 is COR5; where Rs is defined as above.

73. A compound according to claim 70, characterized in that Ri and R2 are COOH and R4 is hydrogen.

74. A compound according to claim 1, characterized in that A is 4, 5, 6, 7-tetrahydro-benzo [b] thiophenyl.

75. A compound according to claim 74, characterized in that Ri and R2 are CORs and R4 is hydrogen; wherein R5 is defined as above.

76. A compound according to claim 74, characterized in that Ri is 5-tetrazolyl and R2 is COR5; where Rs is defined as above.

77. A compound according to claim 74, characterized in that Ri and R2 are COOH and R4 is hydrogen

78. A compound according to claim 1, characterized in that A is 4,7-dihydro-5H-thieno [2, 3-c] thiopyranyl.

79. A compound according to claim 78, characterized in that Ri and R2 are CORs and R is hydrogen; where Rs is defined as above.

80. A compound according to claim 78, characterized in that Ri is 5-tetrazolyl and R2 is COR5; where Rs is defined as ant er iorment e.

81. A compound according to the rei indication 78, characterized in that Ri and R2 are COOH and R4 is hydrogen

82. A compound according to claim 1, characterized in that A is 4,7-dihydro-5H-thieno [2, 3-c] thiopyranyl-6-oxide.

83. A compliant compound, with claim 82, characterized in that Ri and R2 are CORs and R4 is hydrogen; where Rs is defined as above.

84. A compound according to claim 82, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is defined as above.

85. A compound according to claim 82, characterized in that Ri and R2 are COOH and R4 is hydrogen.

86, A compound according to the rei indication 1, characterized in that A is 4,7-dihydro-5H-thieno [2,3-c] thiopyranyl-6,6-dioxide.

87. A compound according to claim 86, characterized in that Ri and R2 are CORs and R4 is hydrogen; where R5 is defined as above.

88. A compound according to claim 86, characterized in that Ri is 5-tetrazolyl and R2 is CORs; where Rs is as defined above.

