JP2002506058A - Modulator of protein tyrosine phosphatase (PTPase) - Google Patents

Abstract

  (57) [Summary] The present invention provides novel compounds, novel compositions, wherein the compounds are pharmaceutically useful inhibitors of protein tyrosine phosphatases (PTPases) such as PTP1B, CD45, SHP-1, SHP-2, PTPα, LAR and HePTP. It provides their use, and their manufacture. These compounds are useful for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immunodeficiencies including autoimmune diseases, diseases involving clotting system dysfunction, allergic diseases including asthma, osteoporosis Proliferative disorders, including cancer and psoriasis, diseases due to reduced or increased growth hormone synthesis or action, diseases due to reduced or increased synthesis of hormones or cytokines that control the release and / or response of growth hormone, Alzheimer's disease and division It is useful in treating brain diseases, including diseases, as well as infectious diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

FIELD OF THE INVENTION The present invention relates to novel compounds, processes for their preparation, compositions containing the compounds, the use of these compounds as medicaments and their use in therapy, wherein such compounds of formula 1 are PTP1B , CD45, SHP-1, SHP-2, PTPα, LAR and HePT
It is a pharmacologically useful inhibitor of protein tyrosine phosphatase (PTPase) such as P.

[0002]

Embedded image

[0003] where A, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₆ and R ₁₇ are more fully defined below. ATPase is a basic enzyme involved in metabolism, growth, proliferation and differentiation. Have been found to play a major role in the intracellular modulation and regulation of specific cellular signaling mechanisms (Flint et al., The EMBO J. 12: 1937-46 (1993); Fisher et al., Science 25
3: 401-6 (1991). Overexpression or altered activity of tyrosine phosphatase may also contribute to the manifestation and progression of various diseases (Wiener et al., J. Natl.
Inst. 86: 372-8 (1994); Hunter and Cooper, Ann. Rev. Biochem. 54: 897-930 (
1985)). In addition, inhibiting these PTPases helps to treat certain types of diseases such as diabetes types I and II, autoimmune diseases, acute and chronic inflammation, osteoporosis, and various forms of cancer There is increasing evidence to suggest. BACKGROUND OF THE INVENTION Protein phosphorylation is now well recognized as an important mechanism used by cells to transduce signals to cells during various stages of cell function
(Fisher et al., Science 253: 401-6 (1991); Flint et al., The EMBO J. 12: 1937-46 (199
3)). There are at least two major classes of phosphatases: (1)
Protein (or peptide) containing a phosphate group on the serine or threonine moiety
Dephosphorylates (referred to as Ser / Thr phosphatase), and (2) removes the phosphate group derived from the amino acid tyrosine (referred to as protein tyrosine phosphatase (PTPase)).

[0004] PTPases are composed of a) intracellular or non-membrane PTPase and b) receptor type or transmembrane
A family of enzymes that can be classified into two groups: PTPases. Intracellular PTPase: The best known intracellular form of PTPase contains a single conserved catalytic phosphatase domain of 220-240 amino acid residues. Regions outside the PTPase domain are thought to play an important role in subcellular localization of intracellular PTPase (Maruo, LJ and Dixon, JE, TIBS 19: 151-155 (
1994)). The first intracellular PTPase to be purified and identified was PTP1B isolated from human placenta (Tonks et al., J. Biol. Chem. 263: 6722-6730 (1988)). Soon after, PTP1B was cloned (Charbonneau et al., Proc. Natl. Acad. Sci. U.
SA 86: 5252-5256 (1989); Chemoff et al., Proc. Natl. Acad. Sci. USA 87: 2735-278.
9 (1989)). Other examples of intracellular PTPases include (1) T-cell PTPase (Cool
Natl. Acad. Sci. USA 86: 5257-5261 (1989)), (2) Rat brain PTPase (Guan et al., Proc. Natl. Acad. Sci. USA 87: 1501-1502 (1990)) (3) Neuronal phosphatase STEP (Lombroso et al., Proc. Natl. Acad. Sci. USA 88: 7242-7246 (
1991)), (4) ezrin domain containing PTPase: PTPMEG1 (Guet et al., Proc. Natl. Ac
ad. Sci. USA 88: 5867-5871 (1991)), PTPH1 (Yang and Tonks, Proc. Natl. Aca
d. Sci. USA 88: 5949-5953 (1991)), PTPD1 and PTPD2 (Moller et al., Proc. Natl.
Acad. Sci. USA 91: 7477-7481 (1994)), FAP-1 / BAS (Sato et al., Science 268: 411-).
415 (1995); Banvile et al., J. Biol. Chem. 269: 22320-22327 (1994); Maekawa et al.,
FEBS Letters 337: 200-206 (1994)), and SH2 domains containing PTPase:
PTP1C / SH-PTP1 / SHP-1 (Plutzky et al., Proc. Natl. Acad. Sci. USA 89: 1123-1127 (
1992); Shen et al., Nature Lond. 352: 736-739 (1991)) and PTP1D / Syp / SH-P
TP2 / SHP-2 (Vogel et al., Science 259: 1611-1614 (1993); Feng et al., Science 259: 16
07-1611 (1993); Bastein et al., Biochem. Biophys. Res. Comm. 196: 124-133 (1993).
).

[0005] Low molecular weight phosphotyrosine protein phosphatase (LMW-PTPase) shows little sequence identity with the intracellular PTPase. However, this enzyme belongs to the PTPase family because of the following features: (i) it has a PTPase active site motif: Cys-Xxx-Xxx-Xxx-Xxx-Xxx-Arg (Cirri et al., Eur.
Biochem. 214: 647-657 (1993)), (ii) this Cys residue forms a phospho-intermediate during catalysis similar to the "classical" PTPase (Cirri et al., Supra; Chiarugi et al.).
FEBS Lett. 310: 9-12 (1992)), (iii) The total folding of the molecule shows surprising similarities to PTP1B and Yersinia PTP (Su et al., Nature 370: 575-578 (1
994)).

[0006] Receptor-type PTPase consists of a) a putative ligand binding extracellular domain, b) a transmembrane segment, and c) an intracellular catalytic domain. The structure and size of the putative ligand-binding extracellular domain of receptor-type PTPases vary considerably. In contrast, the intracellular catalytic domains of the receptor-type PTPase are highly homologous to each other and to the intracellular PTPase. Most receptor-type PTPases have two tandem repeat catalytic PTPase domains.

The first receptor-type PTPase to be identified was recognized as belonging to this class of enzymes based on homology to PTP1B (1) CD45 / LCA (Ralph, SJ, EMBO J. 6: 1251-1257 ( 1
987)) and (2) LAR (Streuli et al., J. Exp. Med. 168: 1523-1530 (1988)).
(Charbonneau et al., Proc. Natl. Acad. Sci. USA 86: 5252-5256 (1989)). CD45 is a group of high molecular weight glycoproteins, one of the most abundant leukocyte cell surface glycoproteins, and is thought to be exclusively expressed on hematopoietic c-lineage cells (Trowbridge
And Thornas, Ann. Rev. Immunol. 12: 85-116 (1994)).

[0008] Immediately after the identification of CD45 and LAR as belonging to the PTPase family,
Several different members of the receptor-type PTPase group have been identified and cloned.
There are five different PTPases: (3) PTPα, (4) PTPβ, (5) PTPδ, (6) PTPε,
And (7) PTPζ were identified in some earlier studies (Krueger et al., EMBO J. 9:32
41-3252 (1990)). Other examples of receptor-type PTPases include a carbon-based anhydrase-like domain in the extracellular region, such as PTPζ (Krueger and Saito, Proc. Natl. Acad. Sci. USA 89: 7417-7421 (1992)). (8) PTPγ (Bamea et al., Mol.
iol. 13: 1497-1506 (1995)), (9) PTPμ (Gebbink et al., FEBS Letters 290: 123-130 (1
991)) and (10) PTP κ (Jiang et al., Mol. Cell. Biol. 13: 2942-2951 (1993)). Receptor-type PTPase is subtype based on structural differences: (I) CD45; (II) LAR
, PTPd, (11) PTP σ; (III) PTPb, (12) 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. 269: 19953-19962 (1994)), and (1
4) DER-1; (IV) can be classified as PTPa, _PTPe (Fisher, Science 253: 401-406 (1991)
). All receptor-type PTPases except type IV contain two PTPase domains. Novel PTPases have been subsequently identified and more than 500 different species are expected to be found near the human genome, a protein tyrosine kinase superfamily of an estimated size (Hanks and Hunter, FASEB J. 9: 576-596 (1
995)).

[0009] PTPase is the biological counterpart of protein tyrosine kinase (PTK). Thus, one important function of PTPase is to regulate, ie, down regulate, PTK activity. However, a more complex picture of the function of PTPase has now emerged. Several studies have shown that some PTPases actually act as positive mediators of cell signaling. As an example, SH2-domain containing PTP1D is insulin-stimulated Ras activation (N
Oguchi et al., Mol. Cell. Biol. 14: 6674-6682 (1994)) and also growth factor-induced mitotic signal transduction (Xiao et al., J. Biol. Chem. 269: 21244-21248 (1994)). Although homologous PTP1C appears to act as a positive mediator of TGF, it appears to act as a negative regulator of growth factor-stimulated growth (Bignon and Simi
novitch, Clin. Immunol. Immunopathol. 73: 168-179 (1994)). Another example of PTPase as a positive regulator comes from studies designed to define the activation of Src family tyrosine kinases. In particular, several lines of evidence indicate that CD45 positively regulates hematopoietic cell activation, presumably by dephosphorylation of the C-terminal tyrosine of Fyn and Lck (Chan et al., Annu. Rev.
Immunol. 12: 555-592 (1994)).

[0010] Bispecific protein tyrosine phosphatases (dsPTPases) define phosphortyrosine as well as subtypes within the PTPase family that are capable of hydrolyzing phosphate from phosphorserine / threonine. dsPTPase contains the characteristic sequence of PTPase: His-Cys-Xxx-Xxx-Gly-Xxx-Xxx-Arg. At least 3
Two dsPTPases produce extracellular signal-regulated kinase (ERK) / mitogen-activated protein kinase (MAPK): MAPK phosphatase (CL100, 3CH134) (Charle
Natl. Acad. Sci. USA 90: 5292-5296 (1993)); PAC-1 (Ward et al., Natu
re 367: 651-654 (1994)); rVH6 (Mourey et al., J. Biol. Chem. 371: 3795-3802 (1996)).
) Has been shown to dephosphorylate and inactivate. dsPTPase transcription is induced by different stimuli, such as oxidative stress or heat shock (Ishibas
hi et al., J. Biol. Chem. 269: 29897-29902 (1994); Keyse and Emslie, Nature 3
59: 644-647 (1992)). They may also be involved in cell cycle regulation: cdc25 (Mi
llar and Russell, Cell 68: 407-410 (1992)); KAP (Hannon et al., Proc.
ad. Sci. USA 91: 1731-1735 (1994)). Interestingly, tyrosine dephosphorylation of cdc2 by the bispecific phosphatase cdc25 is required for induction of mitosis in yeast (reviewed by Waiton and Dixon, Annu. Rev. Biochem. 62: 101-120 (1
993)).

[0011] Initially, PTPases were identified and purified from cell and tissue lysates using a variety of synthetic substrates; therefore, their intrinsic function in dephosphorylation was not well known. Since tyrosine phosphorylation by tyrosine kinases is usually associated with cell proliferation, cell transformation and cell differentiation, it was hypothesized that PTPase was also involved in these events.

This association has now been found to apply to many PTPases.
The phosphatase PTP1B whose structure was recently elucidated (Barford et al., Science 263: 1397
-1404 (1994)) has been shown to be involved in insulin-induced oocyte maturation
(Flint et al., The EMBO J. 2: 1937-46 (1993)), and it has recently been suggested that overexpression of this enzyme is involved in p185 ^c- erb ^B2- related breast and ovarian cancers (Wiener et al.). , J.
Natl. Cancer Inst. 86: 372-8 (1994); Weiner et al., Am. J. Obstet. Gynecol. 17
0: 1177-883 (1994)). The mechanism of insulin-induced oocyte maturation is PTP1B
Correlates with the ability to inhibit S6 kinase activation. Association with cancer is recent evidence suggesting that PTP1B overexpression is statistically correlated with increased levels of p185 ^{c-erb B2} in ovarian and breast cancer. The role of PTP1B in the pathogenesis and progression of the disease has not yet been elucidated. Therefore, PTP1B inhibitors may be
It helps to define the role of P1B and in some cases provides treatment for some forms of cancer.

The activity of several other newly discussed phosphatases is currently under investigation.
Recently, two of these: SHP-1 and Syp / PTP1D / SHPTP2 / PTP2C / SHP-2 have been implicated in platelet-derived growth factor activation and epidermal growth factor-induced responses (Li
Et al., Mole. Cell. Biol. 14: 509-17 (1994)). Since both growth factors are involved in normal cellular processes and in pathologies such as cancer and arteriosclerosis, it is postulated that inhibitors of these phosphatases also show therapeutic efficacy. Accordingly, compounds of the present invention that exhibit inhibitory activity against various PTPases are required for the treatment or management of the above-mentioned diseases. PTPase: the insulin receptor signaling pathway / diabetic insulin is an important regulator of various metabolic processes and plays a key role in controlling blood sugar. Defects related to its synthesis or signaling result in diabetes mellitus. Binding of insulin to its receptor results in rapid (auto) phosphorylation of several tyrosine residues in the intracellular portion of the b subunit. To obtain sufficient activity of insulin receptor tyrosine kinase (IRTK), which transmits signals further downstream by tyrosine phosphorylation of other cell substrates, including insulin receptor substrate-1 (IRS-1), All three tyrosine residues (tyrosine-1150 domain) located at must be phosphorylated (Wilden et al., J. Bio.
l. Chem. 267: 16660-16668 (1992); Myers and White, Diabetes 42: 643-650 (1
993); Lee and Pilch, Am. J. Physiol. 266: C319-C334 (1994); White et al., J.
Biol. Chem. 263: 2969-2980 (1988)). Structural evidence for the function of tyrosine triplets has been obtained by recent IRTK X-ray crystallography studies, indicating that tyrosine-1150 is autophosphorylated in a non-phosphorylated state (Hubbard et al., Nature 372: 746- 754
(1994)).

In some studies, dephosphorylation in vitro with triphosphorylated tyrosine-1150, the most sensitive target for protein tyrosine phosphatase (PTPase) compared to the di- and mono-phosphorylated forms, (Review of Goldstein, Receptor 3: 1-15 (1993); Mooney and Anderson, J. Biol. Chem. 264: 6
850-6857 (1989)) It has been clearly shown that the activity of autophosphorylated IRTK can be reversed (King et al., Biochem. J. 275: 413-418 (1991)). It therefore speculates that this tyrosine triplet functions as a control switch for IRTK activity. Indeed, IRTK appears to be tightly regulated by PTP-mediated dephosphorylation in vivo (Khan et al., J. Biol. Chem. 264: 12931-12940 (1989); Fa
ure et al., J. Biol. Chem. 267: 11215-11221 (1992); Rothenberg et al., J. Biol. Che.
m. 266: 8302-8311 (1991)). The close link between PTPases and the insulin signaling pathway indicates that insulin is present in rat hepatoma cells (Meyerovitch et al., Biochemistry
31: 10338-10344 (1992)) and in liver from alloxan diabetic rats (Boylan
Et al., J. Clin. Invest. 90: 174-179 (1992)), further evidenced by the finding that they differentially regulate PTPase activity.

[0015] Little is known about the identity of PTPases that are relatively involved in IRTK regulation. However, the presence of a PTPase that has activity at the insulin receptor can be demonstrated as indicated above. In addition, the addition of the potent PTPase inhibitor pervanadate to whole cells resulted in almost complete insulin response in adipocytes (Fantus et al., Biochemistry 28: 8864-8871 (1989); Eriks
son et al., Diabetologia 39: 235-242 (1995)) and skeletal muscle (Leighton et al., Biochem.
J. 276: 289-292 (1991)). Furthermore, recent studies have shown that a new class of peroxovanadium compounds act as potent hypoglycemic compounds in vivo (Posner et al., Supra). Two of these compounds have been demonstrated to be more potent inhibitors of insulin receptor dephosphorylation than those of the EGF receptor.

Recently, it has been found that ubiquitously expressed SH2 domains, including the PTPase, PTP1D (Vogel et al., 1993, supra), are clearly associated with and dephosphorylate IRS-1, but not the IR itself. (Kuhne et al., J. Biol. Chem. 268: 11479-11481 (1993); (Kuhn
e et al., J. Biol. Chem. 269: 15833-15837 (1994)). Previous studies have shown that PTPase, which participates in IRTK regulation, is a membrane-associated molecule (Faure
J. Biol. Chem. 267: 11215-11221 (1992)) and glycosylated molecules (Haring
Et al., Biochemistry 23: 3298-3306 (1984); Sale, Adv. Prot. Phosphatases 6: 159
-186 (1991)). Propose that LAR plays a role in the physiological regulation of the insulin receptor in intact cells (Hashimoto et al., J. Biol. Chem. 267: 13811-13814 (1992)). Their conclusions were reached by comparing the rates of dephosphorylation / inactivation of purified IR using recombinant PTP1B and the cytoplasmic domains of LAR and PTPa. Recently, the effect of LAR on insulin signaling in a rat hepatoma cell line using antisense inhibition has been studied (Kulas et al., J. Biol. Chem. 270: 2435-2438 (1995)). Inhibiting LAR protein levels by about 60 percent was comparable to an about 150 percent increase in insulin-induced autophosphorylation. However, in IRTK activity
Although only a 35-percent increase was observed, insulin-dependent phosphatidylinositol 3-kinase (PI3-kinase) activity increased significantly to 350 percent. Decreased LAR levels did not alter basal levels of IRTK tyrosine phosphorylation or activity. The authors speculate that LAR can specifically dephosphorylate a tyrosine substrate that is critical for PI3-kinase activation on either the insulin receptor itself or a downstream substrate.

Previous reports have shown that src is activated (Zheng et al., Nature 359: 336-339 (1992); den He
rtog et al., EMBO J. 12: 3789-3798 (1993)) and interaction with GRB-2 (den Hertog
EMBO J. 13: 3020-3032 (1994); Su et al., J. Biol. Chem. 269: 18731-18734 (1994).
Although the role of PTPa in signal transduction by)) is demonstrated, recent studies suggest this phosphatase as a negative regulator of the insulin receptor signal and its function for closely related PTPe (Moller et al., 1995 supra). . This study also shows that receptor-like PTPases play an important role in regulating IRTK,
Intracellular PTPase has been shown to have little, if any, activity at the insulin receptor. The target of the negative regulatory activity of PTPases a and e appears to be the receptor itself, but the down-regulatory effect of intracellular TC-PTP appears to be due to downstream functions in the IR activation signal. PTP1B
Although closely related to TC-PTP and PTP1B, PTP1B had only a minor effect on the phosphorylation pattern of cells treated with insulin. Both PTPases have distinct structural features that determine their subcellular localization and thereby their access to a given cellular matrix (Frangione et al., Cell 68: 545-560 (1992); Faure and
Posner, Glia 9: 311-314 (1993)). Thus, the lack of activity of PTP1B and TC-PTP on IRTK may be explained, at least in part, by the fact that they do not co-localize with activated insulin receptors. In support of this view,
As a candidate for IR-related PTPase in liver cancer based on subcellular localization studies
Excludes PTP1B and TC-PTP (Faure et al., J. Biol. Chem. 267: 11215-11221
(1992)).

The transmembrane PTPase CD45, which is believed to be hematopoietic cell-specific, was recently found to negatively regulate the insulin receptor tyrosine kinase in the human multiple myeloma cell line U266 (Kulas Et al., J. Biol. Chem. 271: 755-760 (1996)). PTPase: Somatostatin Somatostatin inhibits several biological functions, including cell proliferation
(Larnberts et al., Molec. Endocrinol. 8: 1289-1297 (1994)). While some of the growth inhibitory activity of somatostatin is secondary to inhibition of its hormone and growth factor secretion (eg, growth hormone and epidermal growth factor), other growth inhibitory effects of somatostatin are by direct action on target cells. As an example, somatostatin analogs are likely to have only one PTPase, rather than an overall activation of PTPase levels in cells.
Or inhibit the growth of pancreatic cancer by stimulating a subset of PTPases (Liebow
Natl. Acad. Sci. USA 86: 2003-2007 (1989); Colas et al., Eur. J. Bioc.
hem. 207: 1017-1024 (1992)). A recent study found that somatostatin stimulation of SSTR1, but not somatostatin receptor SSTR2, which was stably expressed in CHO-K1 cells, was able to stimulate PTPase activity, which was susceptible to pertussis toxin. Was. Whether the inhibitory effect of somatostatin on secretion of hormones and growth factors is caused by similar stimulation of PTPase activity in hormone-producing cells has not yet been determined. PTPase: Immune system / autoimmunity In some studies, the receptor-type PTPase CD45 plays a critical role in initiating T cell activation as well as maintaining a T cell receptor-mediated signaling cascade Has been suggested. These studies are described 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 cell surface glycoproteins and is exclusively expressed on hepatoma cells. CD45 has been shown to be one of the important components of the signal transduction mechanism of lymphocytes in T cells. In particular, after the antigen binds to the T cell receptor, CD45
Evidence suggests that phosphatases play a central role in antigen-stimulated proliferation of T lymphocytes (Trowbridge, Annu. Rev. Immunol. 12: 85-116 (1
994)).

Several studies have suggested that PTPase activity of CD45 plays a role in the activation of Lck, a lymphocyte-specific member of the Src family of protein tyrosine kinases (Mustelin et al., Proc. Natl. Acad. Sci. USA 86:63
02-6306 (1989); Ostergaard et al., Proc. Natl. Acad. Sci. USA 86: 8959-8963 (19
89)). These authors hypothesized that the phosphatase activity of CD45, in turn, activated Lck by dephosphorylating C-terminal tyrosine residues involved in T cell activation. Recent studies have found that recombinant p56lck specifically associates with the recombinant CD45 cytoplasmic domain protein, but not with the associated cytoplasmic domain of PTPa (Ng et al.,
J. Biol. Chem. 271: 1295-1300 (1996)). The p56lck-CD45 interaction appears to be mediated by an unconventional SH2 domain interaction that does not require phosphotyrosine. In immature B cells, Fyn, another member of the Src family of protein tyrosine kinases, appears to be a selective substrate for CD45 when compared to Lck and Syk (Katagiri et al., J. Biol. Chem. 270: 27987-27990 (199
Five)) .

In studies using transgenic mice with a mutation in CD45-exon 6, mature
T cells were shown to be defective. These mice did not respond to challenge with a typical T cell-mediated response (Kishihara et al., Cell 74: 143-56 (1993)).
). Therefore, inhibitors of CD45 phosphatase would be very effective therapeutics in conditions associated with autoimmune diseases.

CD45 has also been shown to be essential for antibody-mediated degranulation of mast cells (Berger et al., J. Exp. Med. 180: 471-6 (1994)). These studies also show CD45
Was carried out using a mouse lacking. In this case, wild-type demonstrated IgE-mediated degranulation, but not mouse-derived CD45-deficient T cells. These data suggest that CD45 inhibitors also play a role in the indication or therapeutic treatment of allergic diseases.

Another recently discovered PTPase, the inducible lymphoid-specific protein tyrosine phosphatase (HePTP), is also involved in the immune response. This phosphatase is expressed on both remaining T and B lymphocytes other than non-hematopoietic cells. When these cells are stimulated, mRNA levels from the HePTP gene increase by 10- to 15-fold (Zanke
Et al., Eur. J. Immunol. 22: 235-239 (1992)). In both T and B lymphocytes
HePTP can function to modulate the immune response by dephosphorylating specific residues during sustained stimulation. However, its exact role is unknown.