89. A compound according to claim 86, characterized in that Ri and R2 are COOH and R4 is hydrogen.

90. A compound characterized in that it is selected from the following: 2- (oxalyl-amino) -4,5,6,7-tetrahydro-benzo [b] thiophene-3-carboxylic acid; 2- (Oxalyl-amino) -6-0x0-4, 5,6,7-tetrahydro-benzo [b] thiophene-3-carboxylic acid; 6-Benzoyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 6-Benzyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 6-Methyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [2, 3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -β-phenethyl-4,5,6,7-tetrahydro-thieno [2, 3-c] pyridine-3-carboxylic acid; 5-Benzoyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [3,2- c] pyridine-3-carboxylic acid; 5-Benzyl 1-2- (oxal i 1-amino) -4,5,6,7-tetrahydro-thieno [3,2-c] pyridine-3-carboxylic acid; 5-Methyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [3,2- c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -5-phenethyl-4,5,6,7-tetrahydro-thieno [3,2-c] pyridin-3-carboxylic acid; 2- (Oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -4,5,6,7-tetrahydro-4,7-ethano-thieno [2,3-b] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -6-pi-ridin-2-ymethyl 1-4,5-6,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalylamino) -4,5,6,7-tetrahydro-thieno [2, 3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((4-oxo-chromene-4 H-2 -carbonyl) amino) methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3- carboxylic; 6- (3-methoxy-benzyl) -2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 6- (Oxalyl-amino) -lH-indole-7-carboxylic acid; 6- (Oxalyl-amino) -lH-indole-5-carboxylic acid; 1- (3-Me-toxy-benzyl) -6- (oxalyl-amino) -1H-indole-5-carboxylic acid; 2- (Oxalyl-amino) -6-pyridin-3-ylmethyl-4,5,6,7-tetrahydro-thieno [2, 3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -6-pyridin-4-ylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalylamino) -5- (2'-spiro [1 ', 3'] dioxolan) -6,7-dihydro-4H-benzo- [b] thiophene-3-carboxylic acid; 3- [4- (3-Morpholin-4-yl-propionyl) -piperazin-1-ylmethyl] -6- (oxalyl-amino) -lH-indole-5-carboxylic acid; 2- (Oxalyl-amino) -6-quinolin-2-ylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] t -pipe-3-carboxylic acid; 2 - (Oxal i 1 -.amino) -6-oxo-4,7-dihydro-5 H -thieno [2, 3-c] thiopyran-3-carboxylic acid; 2- (Oxalylamino) -6,6-dioxo-4,7-dihydro-5H-thieno [2, 3-c] thiopyran-3-carboxylic acid; 2- (Oxalylamino) -9H-thieno [2, 3-c] chromen-3-carboxylic acid; 2- ((2-H-tetrazole-5-carbonyl) amino-4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; N- (3- (2H-tetrazol-5-yl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) oxalamic acid; 6-Benzyl acid 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyridin-3,6-dicarboxylic acid ester; 2- (Oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] pyridin-3,6-dicarboxylic acid 6-ethyl ester; 6-Acetyl-2- (oxalyl-amino) -4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 2- (Oxalyl-amino) -6-phenylcarbamoylmethyl-4,5,6,7-tetrahydro-thieno [2,3-c] pyridine-3-carboxylic acid; 5- (1, 3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3 acid -carboxylic; 5- (Benzoylamino-methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5-Benzoyloxymethyl-2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (1-oxo-l, 3-dihydro-isoindol-2-ylmethyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 1- (2- (4-Methyl-piperazin-1-yl) -2-oxo-ethyl) -6- (oxalyl-amino) -lH-indole-7-carboxylic acid; N- (4-carboxymethyl-4,5,6,7-tetrahydro-benzofb] thiophen-2-yl) -oxalamic acid; N- (4-carboxymethylene-4,5,6,7-tetrahydro-benzo [b] thiophen-2-yl) -oxalamic acid; N- (4-ca rboxime t i 1-4,7-dihydro-5 H-1-ene [2, 3-c] pyran-2-yl) -oxalamic acid; N- (4-carboxymethylene-4,4-dihydro-5H-thieno [2, 3-c] pyran-2-yl) -oxalamic acid; N- (4- (2 H- te tra zol-5-ylmethyl) -4,5,6,7-tetrahydro-benzo [b] thiophen-2-yl) -oxalamide acid N- (4- (2H-tetrazol-5-ylmethyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-2-yl) -oxalamic acid; 2- (Oxalylamino) -5- ((3-phenoxy-benzoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3,5-Dimethoxy-benzoylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5 - ((3,5-bis-trif luoromethyl-benzyl-lamino) -methyl) -2- (oxalyl-amino) -, 7-dihydro-5H-thieno [2, 3-c] pyran-3-acid carboxylic; 