[0023] Similarly, hematopoietic cell-specific PTP1C appears to act as a negative regulator and play an essential role in immune cell development. CD45, HePTP and PTP1
According to the above important function of C, selective PTPase inhibitors may be interesting drug candidates as both immunosuppressants and immunostimulants. In one recent study, a vanadium-based system was used to induce apparent B cell-selective apoptosis compared to T cells.
The potential of PTPase inhibitors as immunomodulators has been demonstrated by demonstrating the ability of the PTPase inhibitor BMLOV (Schieven et al., J. Bio.
em. 270: 20824-20831 (1995)). PTPase: cell-cell interaction / cancer- foci-adhering plaque, a phenomenon in vitro in which fibroblasts grow on a suitable substrate and form unique contact points are at least partially responsible for the cells and their natural environment. Seems to be very similar. Some focal adhesion proteins are phosphorylated on tyrosine residues when fibroblasts attach and spread to the extracellular matrix (Gumbine
r, Neuron 11,551-564 (1993)). However, abnormal tyrosine phosphorylation of these proteins can lead to cell transformation. The close association between PTPase and focal deposits is due to the ezrin-like N-terminal domain, such as PTPMEG1 (Gu et al., Pr.
oc. Natl. Acad. Sci. USA 88: 5867-5871 (1991)), PTPH1 (Yang and Tonks, Pro
Natl. Acad. Sci. USA 88: 5949-5953 (1991)) and PTPD1 (Moller et al., Proc.
Natl. Acad. Sci. USA 91: 7477-7481 (1994)) has been supported by the discovery of several intracellular PTPases. The ezrin-like domain shows similarity to several proteins that are thought to act as connections between the cell membrane and the cytoskeleton.
PTPD1 is phosphorylated by c-src in vitro and found to be associated with it, and has been postulated to be involved in the regulation of focal adhesion phosphorylation (Moller et al., Supra).

[0024] PTPases, including those involved in the phosphorylation of focal adhesion proteins, prevent the action of tyrosine kinases and can therefore function as natural inhibitors of transformation.
TC-PTP, and especially truncated forms of this enzyme (Cool et al., Proc. Natl. Acad. Sci. U.
SA 87: 7280-7284 (1990)) can inhibit the transforming activity of v-erb and v-fms (Lammers et al., J. Biol. Chem. 268: 22456-22462 (1993); Zander et al., Oncoge
ne 8: 1175-1182 (1993)). Furthermore, in NIH 3T3 fibroblasts expressing PTP1B, it was found that the transformation of the HER2 / neu gene by the cancer genotype was suppressed (Brown-Shimer et al., Cancer Res. 52: 478-482 ( 1992)).

The expression level of PTP1B was found to be increased in neu transformed mammalian cell lines (Zhay et al., Cancer Res. 53: 2272-2278 (1993)). The close relationship between tyrosine kinases and PTPases in cancer development is that PTPe is c-myc or int-
This is further evidenced by the recent finding that transgenic mice overexpressing c-neu and v-Ha-ras but not 2 are highly expressed in murine mammary carcinomas (Elson and
Leder, J. Biol. Chem. 270: 26116-26122 (1995)). In addition, the human gene encoding PTPg has been mapped to the chromosomal region 3p21, which is frequently deleted in kidney and lung carcinomas (LaForgia et al., Proc. Natl. Acad. Sci. USA 88: 5036-5040 (1991).
)).

In this regard, it appears important that PTPase appears to be involved in regulating fibroblast proliferation. Recent studies have shown that Swiss 3T3 cells harvested at high density show membrane-associated PTP that is eight times higher in average activity than cells harvested at low or medium density.
Acad. Sci. U. (Pallen and Tong, Proc. Natl. Acad. Sci. U.
SA 88: 6996-7000 (1991)). The authors hypothesized that density-dependent inhibition of cell proliferation was accompanied by control over the increase in activity of the PTPase in question. According to this view, a novel membrane-bound receptor-type PTPase, DEP-1, increases expression levels with increasing cell density in WI-38 human fetal lung fibroblasts and the AG1518 fibroblast cell line (> = (10 times)
Stman et al., Proc. Natl. Acad. Sci. USA 91: 9680-9684 (1994)).

[0027] Two closely related receptor-type PTPases, PTPκ and PTPμ, are attached.
When expressed in non-insect cells, it can mediate allophilic cell-cell interactions,
These PTPases have normal physiological functions in intercellular 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, PTP κ and PTP μ have similarities in their structural similarities.
Nevertheless, they do not interact with each other (Zondag et al., J. Biol. Chem. 270: 14247-14
250 (1995)). PTPases play an important role in regulating normal cell growth
It is clear that it is. However, as pointed out earlier, recent
Studies show that PTPase is also a positive mediator of intracellular signaling
Function, thereby inducing or enhancing a mitogen response
ing. Thus, increased cell activity of certain PTPases leads to cell transformation and tumorigenesis.
Tumor formation is caused. Indeed, in one study, overexpression of PTPα
It was found that transformation of rat fetal fibroblasts occurred (Zheng, supra). Sa
A new PTP, SAP-1, is extremely abundant in pancreatic and colorectal cancer cells.
It was found to manifest. SAP-1 maps to chromosome 19 region q13.4 and
q13.2 and may be related to carcinoembryonic antigen (Uchida et al., J. B.
iol. Chem. 269: 12220-12228 (1994)). In addition, dsPTPase cdc25 is Th
Dephosphorylates cdc2 at r14 / Tyr-15, thereby positively regulating mitosis
(Review by Hunter, Cell 80: 225-236 (1995)). Therefore specific
PTPase inhibitors may have important therapeutic value in treating certain forms of cancer. PTPase: Platelet condensation Recent studies indicate that PTPase is centrally involved in platelet condensation
I have. Agonist-induced platelet activation causes concomitant PTPase activity
Calpain-catalyzed cleavage of PTP1B occurs with twice as much stimulation (Fra
ngioni et al., EMBO J. 12: 4843-4856 (1993)). The cleavage of PTP1B is again
Reversible to irreversible platelet condensation in platelet-rich plasma resulting in localization
Associated with metastasis to. SH2 domain containing PTPase SHP-1
Translocates to the cytoskeleton in platelets after thrombin stimulation in a condensation-dependent manner
(Li et al., FEBS Lett. 343: 89-93 (1994)).

Recently, while questioning some details in the above two studies, there is a general understanding that PTP1B and SHP-1 play important functional roles in platelet condensation. (Ezumi et al., J. Biol. Chem. 270: 11927-11934 (1995)). These observations indicate that treatment of platelets with the PTPase inhibitor pervanadate results in a significant increase in tyrosine phosphorylation, secretion and condensation (Pumigli
a et al., Biochem. J. 286: 441-449 (1992)). PTPase: The rate of osteoporosis bone formation is determined by the number and activity of osteoblasts, which in turn are determined by the rate of proliferation and differentiation of the osteoblast parent cells, respectively. Histomorphological studies indicate that osteoblast number is a major determinant of bone formation rate in humans (Gruber et al., Mineral Electrolyte Metab. 12: 246-254 (1987); Lau et al., Biochem. J. 257: 23-36 (1989)). Acid phosphatase / PTPase may be involved in negative regulation of osteoblast proliferation. Thus, it has been found that fluoride having phosphatase inhibitory activity increases vertebral bone density in osteoporosis by increasing osteoblast proliferation (Lau et al., Supra). Consistent with this observation, osteoblastic acid phosphatase with PTPase activity was found to be sensitive to fluoride mitogen concentrations (Lau et al., J. Biol. Chem. 260: 4653-4660). (1985); La
u et al., J. Biol. Chem. 262: 1389-1397 (1987); Lau et al., Adv. Protein Phasphata.
ses 4: 165-198 (1987)).

Interestingly, recently, the level of membrane-bound PTPase activity has increased the osteoblast-like cell line UMR 106.06 compared to uncoated tissue culture plates.
It was found to increase dramatically when grown on type I matrices. A marked increase in PTPase activity was observed in fibroblasts in which density-dependent growth was suppressed (Pallen and Tong, Proc. Natl. Acad. Sci. 88: 6996-7000 (1991)).
It would be speculated that increased PTPase activity directly inhibits cell growth. Thus, the mitogen action of fluoride and other phosphatase inhibitors (molybdate and vanadate) is due to the inhibition of acid phosphatase / PTPase, which negatively regulates osteoblast cell growth. Can be explained by

The complex nature of the involvement of PTPase in bone formation is further suggested by the recent identification of a novel receptor-type PTPase, OST-PTP, regulated by bone and testis-expressed parathyroid glands. (Maruo et al., J. Biol. Chem. 269-30659-30667 (199
Four)) . OST-PTP is up-regulated after primary osteoblast differentiation and matrix formation, and then down-regulated in osteoblasts that are actively mineralizing in culture. It can be hypothesized that PTPase inhibitors inhibit differentiation by inhibiting OST-PTP or other PTPases, thereby resulting in continued growth. This is consistent with the effects of fluoride and the observation that the tyrosine phosphatase inhibitor orthovanadate appears to increase osteoblast proliferation and matrix formation (Lau et al., Endocrinology 116: 2463-2468). (1988)). further,
Recently, it was found that vanadate, vanadyl and pervanadate all increased the proliferation of the osteoblast-like cell line UMR 106. Vanadyl and pervanadate were more potent stimulators of cell proliferation than vanadate. Only vanadate could regulate cell differentiation as measured by cellular alkaline phosphatase activity (Cortizo et al., Mol. Cell. Biochem. 145: 97-102 (1995)).
. PTPase: Microorganism Dixon and co-workers have called attention to the fact that PTPase is a key element in the virulence of Yersinia (reviewed by Clemens et al., Mole
cular Microbiology 5: 2617-2620 (1991)). This finding is rather surprising since tyrosine phosphate is not believed to be present in bacteria. There are three Yersinia species: Y. pestis (cause of glandular plague), and Y. pseudotu.
rberculosis) and Y. enterocolitica (causing enteritis and mesenteric lymphadenitis). Interestingly, a bispecific phosphatase, VH1, has been identified in vaccinia virus (Guan et al., Nature
350: 359-263 (1991)). These observations indicate that PTPases play an important role in microbial and parasitic infections, and they further optimize PTPase inhibitors as a novel putative therapeutic principle of infection.

SUMMARY OF THE INVENTION The present invention relates to compounds of general formula I, wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₆ and R ₁₇ are as defined in the detailed part of this specification. Where such compounds are PTP1B, CD
45, It is a pharmacologically useful inhibitor of protein tyrosine phosphatase (PTPase) such as SHP-1, SHP-2, PTPα, LAR and HePTP. The compound is a type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunction including autoimmunity and AIDS, diseases with coagulation dysfunction, allergic diseases including asthma, osteoporosis Proliferative disorders, including cancer and psoriasis, diseases with reduced or increased growth hormone synthesis or action, diseases with reduced or increased synthesis of hormones or cytokines that regulate the release or response to growth hormone, Alzheimer's It is useful for the treatment, prevention, elimination, alleviation or amelioration of brain diseases including illness and schizophrenia, as well as signs involved in infectious diseases.

In another embodiment, the present invention comprises within its scope at least one compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent as an active ingredient. And a pharmaceutical composition comprising: In another embodiment of the present invention, type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunction including autoimmunity and AIDS, diseases with coagulation dysfunction, allergy including asthma Sexual diseases, osteoporosis, growth disorders including cancer and psoriasis, diseases with reduced or increased growth hormone synthesis or action,
Methods for treating diseases involving decreased or increased synthesis of hormones or cytokines that regulate growth hormone release or response to growth hormone, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases are provided.

[0033] The method of treatment may be described as treating, preventing, eliminating, alleviating or ameliorating one of the above symptoms, which comprises administering a neurologically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof. Administering to the patient. Further aspects of the invention are type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunction including autoimmunity and AIDS, diseases with dysfunction of the coagulation system, allergic diseases including asthma, Osteoporosis, proliferative disorders including cancer and psoriasis, diseases with reduced or increased growth hormone synthesis or action, reduced or increased synthesis of hormones or cytokines that regulate growth hormone release or response to growth hormone It relates to the use of a compound of the invention for the manufacture of a pharmaceutical composition for the treatment of diseases of the brain, including Alzheimer's disease and schizophrenia, as well as of any kind of infectious diseases.

Description of the Invention The present invention relates to optical isomers or optical isomer mixtures or tautomers , including compounds of Formula 1 or a salt thereof with a pharmaceutically acceptable acid or base, or a racemic mixture.

[0035]

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Wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₆ and R ₁₇ are defined below. In the above formula 1, A is, together with the double bond of the formula 1, furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, furazanyl or 1,2,3-triazolyl R ₁ is hydrogen, COR ₅ , OR ₆ , CF ₃ , nitro, cyano, SO ₃ H, SO ₂ NR ₇ R ₈ , PO (OH) ₂ , C
Is selected from _{H 2 PO (OH) 2,} CHFPO (OH) 2, CF 2 PO (OH) 2, C (= NH) NH 2, NR 7 or a R _8, or 5-membered heterocyclic ring follows;

[0037]

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Or R ₁ is

[0039]

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Wherein R ₁₂ , R ₁₃ and R ₁₄ are independently hydrogen, C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl, and these alkyl and aryl groups are R ₂ is COR ₅ , OR ₆ , CF ₃ , nitro, cyano, SO ₃ H, SO ₂ NR ₇ R ₈ , PO (OH) ₂ , CH ₂ PO (O
_{H) 2, CHFPO (OH)} 2, CF 2 PO (OH) 2, C (= NH) NH 2, or a NR ₇ R _8, or is selected from the following 5-membered heterocyclic ring;

[0041]

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R_Three, R₁₆And R₁₇Is independently hydrogen, halo, nitro, cyano, trihalomethyl
, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, hydroxy, oxo,
Carboxy, Carboxy C₁-C₆Alkyl, C₁-C₆Alkyloxycarbonyl, a
Reeloxycarbonyl, aryl C₁-C₆Alkyloxycarbonyl, C₁-C₆A
Lucyloxy, C₁-C₆Alkyloxy C₁-C₆Alkyl, aryloxy, aryl
Le C₁-C₆Alkyloxy, aryl C₁-C₆Alkyloxy C₁-C₆Alkyl, thio
, C₁-C₆Alkylthio, C₁-C₆Alkylthio C₁-C₆Alkyl, arylthio, a
Reel C₁-C₆Alkylthio, aryl C₁-C₆Alkylthio C₁-C₆Alkyl, NR₇R ₈ , C₁-C₆Alkylamino C₁-C₆Alkyl, aryl C₁-C₆Alkylamino C₁-C ₆ Alkyl, di (aryl C₁-C₆Alkyl) amino C₁-C₆Alkyl, C₁-C₆Al
Kill carbonyl, C₁-C₆Alkylcarbonyl-C₁-C₆Alkyl, aryl C₁-C₆A
Alkylcarbonyl, aryl C₁-C₆Alkylcarbonyl C₁-C₆Alkyl, C₁-C₆ Alkyl carboxy, C₁-C₆Alkyl carboxy C₁-C₆Alkyl, arylcal
Boxy, aryl carboxy C₁-C₆Alkyl, aryl C₁-C₆Alkyl carboki
Si, aryl C₁-C₆Alkyl carboxy C₁-C₆Alkyl, C₁-C₆Alkyl carb
Nilamino, C₁-C₆Alkylcarbonylamino C₁-C₆Alkyl, -carbonyl N
R₇ C₁-C₆Alkyl COR₁₁, Aryl C₁-C₆Alkylcarbonylamino, aryl
C₁-C₆Alkylcarbonylamino C₁-C₆Alkyl, CONR₇R₈Or C₁-C₆Archi
Le CONR₇R₈｛(Where the alkyl and aryl groups are optionally substituted
Well, R₁₁Is NR₇R₈Or C₁-C₆Alkyl NR₇R₈Or R_{1 6} And R₁₇When is hydrogen_ThreeIs A-B-C-D-C₁-C₆Alkyl (where A is C₁-C₆Alkyl, aryl or aryl C₁-C₆B is amino, thio, SO, SO_TwoOr oxo; C is C₁-C₆D is a chemical bond, amino or C₁-C₆Alkyl (where alkyl and ant
The aryl group may be optionally substituted), or

[0043]

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(Where R₁₂, R₁₃And R₁₄Is independently hydrogen, C₁-C₆Alkyl, aryl, a
Reel C₁-C₆Alkyl and the alkyl and aryl groups are optional
); R;_FourIs hydrogen, hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl
, NR₇R₈, C₁-C₆Alkyloxy (where the alkyl and aryl groups are optionally
R may be more substituted); R_FiveIs hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, C₁-C ₆ Alkyloxy, C₁-C₆Alkyl-oxy C₁-C₆Alkyloxy, arylo
Xy, aryl C₁-C₆Alkyloxy, CF_Three, NR₇R₈(Where alkyl and
An aryl group is optionally substituted); R₆Is hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl (where
Alkyl and aryl groups may be optionally substituted);₇And R₈Is independently hydrogen, C₁-C₆Alkyl, adamantyl, aryl, ant
Rule C₁-C₆Alkyl, C₁-C₆Alkylcarbonyl, arylcarbonyl, aryl
Le C₁-C₆Alkylcarbonyl, C₁-C₆Alkyl carboxy or aryl C₁-C₆ Alkylcarboxy, wherein the alkyl and aryl groups are optionally substituted
R); R₇And R₈Together with the nitrogen to which they are attached, 3 to 14 carbon atoms, and
And saturated with 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur
Forms a partially saturated or aromatic, monocyclic, bicyclic or tricyclic structure, or
The structure may optionally include at least one C₁-C₆Alkyl, aryl, aryl C₁-C₆ Alkyl, hydroxy, oxo, C₁-C₆Alkyloxy, aryl C₁-C₆Archi
Luoxy, C₁-C₆Alkyloxy C₁-C₆Alkyl, NR₉R_TenOr C₁-C₆Alkyria
Mino C₁-C₆Optionally substituted with alkyl (where R₉And R_TenIndependently
Hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, C₁-C₆Alkylka
Rubonyl, arylcarbonyl, arylC₁-C₆Alkylcarbonyl, C₁-C₆A
Alkyl carboxy or aryl C₁-C₆Selected from alkyl carboxy) (
Wherein the alkyl and aryl groups may be optionally substituted)
Or R₇And R₈Is independently a saturated or partially saturated cyclic 5-, 6- or 7-membered amine
, Imide or lactam.

Definitions Signal transduction is a collective term used to define all cellular processes that occur as a result of the activation of a given cell or tissue. Without limiting the scope of the claims of the invention, examples of signal transduction include polypeptide hormones and growth factors (eg, insulin, insulin-like growth factors I and II, growth hormone, epidermal growth factor, platelet Derived growth factors), cytokines (eg, interleukins), extracellular matrix components, and intracellular events induced by cell-cell interactions.

A phosphotyrosine recognition unit / tyrosine phosphate recognition unit / pTyr recognition unit is defined as a region or domain of a protein or glycoprotein that has an affinity for a molecule containing a phosphorylated tyrosine residue (pTyr). Examples of pTyr recognition units include, but are not limited to, the claims of the present invention, including PTPases, SH2 domains, and PTB domains.

PTPase is defined as an enzyme that has the ability to dephosphorylate proteins or glycoproteins containing pTyr. Examples of PTPases, which do not limit the scope of the invention in any way, include "classical" PTPases (such as intracellular PTPases (e.g., PTPD2) and receptor-type PTPases (eg, PTPα, PTPε, PTPβ, PTPγ, CD45, PTPκ, PTP
μ), bispecific phosphatases (VH1, VHR, cdc25), LMW-PTPase or acid phosphatase.

The SH2 domain (Src homology 2 domain) is a non-catalytic protein module that binds proteins containing ptyr (phosphotyrosine residues), ie, the SH2 domain is a pTyr recognition unit. The SH2 domain consists of about 100 amino acid residues and is found on several different molecules involved in the signal transduction process.
The following is a non-limiting list of proteins containing SH2 domains: Src, Hck, Lck, Syk, Zap70, SHP-1, SHP-2, STAT, Grb-2, Shc
, P85 / P13K, Gap, vav (Russell et al., FEBS Lett. 304: 15-20 (1992); Pawson,
Nature 373: 573-580 (1995); Sawyer, Biopolymers (Peptide Science) 47: 243-2
61 (1998); and references herein).

As used herein, “bond” or “−” (eg, —COR ₁₁ , which indicates a carbonyl point of attachment to the backbone) refers to a stable covalent bond, of points of attachment apparent to one skilled in the art. Indicates certain preferred points. “Halogen” or “halo” includes fluorine, chlorine, bromine, and iodine.

“Alkyl” includes C ₁ -C ₆ or C ₁ -C ₈ linear saturated and C ₂ -C ₈ unsaturated aliphatic hydrocarbon groups, C ₁ -C ₆ or C ₁ -C ₈ branched. Jo saturated and C ₂ -C ₆ or C ₂ -C ₈ unsaturated aliphatic hydrocarbon group, C ₃ -C ₆ or C ₃ -C ₈ cyclic saturated and C ₁ -C ₆ or C ₅ -C ₈ unsaturated aliphatic hydrocarbon group, and C ₃ -C ₆ cyclic saturated C ₁ -C ₆ or substituted with and unsaturated aliphatic hydrocarbon groups C ₁ -C ₈ linear having the specified number of carbon atoms or branched saturated and C ₂ -C ₆ or C ₂ -C ₈ linear or branched unsaturated aliphatic hydrocarbon groups include. For example, this definition includes, but is not limited to, methyl (Me), ethyl (Et)
, Propyl (Pr), butyl (Bu), pentyl, hexyl, heptyl, octyl, ethenyl, propenyl, butenyl, penentyl, hexenyl, octenyl, isopropyl (i-Pr), isobutyl (i-Bu), t-butyl (t -Bu), s-butyl (s-Bu), isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentenyl, cyclohexenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl and the like.

“Substituted alkyl” refers to the same alkyl groups as previously defined, wherein the substituents are independently
Halo, cyano, nitro, trihalomethyl, carbamoyl, hydroxy, oki
Seo, COR_Five, C₁-C₆Alkyl, C₁-C₆Alkyloxy, aryloxy, aryl
C₁-C₆Alkyloxy, thio, C₁-C₆Alkylthio, arylthio, aryl C₁ -C₆Alkylthio, NR₇R₈, C₁-C₆Alkylamino, arylamino, aryl
C₁-C₆Alkylamino, di (aryl C₁-C₆Alkyl) amino, C₁-C₆Alkyl
Carbonyl, aryl C₁-C₆Alkylcarbonyl, C₁-C₆Alkyl-carboxy
, Aryl C₁-C₆Alkyl carboxy, C₁-C₆Alkylcarbonylamino, C₁-C ₆ Alkyl-amino COR₁₁, Aryl C₁-C₆Alkylcarbonylamino, tetra
Hydrofuranyl, morpholinyl, piperazinyl, -CONR₇R₈, -C₁-C₆Alkyl CONR ₇ R₈Or saturated or partially saturated cyclic 5, 6 or 7 membered amines, imides
Or lactam (where R₁₁Is hydroxy, C₁-C₆Alkyl, aryl, ant
Rule C₁-C₆Alkyl, C₁-C₆Alkyloxy, aryloxy, aryl C₁-C₆ Alkyloxy and R_FiveIs the same as defined above, or NR₇R₈Is (this
Where R₇And R₈Is the same as defined above))Is selected from

“Saturated, partially saturated or aromatic, monocyclic, bicyclic or tricyclic structure” includes, but is not limited to, aziridinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl , 2-pyrazolinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, morpholinyl, piperidinyl,
Thiomorpholinyl, piperazinyl, indolyl, isoindolyl, 1,2,3,4, -tetrahydro-quinolinyl, 1,2,3,4, -tetrahydro-isoquinolinyl, 1,2,3,4,
-Represents tetrahydroquinoxalinyl, indolinyl, indazolyl, benzimidazolyl, benzotriazolyl, purinyl, carbazolyl, acridinyl, phenothiazinyl, phenoxazinyl, iminodibenzyl, iminostilbenyl.
"Alkyloxy" (eg, methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an "alkyl" group as defined above with the indicated number of carbon atoms attached through an oxygen bridge. “Alkyloxyalkyl” represents an “alkyloxy” group attached through an alkyl group as defined above with the indicated number of carbon atoms. "Alkyloxyalkyloxy" represents an "alkyloxyalkyl" attached through an oxygen atom as defined above with the indicated number of carbon atoms. “Aryloxy” (eg, phenoxy, naphthyloxy, etc.) represents an aryl group as defined below attached through an oxygen bridge. "Arylalkyloxy" (eg, phenethyloxy, naphthylmethyloxy, etc.) represents an "arylalkyl" group, as defined below, attached through an oxygen bridge. “Arylalkyloxyalkyl” is an “arylalkyloxy” as defined above attached through an “alkyl” group as defined above having the indicated number of carbon atoms.
Represents a group. “Arylthio” (eg, phenylthio, naphthylthio, etc.) represents an “aryl” group as defined below attached through a sulfur bridge. “Alkylcarbonyl” (eg, methylformiat, ethylformate, etc.) represents an “alkyloxy” group as defined above attached through a carbonyl group.