5- ((Ci-Clohexanca-rboni-1-amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3-Dimethylamino-benzoylamino) -methyl) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((4-Acetyl-amino-benzyl-lamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2-Cyclopent-2-eni-1-acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 acid -carboxylic; 5- ((2-Acetylamino-benzoylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3-methoxy-benzoylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((4-Dimethylamino-benzoylamino) -methyl) -2 (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((4-phenoxy-benzoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5 - ((4-Acetoxy-benzoylamino) -methyl) -2 acid (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (But-2-eneylamino-methyl-1) -2- (oxal-yl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((4-oxo-4-phenyl-butyrylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2 - (Oxalyl-amino) -5 - ((5-oxo-hexanoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 4-Carboxymethyl-2- (oxalyl-amino) -4,5,6,7,7-tetrahydro-benzo [b] thienophen-3-carboxylic acid; 2- (Oxalylamino) -5- ((2-thiophen-2-yl-acetylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (((1H-Indol-2-carbonyl) -amino) -methyl) -2 (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (((lH-Indol-3-carbonyl) -amino) -methyl) -2 (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid 1 ico; 5- (((lH-Indole-5-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- carboxylic; 2- (Oxalylamino) -5- ((3-pyridin-3-yl-acryloylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((4-oxo-4-phenyl-but-2'-enoylamino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 acid -carboxylic; 5- ((2- (4-Benzyloxy-phenoxy) -acetylamino) methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((4-oxo-4H-chromen-3-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran- 3-carboxylic; 5- (((5-Benzyloxy-lH-indole-2-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran- 3-carboxylic; 2- (Oxalyl-amino) -5- ((3-t-iiophen-2-yl-acryloylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- (((4-oxo-chromen-4H-3-carbonyl) amino) methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 acid -carboxylic; 2- (Oxalylamino) -5- ((3-phenyl-propionylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (((Furan-2-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (((Naphthalene-2-carbonyl) -amino) -methyl) -2 (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((2-phenoxy-acetylamino) methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2 - (Oxal-yl-amino) -5- (f enylamino -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- ((2- (3,4-Dimethoxy-phenyl) -acetylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-acid carboxylic; 5- ((2- (4-Ethoxy-phenyl) -acetylamino) -methyl) 2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((3-phenyl-acryloylamino-methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3 - (3,5-dimethoxy-1-enyl) -acryloylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic; 2- (Oxalyl-amino) -5- (((5-oxo-pyrrolidin-2-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- acid carboxylic; 5- (((furan-3-carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- (((thiophene-2-carbonyl) • amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid 2, 3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- (((pyrazin-2-carbonyl) amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((((l-oxy-pyridine-2-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- acid carboxylic; 2- (Oxalyl-amino) -5- (((pyridine-2-carbonyl) amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- (((pi-Ridin-3-carbonyl) amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5 - ((2- (3,5-bis-trifluoromethyl-phenyl) -acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3-carboxylic; 5- ((3-Benzenesulfonyl-1-propylamino) -methyl) 2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3- (3,5-difluoro-phenyl) -acyloylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-acid carboxylic; 2- (Oxalylamino) -5- ((4-oxo-pent-2-enoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid 2, 3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((6-oxo-hept an oi 1-amino) methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2- (4-Dimethylamino-phenyl) -acetylamino) methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (((Benzo (1,3) dioxol-5-carbonyl) -amino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3-carboxylic; 5- ((2-Cetyl-amino-3-f-en-1-propylamine) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic; 5- ((2-Acetoxy-benzoylamino) -methyl) -2 acid (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5 - ((2-oxo-3-phenylpropionylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2-Benzoylamino-acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- ((4-oxo-pentanoylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3-furan-2-yl-acryloylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2-Acetylamino-acetylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalyl-amino) -5- ((2-phenylsulfanyl-acetylamino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5 - ((2-Benzyl sulf ani 1-acetylamino) -me ti 1) -2 (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2 - (lH-Indol-3-y1) -2 -oxo-acetylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- ((3- (lH-Indol-3-yl) -2-oxo-propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; 5- ((3- (2-Nitro-phenyl) -2-oxo-propionylamino) methyl-2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3 -carboxylic; 5- ((2-Acetylamino-3-phenyl-acryloylamino-methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (((L-Acetyl-pyrrolidine-2-carbonyl) -amino'-methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- carboxylic; 5- ((2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) 3- (1H-imidazol-4-yl) -propionylamino) -methyl) -2 - (oxalyl-amino) ) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- ((4 - (3, 4-dimethoxy-1-ene-2-oxo-but-3-enylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H- acid thieno [2, 3-c] pyran-3-carboxylic acid; 5- ((3-1H-ben zoimide zol-2 -i 1-propioni lami) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; 5- ((2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -butyrylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic acid; 5- ((2-Ace t i 1 amino-propionilamino) -me ti 1) -2 (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2-Acetylamino-4-met ilsul fañyl butyrylamino) -methyl) -2- (oxalylamino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-acid carboxylic; 5- ((2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -4-methyl-pentanoylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro- 5H-thieno [2, 3-c] pyran-3-carboxylic; 5- ((2-Acetyl-amino-3-methyl-butylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 -carboxylic; 5- ((2- (1, 3-dioxo-l, 3-dihydro-isoindol-2-yl) 3-phenyl-propi oni lamino-propionyl amino) -methyl) -2 - (oxalyl-amino) -4 , 7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((3-furan-3-yl-acryloylamino) -methyl) -2 - (oxalylamino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2-Indan-2-yl-acetylamino) -methyl) -2 (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (((9,10-Dioxo-9,10-dihydro-anthracene-2 carbonyl) -amino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (2- (Naphthalen-1-yloxy) -acetylamino) methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pi n-3- acid carboxylic; 2- (Oxalyl-amino) -5- (((4-oxo-4 H-cromen-2-carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic; 2- (Oxalyl-amino) -5- ((3-oxo-indan-l carbonyl) -amino) -methyl) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- ((2- (1,3-Dioxo-1,3-dihydro-isoindol-2-yl-propionylamino) -methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2] , 3-c] pyran-3-carboxylic acid; 7- (1,3-dioxo-1,3-dihydro-isoindol-2'-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3 acid -carboxylic; 7- (Acetylamino-methyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 2- (Oxalylamino) -5- (((3-oxo-i ndan-1-carbonyl) amino) methyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; Acid 5 - (2, 4-di oxo- 1 ia zol idin-3 -i lme ti 1) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran- 3-carboxylic; 5- (5,6-Dichloro-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3 -c] pyran-3-carboxylic; 5- (1, 3-Dioxo-l, 3, 4, 5, 6, 7-hexahydro-isoindol 2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic; 2- (Oxalyl-amino) -5- (1, 1,3-trioxo-1,3-dihydro-lH-benzo [d] isothiazol-2-ylmethyl) -4,7-dihydro-5H-thieno [2] acid 3-c] pyran-3-carboxylic acid; 