“Aryloxycarbonyl” (eg, phenyl formate, 2-thiazolyl formate, and the like) represents an “aryloxy” group as defined above attached through a carbonyl group. “Arylalkyloxycarbonyl” (eg, benzyl formate, phenylethyl formate, and the like) represents an “arylalkyloxy” group as defined above attached through a carbonyl group. "Alkyloxycarbonylalkyl" represents an "aryloxycarbonyl" group as defined above linked via an "aryl" group as defined above having the indicated number of carbon atoms. "Arylalkyloxycarbonylalkyl" represents an "arylalkyloxycarbonyl" as defined above linked through an "alkyl" group as defined above having the indicated number of carbon atoms. “Alkylthio” (eg, methylthio, ethylthio, propylthio, cyclohexenylthio, etc.) represents an “alkyl” group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. “Arylalkylthio” (eg, phenylmethylthio, phenylethylthio, etc.) represents an “arylalkyl” group as defined above with the indicated number of carbon atoms attached through a sulfur bridge. “Alkylthioalkyl” represents an “alkylthio” group attached through an alkyl group as defined above with the indicated number of carbon atoms. "Arylalkylthioalkyl" represents an "arylalkylthio" group attached through the above defined alkyl group having the indicated number of carbon atoms. “Alkylamino” (eg, methylamino, diethylamino, butylamino,
N-propyl-N-hexylamino, (2-cyclopentyl) propylamino, hexenylamino, pyrrolidinyl, piperidinyl, etc.) are one or two as defined above having the indicated number of carbon atoms attached through an amine bridge. Represents an "alkyl" group. The two alkyl groups may be saturated, partially saturated or partially saturated, containing 3-4 carbon atoms with the nitrogen to which they are attached, and 0-3 additional heteroatoms selected from nitrogen, oxygen or sulfur. It may form an aromatic, mono-, bi- or tricyclic structure, wherein said ring structure is optionally at least one C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl, hydroxy, oxo, C ₁ -C ₆ alkyloxy, aryl
C ₁ -C ₆ alkyloxy, C ₁ -C ₆ alkyloxy C ₁ -C ₆ alkyl, NR ₉ R ₁₀ or C ₁ -C ₆ alkylamino C ₁ -C ₆ alkyl (where R ₉ and R ₁₀ are Independently hydrogen, C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl, C ₁ -C ₆ alkylcarbonyl, arylcarbonyl, aryl C ₁ -C ₆ alkylcarbonyl, C ₁ -C ₆ alkyl carboxy or Aryl C ₁ -C ₆ alkyl carboxy (where the alkyl and aryl groups are optionally substituted);
Alternatively, the two alkyl groups may form a saturated or partially saturated cyclic 5, 6 or 7 membered amine, imide or lactam.

“Arylalkylamino” (eg, benzylamino, diphenylethyla
Mino) have the indicated number of carbon atoms attached through an amine bridge.
Represents one or two "arylalkyl" as defined. These two "aryl al
A `` kill '' group contains three to four carbon atoms, with the nitrogen to which they are attached, and nitrogen
, Saturated, containing from 0 to 3 additional heteroatoms selected from oxygen or sulfur
May form a monocyclic, bicyclic or tricyclic structure, or a monocyclic, bicyclic or tricyclic structure.
Is optionally at least one C₁-C₆Alkyl, aryl, aryl C₁-C₆Al
Kill, hydroxy, oxo, C₁-C₆Alkyloxy, C₁-C₆Alkyloxy C₁-C ₆ Alkyl, NR₉R_Ten, C₁-C₆Alkylamino C₁-C₆An alkyl substituent (where
Alkyl and aryl are optionally substituted as defined in the definition section;
Well, R₉And R_TenIs the same as defined above). “Alkylaminoalkyl” refers to an atom as defined above having the indicated number of carbon atoms.
Represents an "alkylamino" group attached through a alkyl group. “Arylalkylaminoalkyl” is an arylalkylaminoalkyl as defined above having the indicated number of carbon atoms.
Represents an "arylalkylamino" group linked through an alkyl group as defined. “Arylalkyl” (eg, benzyl, phenylethyl) is a compound of the indicated number
Attached through a carbon atom or an alkyl having a substituted alkyl group as defined above
Represents an "aryl" group as defined below. “Alkylcarbonyl” (eg, cyclooctylcarbonyl, pentylcarbo)
Nyl, 3-hexenylcarbonyl) is shown attached through a carbonyl group
Represents an "alkyl" group as defined above having a number of carbon atoms. “Arylcarbonyl” (benzoyl) is a compound as defined above linked via a carbonyl group.
Represents an "aryl" group, as defined. “Arylalkylcarbonyl” (eg, phenylcyclopropylcarbonyl
, Phenylethylcarbonyl, etc.) are linked via a carbonyl group
Represents an "arylalkyl" group as defined above having an integer number of carbon atoms. "Alkylcarbonylalkyl" is as defined above having the indicated number of carbon atoms.
Represents an “alkylcarbonyl” group linked through an “alkyl” group of “Arylalkylcarbonylalkyl” has the indicated number of carbon atoms
An “arylalkylcarbonyl” group linked through an “alkyl” group as defined above
Represents

“Alkylcarbonyl” (eg, heptylcarboxy, cyclopropylcarboxy, 3-pentenylcarboxy) represents an “alkylcarbonyl” group, as defined above, wherein the carbonyls are in turn connected via an oxygen bridge. "Arylcarboxyalkyl" (eg, phenylcarboxymethyl) refers to an "arylcarbonyl" group as defined above in which the carbonyl is in turn connected via an oxygen bridge to an alkyl chain having the indicated number of carbon atoms. "Arylalkylcarboxy" (eg, benzylcarboxy, phenylcyclopropylcarboxy, etc.) represents an "arylalkylcarbonyl" group, as defined above, wherein the carbonyls are in turn connected via an oxygen bridge. "Alkylcarboxyalkyl" refers to an "alkylcarboxy" group attached through an "alkyl" group as defined above having the indicated number of carbon atoms. "Arylalkylcarboxyalkyl" represents an "arylalkylcarboxy" group attached through the above defined "alkyl" group having the indicated number of carbon atoms.

“Alkylcarbonylamino” (eg, hexylcarbonylamino, cyclopentylcarbonylaminomethyl, methylcarbonylaminophenyl) is an “alkylcarbonyl” as defined above in which the carbonyl is bonded in sequence through the nitrogen atom of the amino group. Represent. The nitrogen atom may itself be substituted by an alkyl or aryl group. "Arylalkylcarbonylamino" (eg, benzylcarbonylamino, etc.) represents an "arylalkylcarbonyl" group as defined above wherein the carbonyls are in turn attached through the nitrogen atom of the amine group. This nitrogen atom may itself be substituted by an alkyl or aryl group. "Alkylcarbonylaminoalkyl" represents an "alkylcarbonylamino" group attached through the above defined "alkyl" group having the indicated number of carbon atoms. This nitrogen atom may itself be substituted by an alkyl or aryl group. "Arylalkylcarbonylaminoalkyl" represents an "arylalkylcarbonylamino" group attached through the above defined "alkyl" group having the indicated number of carbon atoms. This nitrogen atom may itself be substituted by an alkyl or aryl group.

“Alkylcarbonylaminoalkylcarbonyl” is via a carbonyl group
Represents a bonded alkylcarbonylaminoalkyl group. This nitrogen atom is
Or an "aryl" group. “Aryl” may be at any of the ring positions that can form a stable covalent bond (at a particular
Preferred points of attachment will be apparent to those skilled in the art (eg, 3-indoleyl, 4-imida
Zolyl)) bridged unsaturated, mono-, di- or trisubstituted monocyclic, polycyclic, diaryl
And a heterocyclic aromatic group. The aryl substituents are independently halo, nitro,
Cyano, trihalomethyl, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl
, Hydroxy, COR_Five, C₁-C₆Alkyloxy, C₁-C₆Alkyloxy C₁-C₆Al
Kill, aryloxy, aryl C₁-C₆Alkyloxy, aryl C₁-C₆Archi
Luoxy C₁-C₆Alkyl, thio, C₁-C₆Alkylthio, C₁-C₆Alkylthio C₁-C ₆ Alkyl, arylthio, aryl C₁-C₆Alkylthio, aryl C₁-C₆Al
Kircio C₁-C₆Alkyl, NR₈R₉, C₁-C₆Alkylamino, C₁-C₆Alkylam
No C₁-C₆Alkyl, arylamino, aryl C₁-C₆Alkylamino, aryl
C₁-C₆Alkylamino C₁-C₆Alkyl, di (aryl C₁-C₆Alkyl) amino C₁ -C₆Alkyl, C₁-C₆Alkylcarbonyl, C₁-C₆Alkylcarbonyl C₁-C₆A
Lucil, aryl C₁-C₆Alkylcarbonyl, aryl C₁-C₆Alkyl carboni
Le C₁-C₆Alkyl, C₁-C₆Alkyl carboxy, C₁-C₆Alkyl carboxy C₁-C ₆ Alkyl, aryl C₁-C₆Alkyl carboxy, aryl C₁-C₆Alkyl cal
Boxy C₁-C₆Alkyl, carboxy C₁-C₆Alkyloxy, C₁-C₆Alkyl cal
Bonylamino, C₁-C₆Alkylcarbonyl-amino C₁-C₆Alkyl, -carboni
Le NR₇ C₁-C₆Alkyl COR₁₁, Aryl C₁-C₆Alkylcarbonylamino, ant
Rule C₁-C₆Alkylcarbonylamino C₁-C₆Alkyl, -CONR₈R₉Or -C₁-C₆A
Lucil-CONR₈R₉(Where R₇, R₈, R₉And R₁₁Is defined as above,
The kill and aryl groups are optionally substituted as defined in the definition section.
May be selected from the group consisting of:

The definition of aryl includes, but is not limited to, phenyl, biphenyl, indenyl, fluorenyl, naphthyl (1-naphthyl, 2-naphthyl), pyrrolyl (2-
Pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-
Imidazolyl, 4-imidazolyl, 5-imidazolyl), triazolyl (1,2,3-triazol-1-yl, 1,2,3-triazol-2-yl, 1,2,3-triazol-4-yl, 1 , 2,
4-triazol-3-yl), oxazolyl (2-oxazolyl, 4-oxazolyl, 5-
Oxazolyl), isoxazolyl (3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl), thiazolyl (2-thiazolyl, 4-thiazolyl, 5-thiazolyl),
Thiophenyl (2-thiophenyl, 3-thiophenyl, 4-thiophenyl, 5-thiophenyl), 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-pyrimidinyl, 6-pyrimidinyl), pyrazinyl, pyridazinyl (3-pyridazinyl, 4-pyridazinyl, 5-pyridazinyl), quinolyl (2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-
Quinolyl, 7-quinolyl, 8-quinolyl), isoquinolyl (1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl, 8-isoquinolyl), benzo [b] furanyl (2- Benzo [b] furanyl, 3-benzo [b
] Furanyl, 4-benzo [b] furanyl, 5-benzo [b] furanyl, 6-benzo [b] furanyl, 7-benzo [b] furanyl), 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] furanyl), 7- (2 , 3-dihydro-benzo [b
] Furanyl)), benzo [b] thiophenyl (2-benzo [b] thiophenyl, 3-benzo
[b] thiophenyl, 4-benzo [b] thiophenyl, 5-benzo [b] thiophenyl, 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] thiophenyl
), 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-tetrahydro-thieno [2,3-c] pyridyl), 7- (4,5,6,7-tetrahydro-thieno [2,3-c] pyridyl)), indolyl (1-indolyl, 2-indolyl) , 3-Indolyl, 4-Indolyl, 5-Indolyl, 6-Indolyl, 7-Indolyl) Isoindolyl), 1,3-dihydro-isoindolyl (1- (1,3-dihydro-isoindolyl), 2- (1,3-dihydro
-Isoindolyl), 3- (1,3-dihydro-isoindolyl), 4- (1,3-dihydro
-Isoindolyl), 5- (1,3-dihydro-isoindolyl), 6- (1,3-dihydro
-Isoindolyl), 7- (1,3 di-hydro-isoindolyl)), indazole (1-
Indazolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, 7-indazolyl), benzimidazolyl (1-benzimidazolyl, 2-benzimidazolyl, 4-benzimidazolyl, 5-benzimidazolyl, 6-benzimidazolyl, 7-benzimidazolyl, 8 -Benzoimidazolyl), benzoxazolyl (1-benzoxazolyl, 2-benzoxazolyl), benzothiazolyl (1-benzothiazolyl, 2-benzothiazolyl, 4-benzothiazolyl, 5-benzothiazolyl, 6-benzothiazolyl, 7-benzothiazolyl) , Carbazolyl (1-carbazolyl, 2-carbazolyl, 3-carbazolyl, 4-carbazolyl), 5H-dibenz [b, f]
Azepine (5H-dibenz [b, f] azepin-1-yl, 5H-dibenz [b, f] azepin-2
-Il, 5H-dibenz [b, f] azepine-3-yl, 5H-dibenz [b, f] azepine-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,
10,11-dihydro-5H-dibenz [b, f] azepin-5-yl), piperidinyl (2-piperidinyl, 3-piperidinyl, 4-piperidinyl), pyrrolidinyl (1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl) , Phenylpyridyl (2-phenyl-pyridyl, 3-phenyl-pyridyl, 4-phenylpyridyl), phenylpyrimidinyl (2-
Phenylpyrimidinyl, 4-phenylpyrimidinyl, 5-phenylpyrimidinyl, 6-
Phenylpyrimidinyl), phenylpyrazinyl, phenylpyridazinyl (3-phenylpyridazinyl, 4-phenylpyridazinyl, 5-phenylpyridazinyl).

“Arylcarbonyl” (eg, 2-thiophenylcarbonyl, 3-methoxy-
Anthrylcarbonyl, oxazolylcarbonyl) represents an "aryl" group as defined above attached through a carbonyl group. “Arylalkylcarbonyl” (eg, (2,3-dimethoxyphenyl) -propylcarbonyl, (2-chloronaphthyl) pentenylcarbonyl, imidazolylcyclo-pentylcarbonyl) is an “alkyl” group in which the “alkyl” groups are sequentially bonded through a carbonyl group. "Arylalkyl" group as defined above.

The compounds of the present invention have asymmetric centers and can occur as racemates, racemic mixtures, or as individual enantiomers or diastereomers, and the invention includes all isomeric forms and their A mixture is included. Pharmaceutically acceptable salts of the compounds of Formula 1 wherein a basic or acidic group is present in the structure are also included within the scope of this invention. If acidic substituents such as -COOH, 5-tetrazolyl or -P (O) (OH) ₂ are present, they should form ammonium, morpholinium, sodium, potassium, barium, calcium salts, etc. for use as dosage forms Can be. When a basic group is present, when a basic group such as a basic heteroaryl radical such as amino or pyridyl is present, hydrochloride, hydrobromide,
Phosphate, sulfate, trifluoroacetate, trichloroacetate, acetate, oxalate,
Maleate, pivalate, malonate, tartrate, citrate, tartrate, fumarate, mandelate, benzoate, cinnamate, methanesulfonate, ethanesulfonate, picric acid Acid salts such as salts and the like, and acids associated with the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2 (1977), which is incorporated herein by reference. it can.

When —COOH or —P (O) (OH) ₂ is present, as a pharmaceutically acceptable ester, eg, methyl, t-butyl, pivaloyloxymethyl, and as a sustained release or prodrug formulation Esters known in the art to improve the solubility or hydrolysis properties used can be used. In addition, some of the compounds of the present invention may form solvates with water or common organic solvents. Such solvates are included within the scope of the present invention. By "therapeutically effective amount" is meant an amount of an agent or medicament that elicits a biological or medical response in a tissue, system, animal or human sought by a researcher, veterinarian, physician, or the like.

Preferred Embodiments of the Invention The compounds of formula 1a are preferred compounds of the invention:

[0063]

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Wherein A is furanyl, thiophenyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, with the double bond of formula 1a
1,2,3-oxadiazolyl, be furazanyl or 1,2,3-triazolyl; R ₁ is _{COR 5, OR 6, CF 3} , nitro, _{cyano, SO 3 H, SO 2 NR} 7 R 8, PO (OH ) ₂ , CH ₂ PO
(OH) ₂ , CHFPO (OH) ₂ , CF ₂ PO (OH) ₂ , C (NHNH) NH ₂ , NR ₇ R ₈ or selected from the following 5-membered heterocycles:

[0065]

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Or R ₁ is

[0067]

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Wherein R ₁₂ , R ₁₃ and R ₁₄ are independently hydrogen, C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl, wherein these alkyl and aryl groups are optionally substituted R ₂ is COR ₅ , OR ₆ , CF ₃ , nitro, cyano, SO ₃ H, SO ₂ NR ₇ R ₈ , PO (OH) ₂ , CH ₂ PO (O
_{H) 2, CHFPO (OH)} 2, CF 2 PO (OH) 2, C (= NH) NH 2, or a NR ₇ R _8, or is selected from the following 5-membered heterocyclic ring;

[0069]

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R_Three, R₁₆And R₁₇Is independently hydrogen, halo, nitro, cyano, trihalomethyl
, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, hydroxy, carboxy
Si, carboxy C₁-C₆Alkyl, C₁-C₆Alkyloxycarbonyl, arylo
Xycarbonyl, aryl C₁-C₆Alkyloxycarbonyl, C₁-C₆Alkylo
Kissi, C₁-C₆Alkyloxy C₁-C₆Alkyl, aryloxy, aryl C₁-C₆ Alkyloxy, aryl C₁-C₆Alkyl-oxy C₁-C₆Alkyl, thio, C₁-C ₆ Alkylthio, C₁-C₆Alkylthio C₁-C₆Alkyl, arylthio, aryl
C₁-C₆Alkylthio, aryl C₁-C₆Alkylthio C₁-C₆Alkyl, NR₇R₈, C₁ -C₆Alkyl-amino C₁-C₆Alkyl, aryl C₁-C₆Alkylamino C₁-C₆A
Ruquil, di (aryl C₁-C₆Alkyl) -amino C₁-C₆Alkyl, C₁-C₆Alkyl
Carbonyl, C₁-C₆Alkylcarbonyl C₁-C₆Alkyl, aryl C₁-C₆Archi
Lecarbonyl, aryl C₁-C₆Alkylcarbonyl C₁-C₆Alkyl, C₁-C₆Al
Kill-carboxy, C₁-C₆Alkyl-carboxy C₁-C₆Alkyl, arylcal
Boxy, aryl C₁-C₆Alkyl-carboxy, aryl C₁-C₆Alkyl carb
Kiss C₁-C₆Alkyl, C₁-C₆Alkylcarbonylamino, C₁-C₆Alkyl carb
Nil-amino C₁-C₆Alkyl, -carbonyl NR₇ C₁-C₆Alkyl COR₁₁, Ally
Le C₁-C₆Alkyl-carbonylamino, aryl C₁-C₆Alkylcarbonylamido
No C₁-C₆Alkyl, CONR₇R₈Or C₁-C₆Alkyl CONR₇R₈(Where alkyl
And the aryl group may be optionally substituted;₁₁Is NR₇R₈Or C₁-C ₆ Alkyl NR₇R₈Or R_ThreeIs

[0071]

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In the formula, R₁₂, R₁₃And R₁₄Is independently hydrogen, C₁-C₆Alkyl, aryl, a
Reel C₁-C₆Alkyl (the alkyl and aryl groups are optionally
Optionally substituted); R_FourIs hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, NR₇R ₈ , C₁-C₆Alkyloxy (where the alkyl and aryl groups are optional
May be replaced); R_FiveIs hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, CF_Three , NR₇R₈(Where the alkyl and aryl groups may be optionally substituted
R); R₆Is hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl (where
Alkyl and aryl groups may be optionally substituted);₇And R₈Is independently hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Al
Kill, C₁-C₆Alkyl-carbonyl, arylcarbonyl, aryl C₁-C₆Al
Kill-carbonyl, C₁-C₆Alkyl-carboxy or aryl C₁-C₆Alkyl-
Carboxy (where the alkyl and aryl groups are optionally substituted
Good); or R₇And R₈Has 3 to 11 carbon atoms along with the nitrogen to which they are attached, and
Monocyclic containing 0 to 2 additional heteroatoms selected from nitrogen, oxygen or sulfur
Or forms a bicyclic structure, which optionally has at least one C₁-C ₆ Alkyl, aryl, aryl C₁-C₆Alkyl, hydroxy, C₁-C₆Alkyl
Oxy, aryl C₁-C₆Alkyloxy, C₁-C₆Alkyloxy C₁-C₆Alkyl
, NR₉R_TenOr C₁-C₆Alkylamino-C₁-C₆Alkyl (where R₉And R_TenIs
Independently hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, C₁-C₆A
Alkylcarbonyl, arylcarbonyl, arylC₁-C₆Alkylcarbonyl,
C₁-C₆Alkyl-carboxy or aryl C₁-C₆Select from alkyl carboxy
Wherein the alkyl and aryl groups are optionally
Or more substituted)｝; or R₇And R₈Is independently a saturated or partially saturated cyclic 5-, 6- or 7-membered amine
Or a lactam.

Further, preferred compounds of the present invention include those wherein R ₁₆ and R ₁₇ are hydrogen. The invention in its broadest aspect encompasses a compound of Formula 1 below, or a salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or mixture of optical isomers or a tautomer, including a racemic mixture. I do.