5- [(4-Methoxy-benzenesulfonylamino) -methyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; N- (6-hydroxy-3-hydroxymethyl-4,5,6,7-tetrahydro-benzo [b] thiophen-2-yl) -oxalamic acid; 2- (Oxalyl-amino) -6- (2'-spiro [1 ', 3'] dioxolan) -6,7-dihydro-4H-benzo [b] thiophene-3-carboxylic acid; 5- (2-Methyl-4-oxo-4H-quinazolin-3-ylmethyl) -2 - (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (5-Chloro-l, 3-dioxo-6-sulfamoyl-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (5,7-Dioxo-5, 7-dihydro-pyrrolo [3,4-] iridin-6-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (1, 3-di-oxo-1,3-dihydro-pyrrolo [3, 4 c] pyridin-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid 2, 3-c] pyran-3-carboxylic acid; 5- (5,7-Dioxo-5,7-dihydro-pyrrolo [3,4-b] pyrazin-6-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (5-Nitro-1, 3-dioxo-1,3-dihydro-o-soindol-2-methylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3 -c] pyran-3-carboxylic acid; 5- (1, 3-dioxo-3,4-dihydro-lH-isoquinolin-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran -3-carboxylic acid; 5- (4,6-Dioxo-4,6-dihydro-thieno [2, 3-c] pyrrole-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2] , 3-c] pyran-3-carboxylic acid; 5- (4,6-Dioxo-4H, 6H-thieno [3,4-c] pyrrol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; 5- (4,6-Dioxo-2,6-dihydro-4H-pyrrolo [3,4-c] pyrazol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] pyran-3-carboxylic acid; 5- (4,6-Dioxo-4,6-dihydro-pyrrolo [3,4-d] thiazol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2] 3-c] pyran-3-carboxylic acid; 5- (2-Acetylamino-4,6-dioxo-4,6-dihydro-pyrrolo [3,4-d] thiazol-5-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro acid -5H-Thieno [2,3-c] pyran-3-carboxylic acid; 5- (5-Hydroxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] acid ] pyran-3-carboxylic; 5- (5-Methoxy-l, 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thiol [2-3] c] pyran-3-carboxylic; 5- (4-Hydroxy-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylme ti 1) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3 -c] pyran-3-carboxylic acid; 5- (4-Methoxy-1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] acid ] pyran-3-carboxylic; 5- (4-Nitro-l, 3-dioxo-l, 3-dihydro-i soindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; Acid 5 - (4 -acetyl 1 - 2, 6-dioxo-pipe ra z in-1-ylme ti 1) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3 -c] pyran-3-carboxylic acid; 5- (2,6-dioxo-4-tri fluorine orne tansulfonyl-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran 3-carboxylic; 5- (4-Methanesulfonyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-ti-ene [2, 3-c] pyran-3-carboxylic acid; 5- (5-Methylcarbamoyl-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] acid ] pyran-3-carboxylic; 5- (5-ethylcarbamoyl-l, 3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] acid ] pyran-3-carboxylic; 5- (5-Propylcarbamoyl-l, 3-dioxo-l, 3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno acid [2, 3-c] ] pyran-3-carboxyli co; 2- (Oxalyl-amino) -5- (1-thioxo-1,3-dihydro-isoindol-2-ylmethyl) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3- acid carboxylic; 5- (4-dimethyl t-carbamoi-l, 2, 6-di-oxo-pipera-zi n-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-t-ene [2, 3 -c] pyran-3-carboxylic acid; 5- (4-Methylcarbamoyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (2,6-Dioxo-piperazin-1-ylmethyl) -2- (oxalyl amino) -4,7-dihydro-5H-thieno [2,3-c] pran-3-carboxylic acid; 5- (4-Ca rbamoyl-lme-ti-2, 6-di-oxo-piperaz-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-] c] piran-3-ca rboxí lico; 5- (4-Carboxymethyl-2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2,3-c] pyran-3-carboxylic acid; 5 - (3,5-di-oxo-2,3-dihydro-5H-benzo [f] [1,4] oxazepin-4-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro- 5H-thieno [2,3-c] pyran-3-carboxylic acid; 5- (2-Acetylamino-5,7-dioxo-5,7-dihydro-pyr-ol or [3,4-d] pyrimidin-6-ylme ti 1) -2- (oxalyl-amino) -4, 7-dihydro-5H-thieno [2, 3-c] pyran-3-carboxylic acid; 5- (4- (4-Acetylamino-benzenesulfonyl) -2,6-dioxo-piperazin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; 5- (4- (Methoxy-methyl-carbamoyl) -2,6-dioxo-piperidin-1-ylmethyl) -2- (oxalyl-amino) -4,7-dihydro-5H-thieno [2, 3-c] ] pyran-3-carboxylic; a pharmaceutically acceptable salt of the same