[0074]

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Wherein A is an aryl group with a double bond of formula 1; R ₁ is hydrogen, COR ₅ , OR ₆ , CF ₃ , nitro, cyano, CH ₂ OH, SO ₃ H, SO ₂ NR ₇ R ₈ , PO (
OH) ₂ , CH ₂ PO (OH) ₂ , CHFPO (OH) ₂ , CF ₂ PO (OH) ₂ , C (= NH) NH ₂ , NR ₇ R ₈ , or from the following 5-membered heterocycle Is selected;

[0076]

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Wherein R ₁₂ , R ₁₃ and R ₁₄ are independently hydrogen, C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl, wherein these alkyl and aryl groups are optionally substituted R ₂ is COR ₅ , OR ₆ , CF ₃ , nitro, cyano, SO ₃ H, SO ₂ NR ₇ R ₈ , PO (OH) ₂ , CH ₂ PO (O
Selected from heterocycle or less _{5-membered; H) 2, CHFPO (OH} ) 2, CF 2 PO (OH) 2, C (= NH) NH 2, or a NR ₇ R _8;

[0078]

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R_Three, R₁₆And R₁₇Is independently hydrogen, halo, nitro, cyano, trihalomethyl
, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, hydroxy, oxo,
Carboxy, Carboxy C₁-C₆Alkyl, C₁-C₆Alkyloxycarbonyl, a
Reeloxycarbonyl, aryl C₁-C₆Alkyloxycarbonyl, C₁-C₆A
Lucyloxy, C₁-C₆Alkyloxy C₁-C₆Alkyl, aryloxy, aryl
Le C₁-C₆Alkyloxy, aryl C₁-C₆Alkyloxy C₁-C₆Alkyl, thio
, C₁-C₆Alkylthio, C₁-C₆Alkylthio C₁-C₆Alkyl, arylthio, a
Reel C₁-C₆Alkylthio, aryl C₁-C₆Alkylthio C₁-C₆Alkyl, NR₇R ₈ , C₁-C₆Alkylamino C₁-C₆Alkyl, aryl C₁-C₆Alkylamino C₁-C ₆ Alkyl, di (aryl C₁-C₆Alkyl) amino C₁-C₆Alkyl, C₁-C₆Al
Kill carbonyl, C₁-C₆Alkylcarbonyl-C₁-C₆Alkyl, aryl C₁-C₆A
Alkylcarbonyl, aryl C₁-C₆Alkylcarbonyl C₁-C₆Alkyl, C₁-C₆ Alkyl-carboxy, C₁-C₆Alkyl carboxy C₁-C₆Alkyl, arylka
Ruboxy, arylcarboxy C₁-C₆Alkyl, aryl C₁-C₆Alkyl carb
Xy, aryl C₁-C₆Alkyl carboxy C₁-C₆Alkyl, C₁-C₆Alkyl cal
Bonylamino, C₁-C₆Alkylcarbonylamino C₁-C₆Alkyl, -carbonyl
 NR₇ C₁-C₆Alkyl COR₁₁, Aryl C₁-C₆Alkylcarbonylamino, ally
Le C₁-C₆Alkylcarbonylamino C₁-C₆Alkyl, CONR₇R₈Or C₁-C₆Al
Kill CONR₇R₈(Where the alkyl and aryl groups are optionally substituted
Well, R₁₁Is NR₇R₈Or C₁-C₆Alkyl NR₇R₈Or R₁₆ And R₁₇R is hydrogen_ThreeIs A-B-C-D-C₁-C₆Alkyl (where A is C₁-C₆Alkyl, aryl or aryl C₁-C₆B is amino, thio, SO, SO_TwoOr oxo; C is C₁-C₆D is a chemical bond, amino or C₁-C₆Alkyl (where alkyl and ant
The aryl group may be optionally substituted), or

[0080]

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(Wherein R₁₂, R₁₃And R₁₄Is independently hydrogen, C₁-C₆Alkyl, aryl, a
Reel C₁-C₆Alkyl (the alkyl and aryl groups are optionally
R may be substituted));_FourIs hydrogen, hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl
, NR₇R₈, C₁-C₆Alkyloxy (where the alkyl and aryl groups are optional)
R may be substituted); R_FiveIs hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, C₁-C ₆ Alkyloxy, C₁-C₆Alkyl-oxy C₁-C₆Alkyloxy, arylo
Kishi, CF_Three, NR₇R₈(Where the alkyl and aryl groups are optionally substituted
R)₆Is hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl (where
Alkyl and aryl groups may be optionally substituted);₇And R₈Is independently hydrogen, C₁-C₆Alkyl, adamantyl, aryl, ant
Rule C₁-C₆Alkyl, C₁-C₆Alkylcarbonyl, arylcarbonyl, aryl
Le C₁-C₆Alkylcarbonyl, C₁-C₆Alkyl carboxy or aryl C₁-C₆ Alkylcarboxy, wherein the alkyl and aryl groups are optionally substituted
R) or R₇And R₈Together with the nitrogen to which they are attached, 3 to 14 carbon atoms, and
And saturated with 0 to 3 additional heteroatoms selected from nitrogen, oxygen or sulfur
Forms a partially saturated or aromatic, monocyclic, bicyclic, or heterocyclic structure
The ring structure optionally has at least one C₁-C₆Alkyl, aryl, aryl C₁-C ₆ Alkyl, hydroxy, oxo, C₁-C₆Alkyloxy, aryl C₁-C₆Al
Killoxy, C₁-C₆Alkyloxy C₁-C₆Alkyl, NR₉R_TenOr C₁-C₆Alkyl
Amino-C₁-C₆Alkyl (where R₉And R_TenIs independently hydrogen, C₁-C₆Alkyl
, Aryl, aryl C₁-C₆Alkyl, C₁-C₆Alkylcarbonyl, arylka
Rubonyl, aryl C₁-C₆Alkylcarbonyl, C₁-C₆Alkyl carboxy or
Aryl C₁-C₆Selected from alkyl carboxy)
Here, the alkyl and aryl groups may be optionally substituted).
Or R₇And R₈Are independently saturated or partially saturated cyclic 5, 6 or 7 membered amines
Imides or lactams.

Particularly preferred compounds of the invention include those wherein R ₁ is 5-tetrazolyl, ie,

[0083]

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[0084] or a COR _5, R ₂ is COR _5, are the compounds of formula 1. Particularly preferred compounds are those in which R ₅ is OH and R ₄ is hydrogen. The following compounds are preferred: 2-methyl-4- (oxalyl-amino) -1H-pyrrole-3-carboxylic acid; 1-benzyl-3- (oxalyl-amino) -1H-pyrazole-4-carboxylic acid; 3- (Oxalyl-amino) -1H-pyrazole-4-carboxylic acid; 4-cyclohexyl-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2 -(Oxalyl-amino) -4-phenyl-thiophen-3-carboxylic acid; 3- (oxalyl-amino) -thiophen-2-carboxylic acid; 3- (oxalyl-amino) -5-phenyl-thiophen-2-carboxylic acid Acid; 4- (oxalyl-amino)-[2,3] -bithiophenyl-5-carboxylic acid; 4-methyl-3- (oxalyl-amino) -thiophen-2-carboxylic acid; 2- (oxalyl-amino)- 5-phenyl-thiophen-3-carboxylic acid; 5- (4-chloro-phenyl) -3- (oxalyl-amino) -thiophen-2-ca Bonn acid
; 5- (4-fluoro-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-isobutyl-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid ; 3- (oxalyl-amino) -5- (4-phenoxy-phenyl) -thiophen-2-carboxylic acid; 5- (4-benzyloxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid Acid; 5- (4- (4-methoxy-phenoxy) -phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-hydroxy-phenyl) -3- (oxalyl-amino) -Thiophen-2-carboxylic acid; 5- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino) thioene-3-carboxylic acid; 2- (oxalyl- (Amino) -5- (phenyl-methyl) thiophen-3-carboxylic acid; 5- (2- (4-chloro-phenyl) -ethyl) -2- (oxalyl-amino) -thiophen-3-
Carboxylic acid; 5- (naphthalen-2-yl) -2- (oxalyl-amino) -thiophene-3-carboxylic acid
; 5- (3-nitro-phenyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid
; 5- (2-fluoro-phenyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-chloro-phenyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid
; 5- (2,4-dichloro-phenyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (4-bromo-phenyl) -2- (oxalyl-amino) -thiophen-3- carboxylic acid
5-ethyl-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-methyl-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-methyl-phenyl) -2 -(Oxalyl-amino) -thiophene-3-carboxylic acid
5-Dibenzofuran-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3,4-dimethoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- ( 3- (dimethoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (3,5-dimethoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5 -(3-Nitro-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid
; 5- (3-amino-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid
; 5- (4-methoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4- (2- (2-methoxy-phenyl) -2-oxo-ethoxy) -phenyl ) -3- (Oxalyl-amino) -thiophene-2-carboxylic acid; 5- (4-carboxymethoxy-phenyl) -3- (oxalyl-amino) -thiophene-2
-Carboxylic acid; 5- (4- (4-fluoro-benzyloxy) -phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-amino-phenyl) -3- (oxalyl -Amino) -thiophene-2-carboxylic acid
; 5- (4-carbamoylmethoxy-phenyl) -3- (oxalyl-amino) -thiophene
-2-carboxylic acid; 5-((2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -acetylamino) -methyl) -2- (oxalyl-amino) -thiophene- 3-carboxylic acid; 5- (3-ethoxycarbonylmethyl-ureidomethyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 5- (3-t-butyl-ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((3-ethyl-ureido) -methyl) -2 -(Oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (2-nitro-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3 -(3-methoxy-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (3-acetyl-phenyl) -ureidomethyl) -2- (oxalyl- (Amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((3-propyl-ureido) -methyl) -thiophen-3
-Carboxylic acid; 5- (3- (3-bromo-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophene-3-carboxylic acid; 5- (3- (2,6-diisopropyl-phenyl) -Ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (4-nitro-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid Acid; 5-((3-naphthalen-1-yl-ureido) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((3-biphenyl-2-yl-ureido)- Methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (3,5-bis-trifluoromethyl-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophene -3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (2-trifluoromethyl-phenyl) -ureidomethyl) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (3-bird Ruoromechiru - phenyl) - ureidomethyl) - thiophene-3-carboxylic acid; 5- (3-isopropyl - ureidomethyl) -2- (oxalyl - amino) - thiophene -3
-Carboxylic acid; 5-((3-cyclohexyl-ureido) -methyl) -2- (oxalyl-amino) -thiophene-3-carboxylic acid; 5- (3- (2-methoxy-phenyl) -ureidomethyl)- 2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-benzyl-ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (2,4 -Dimethoxy-phenyl) -ureidomethyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 5-((3-adamantan-1-yl-ureido) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- ((3-phenyl-ureido) -methyl) -thiophen-3-
Carboxylic acid; 5- (3- (3-nitro-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (3 2,4,5-trimethoxy-phenyl) -ureidomethyl) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (phenylsulfonyl) ureidomethyl) -thiophen-3-carboxylic acid; 2 -(Oxalyl-amino) -5- (3- (2-methyl-phenylsulfonyl) ureidomethyl) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (4-chloro-phenyl Sulfonyl) ureidomethyl) -thiophen-3-carboxylic acid; 5-((4-bromo-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((4-fluoro-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((2,2-dimethyl- (Propoxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((2-nitro-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 2-oxalyl-amino-5- (3- (4-methyl-phenylsulfonyl) ureidomethyl
) -Thiophen-3-carboxylic acid; 5-((2-ethyl-hexyloxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (benzyloxycarbonylamino-methyl ) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (propoxycarbonylamino-methyl) -thiophen-3-carboxylic acid; 5- (isopropoxycarbonylamino- Methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((4-nitro-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((4-nitro-benzyloxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((4-methoxy-phenoxy) Carbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (octyloxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (Oxalyl-amino) -5- (prop-2-ynyloxycarbonylamino-methyl) -thiophen-3-carboxylic acid; 5- (ethoxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophene
-3-carboxylic acid; 5- (isobutoxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophene-3-carboxylic acid; 5- (allyloxycarbonylamino-methyl) -2- (oxalyl-amino) -Thiophen-3-carboxylic acid; 5- (but-3-enyloxycarbonylamino-methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((4-bromo-benzenesulfonylamino) -methyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 5- (methoxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophene
-3-carboxylic acid; 2- (oxalyl-amino) -5- (phenoxycarbonylamino-methyl) -thiophen-3-carboxylic acid; 5-((2-nitro-phenylmethanesulfonylamino) -methyl) -2- (Oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((4-trifluoromethoxy-benzenesulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-(( 4-chloro-benzenesulfonylamino) -methyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 2- (oxalyl-amino) -5-((propane-2-sulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-((4-fluoro-benzenesulfonylamino)- Methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5- (methanesulfonylamino-methyl) -2- (oxalyl-amino) -thiophene-3
-Carboxylic acid; 5-((naphthalene-1-sulfonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (ethanesulfonylamino-methyl) -2- (oxalyl-amino ) -Thiophene-3
-Carboxylic acid; 2- (oxalyl-amino) -5-((3-trifluoromethyl-benzenesulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-((4-acetylamino-benzenesulfonylamino) -Methyl) -2- (oxalyl-
Amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((propane-1-sulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5- (4- (t-butyl- (Benzenesulfonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((2-nitro-4-trifluoromethyl-benzenesulfonylamino) -methyl) -2-
(Oxalyl-amino) thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((2,2,2-trifluoro-ethanesulfonylamino)-
Methyl) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((2-phenyl-ethanesulfonylamino) -methyl)-
Thiophene-3-carboxylic acid; 5- (benzenesulfonylamino-methyl) -2- (oxalyl-amino) -thiophene
-3-carboxylic acid. Pharmacological methods Truncated form of PTP1B expressed in E. coli and purified to apparent homogeneity using published methods well known to those skilled in the art (corresponding to the first 321 amino acids) Is used to evaluate the biological activity of the compound. The enzymatic reaction is essentially a Burke et al.
(Biochemistry 35; 15989-15996 (1996)) using standard conditions. The assay conditions are as follows. Appropriate concentrations of a compound of the invention are added to a reaction mixture containing various concentrations of the substrate, p-nitrophenyl phosphate (
Final assay concentration range: 0.16-10 mM). Buffer used was 100 mM sodium acetate pH 5.5, 50 mM sodium chloride, 0.1% (w / v) bovine serum albumin and 5 mM
Dithiothreitol (100 ml in total). The reaction is started by the addition of the enzyme, 25
Performed in microtiter plates at 60 ° C for 60 minutes. The reaction is stopped by the addition of NaOH. Correct for the absorbance of the compound and p-nitrophenyl phosphate at 405 nm
Enzyme activity was determined by measuring absorbance at 405 nm. Standard Michaeli
s Analyze the data using a non-linear regression fit to the Menten enzyme kinetic model. Inhibition expressed as K _i values in [mu] M. Table 1 shows the results of typical experiments.