91. The compounds according to any of the preceding indications, characterized in that they act as inhibitors or modulators of the Tyrosine Protein Phosphatases.

92. A pharmaceutical composition suitable for the treatment of type I diabetes, type II diabetes, tolerance to glucose deterioration, insulin resistance or obesity characterized in that it comprises a compound according to any one of claims 1 to 90 or a pharmaceutically salt thereof. with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the tautomeric forms together with one or more pharmaceutically acceptable carriers or diluents.

93. A pharmaceutical composition suitable for the treatment of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, priorative disorders including cancer and psoriasis, diseases with decrease or increase in synthesis or effects of hormonal growth, diseases with decrease 0 increase in the synthesis of hormones or cytokines that regulate the release of / or response to hormonal growth, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases characterized in that they comprise a compound according to any of the claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the tautomeric forms together with one or more pharmaceutically acceptable carriers or diluents.

94. The composition according to claim 91, 92 or 93 characterized in that it is in the form of a single oral dosage or single parenteral dosage.

95. A composition according to rei indication 91, 92 or 93 characterized in that said compound is administered as a dose in a range from about 0.05 to 1000 mg, preferably from about 0.1 to 500 mg and especially in the range from 50 at 200 mg per day.

96. A compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the tautomeric forms for the Therapeutic use.

97. A compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the tautomeric forms for the therapeutic use in the treatment or prevention of type I diabetes, type II diabetes, tolerance of glucose deterioration, insulin resistance or obesity.

98. A compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the tautomeric forms for the therapeutic use in the treatment or prevention of immune dysfunctions including aut oimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, pr opertory disorders including cancer and psoriasis, diseases with decrease or increase in synthesis or effects of hormonal growth, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of / or response to hormonal growth, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases.

99. The use of a compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the tautomeric forms as a medicament.

100. The use of a compound according to any of claims 1 to 90 for preparing a medicament.

101. The use of a compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the forms tautomerics for the preparation of a suitable drug for the treatment or prevention of type I diabetes, type II diabetes, tolerance of glucose deterioration, insulin resistance or obesity.

102. The use of a compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or any optical isomer or mixture of optical isomers, including a racemic mixture, or any of the forms tautomerics for the preparation of a suitable medicament for the treatment or prevention of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, teoporosis, prolific disorders including cancer and psoriasis, diseases with diminution or increase in the synthesis or effects of hormonal growth, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of / s response to hormonal growth, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases.

103. A method of treating type I diabetes, type II diabetes, tolerance of glucose deterioration, insulin resistance or obesity, characterized in that it comprises administering to a subject in need thereof an effective amount of a compound in accordance with any of claims 1 to 90 to said subject.

104. A method of treating immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, prolific disorders including cancer and psoriasis, diseases with decrease or increase in synthesis or effects of hormonal growth, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of / or response to hormonal growth, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases, characterized in that it comprises the administration to a subject in need of this an effective amount of a compound according to any of claims 1 to 90 to said subject.

105. A process for the production of a medicament, in particular to be used in the treatment or prevention of type I diabetes, type II diabetes, tolerance of glucose deterioration, insulin resistance or obesity, characterized in that the process comprises producing a compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof in a galenic dosage form.

106. A process for the production of a medicament, in particular to be used in the treatment or prevention of immune dysfunctions including autoimmunity, diseases with dysfunctions of the coagulation system, allergic diseases including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or hormonal growth effects, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of / or response to hormonal growth, brain diseases including Alzheimer's disease and schizophrenia , and infectious diseases, characterized in that the process comprises producing a compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof in a galenic dosage form.

107. Any new feature or combination of features as described here.

108. A method for the preparation of a compound of formula 1, characterized in that to) allowing a substituted amino compound (I) to react with an acid chloride of the formula (II), wherein A, Ri, R2, R3, R4, Rie and Ri7 are defined as above, or allowing a carboxylic acid (I), a primary amine (II) and an aldehyde (III) to react with an isocyanide (IV) wherein R? 2, Rp, R14, and Ris are independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl, arylCi-Csal or as defined above and the alkyl and aryl groups are optionally substituted as defined above; or R12, R13, Ri4, and Ris are independently selected from where Y indicates the point of attachment for R12, R13, R14, and Ris and A, Ri, R2, and R4, are as defined above, or c) the Ugi reaction of the fourth component described above (method b)) is carried out by joining some of the components to a solid support, therefore, the synthesis can be carried out in a binding chemistry style.

109. The compounds according to claim 1 to 90 which act as ligands, inhibitors or modulators of molecules with pTyr recognition units including proteins containing SH2 domains. SUMMARY OF THE INVENTION The present invention provides novel compounds, novel compositions, methods for their use, and methods for their production, wherein such compounds are pharmacologically useful inhibitors of the Tyrosine Phosphatases Protein (PTPases) such as PTPIB, CD45, SHP-1, SHP-2. , PTPa, LAR and HePTP or similar. The compounds are useful in the treatment of type I diabetes, type II diabetes, tolerance of glucose deterioration, insulin resistance, obesity, immune dysfunctions including au to immunity, diseases with coagulation system dysfunctions, allergic diseases including asthma, osteoporosis. , Proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of hormonal growth, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of / or response to hormonal growth, brain diseases including Alzheimer's disease schizophrenia, and infectious diseases.