[0085]

[Table 1]

In addition, the biological activities of the compounds are evaluated for their effect as PTPα inhibitors in substantially the same manner as described for the inhibition of PTP1B. Inferring from their activities evaluated above, the compounds of the present invention may be useful in the treatment of diseases selected from the group consisting of diabetes type I, diabetes type II, impaired glucose tolerance, insulin resistance and obesity. In addition, inferring from their activities evaluated above, the compounds of the present invention can be used to reduce immune dysfunction, including autoimmunity, diseases with dysfunction of the coagulation system, allergic diseases, including asthma, osteoporosis, cancer and psoriasis. Proliferative disorders, including diseases with reduced and enhanced growth hormone synthesis and action, diseases with reduced and enhanced synthesis of hormones or cytokines that regulate growth hormone release or response to growth hormone, Alzheimer's disease and schizophrenia. Brain disease, as well as diseases selected from the group consisting of infectious diseases.

Compound Synthesis According to one aspect of the present invention, compounds of the present invention are prepared as shown in the following reaction scheme. Method A

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By reacting an amino-substituted aryl or heteroaryl (I) with an acid chloride of formula (II), wherein A ₁ , R ₁ , R ₂ , R ₃ , R ₄ , R ₁₆ and R ₁₇ are Same as above definition)
. Method B

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The carboxylic acids (I), primary amines (II) and aldehydes (III) are converted to isocyanides (IV)
Wherein R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ are independently hydrogen, C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl Selected (the alkyl and aryl groups may be optionally substituted as defined above), or R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ are independently

[0092]

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Wherein Y represents a point of attachment to R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ ;
A, R ₁ , R ₂ and R ₄ are the same as defined above). In a preferred method, the four-component Ugi reaction described above can be performed by binding any one of the components to a solid support. Thus, synthesis can be achieved by combinatorial chemistry methods.

General Procedure for the Preparation of Acetoxymethyl Ester (C. Schultz et al., The Journal
of Biological Chemistry, 1993, 268, 6316-6322): A carboxylic acid (1 equivalent) is suspended in dry acetonitrile (2 ml per 0.1 mmol). Diisopropylamine (3.0 eq) was added, followed by bromomethyl acetate (1.5 eq). The mixture was stirred at room temperature under nitrogen overnight. The acetonitrile was removed under reduced pressure to give an oil, which was diluted with ethyl acetate and washed three times with water. The organic layer was dried with anhydrous magnesium sulfate. Filtration and removal of the solvent under reduced pressure gave a crude oil. The product was purified by silica gel column chromatography using a suitable solvent system.

The present invention also has the object of providing suitable topical, oral and parenteral pharmaceutical formulations for use in the novel methods of treatment of the present invention. The compounds of the present invention may be administered orally as tablets, aqueous or oily suspensions, lozenges, troches, powders, granules, emulsions, capsules, syrups, or elixirs. Oral compositions may include one or more agents selected from the group of sweetening, flavoring, coloring, and preservative agents to produce pharmaceutically sophisticated and palatable formulations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients include, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; (2) granulating disintegrants such as corn starch or alginic acid; (3) starch, gelatin or Binders such as gum arabic; and (4) lubricants such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over time. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be accomplished using the techniques described in U.S. Patent Nos. 4,256,108; 4,160,452 and 4,265,874 to form sustained release osmotic therapeutic tablets.

Formulations for oral use include those wherein the active ingredient is an inert solid diluent such as calcium carbonate,
It may be in the form of a hard capsule, mixed with calcium phosphate or kaolin. They may also be in the form of soft capsules wherein the active ingredient is mixed with water or an oily medium such as peanut oil, liquid paraffin or olive oil. Aqueous suspensions normally contain the active ingredients in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include (1) antisedimentation agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum and gum arabic; (2) (a)
Naturally occurring phosphatides such as lecithin; (b) condensation products of alkylene oxides with fatty acids, such as polyoxyethylene stearate; (c) condensation products of ethylene oxide with long chain fatty alcohols, such as heptadecaethyleneoxycetanol (D) condensation products of ethylene oxide with fatty acid-derived partial esters and hexitol, such as polyoxyethylene sorbitol monooleate, or (e) condensation products of ethylene oxide with fatty acid-derived partial esters and anhydrous hexitol, For example, it may be a dispersant or wetting agent which may be polyoxyethylene sorbitan monooleate. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.

The compounds of the present invention may also be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing the drug with a suitable nonirritating excipient that is solid at room temperature but liquid at rectal temperature and melts in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols. The compositions of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vehicles, large unilamellar vehicles and multilamellar vehicles. Liposomes can be formed from various phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound of Formula 1 are employed. Dosage levels for the compounds of this invention are on the order of about 0.5 mg to about 100 mg / kg of body weight, with a preferred dosage range of about 20 mg to about 50 mg / kg of body weight / day (about 25 mg to about 5 g / patient / day).
It is. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration to humans may contain from 5 mg to 1 g of active compound and a convenient amount of carrier material which may vary from about 5 to about 95% of the total composition. Dosage unit forms will generally contain between from about 5 mg to about 500 mg of an active ingredient.

However, the particular dosage level of any individual patient will depend on the particular activity, age, weight, general health, sex, diet, duration of administration, route of administration, elimination rate, drug combination used. , And the severity of the particular disease under treatment. Dosages need to be determined individually by the clinician. EXAMPLES The processes for making the compounds of formula 1 and the formulations containing these compounds are further described in the following examples, which do not limit the invention.

In the following, TLC refers to thin film chromatography, CDCL ₃ refers to deuterochloroform, and DMSO-d ₆ refers to hexadeuterodimethylsulfoxide. The structure of the compound is confirmed by elemental analysis or NMR. NMR shows peaks for the characteristic protons of the title compound where appropriate. ¹ H-NMR shifts ([delta] _H) are shown in ppm downward from tetramethylsilane as reference standard. Mp is melting point, given in ° C., uncorrected. For column chromatography, use stills (St
ill, WC, et al. (1978) J. Org. Chem., 43 , 2923), using Merck silica gel 60 (Art. 9385). As described in the experimental section, using a 5 μm C 184 x 250 mm column eluted with various mixtures of water and acetonitrile,
Perform HPLC (High Performance Liquid Chromatography) analysis at a flow rate of 1 ml / min. Wang (
Wang) resin is polystyrene with a 4-hydroxymethylphenol ether linker.

The compound used as a starting material is a known compound or a compound which can be easily prepared by a method known per se. 2-Aminothiophenes are described by Gewald et al. (1966) Chem. Ber.
99 , 94). 3-Aminothiophenes are available from Hartmann, H.,
and Libscher, J. (1984) Synthesis 275 ). Example 1

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2-Methyl-4- (oxalylamino) -1H-pyrrole-3-carboxylic acid 4- (methoxyoxalylamino) -2-methyl-1H-pyrrole-3-
Carboxylic acid tert-butyl ester (2.0 g, 7.09 mmol) in dichloromethane (20 ml)
) While stirring the solution, trifluoroacetic acid (10 ml) was added thereto. The resulting reaction mixture was stirred at room temperature for 2 hours. Evaporate volatiles in vacuo to 1.6
g (100%) of 4- (methoxyoxalylamino) -2-methyl-1H-pyrrole-3-carboxylic acid was obtained as a solid.

The above pyrrole-3-carboxylic acid (1.2 g, 5.31 mmol) in ethanol (100
A solution of sodium hydroxide (0.47 g, 11.7 mmol) in water (50 ml) was added to the solution. The resulting reaction mixture was stirred at room temperature for 18 hours. The volatiles were evaporated in vacuo and the residue was dissolved in water (100 ml). Concentrated hydrochloric acid is added to the aqueous phase, pH =
It was set to 1. The suspension was washed with ethyl acetate (50 ml) and dichloromethane (50 ml), the precipitate was filtered off and dried in vacuo at 50 ° C. for 2 hours. The solid obtained was dissolved in isopropanol (100 ml), filtered and evaporated in vacuo to give 0.4 g (36%)
The title compound was obtained as a solid. Calculated for C ₈ H ₈ N ₂ O ₅ , 0.1 x H ₂ O: C, 44.91%; H, 3.86%; N, 12.98% Found: C, 45.06%; H, 3.89%; N, 12.72% implemented Example 2

[0105]

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[0106] 1-benzyl-3- (oxalyl-amino) 1H-pyrazol-4-phosphate 3-amino -1H- pyrazole-4-carboxylic acid ethyl (5.0 g, 0.032mo
l) and triethylamine (9 ml) in dry tetrahydrofuran (150 ml) (0 ° C) were stirred while ethyl oxalyl chloride (5.3 g, 0.039 mol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 18 hours. Ethyl oxalyl chloride (5.3 g, 0.039 mol) was added dropwise and the reaction mixture was added at room temperature for an additional 18 minutes.
Stirred for hours. The volatiles were evaporated in vacuo and the residue was dissolved in a mixture of water (200ml) and ethyl acetate (200ml). The insoluble material is filtered off and removed at 50.degree.
Drying over time gave 4.0 g (49%) of 3- (ethoxyoxalylamino) 1H-pyrazole-4-carboxylic acid ethyl ester as a solid. The organic phase was separated, washed with a saturated aqueous solution of sodium chloride (100 ml), dried (MgSO4), filtered and the solvent was evaporated in vacuo to give 3.7 g (45%) of 3- (ethoxyoxalyl). amino)
1H-Pyrazole-4-carboxylic acid ethyl ester was obtained as a solid. Total yield was 7.7 g (94%).

To a solution of the above pyrazole-4-carboxylic acid ethyl ester (3.7 g, 0.015 mol) in dry N, N-dimethylformamide (75 ml) was added sodium hydride (640 mg, 0.0
16 mol, 60% in mineral oil) was added. The resulting reaction mixture was stirred at room temperature for 0.5 hours. Benzyl bromide (2.7 g, 0.016 mol) was added to the reaction mixture, and the mixture was
Stirred at C for 4 hours. Water (100 ml) was added and the reaction mixture was diethyl ether (2 x
100 ml). The combined organic extracts were washed with water (100 ml), saturated aqueous sodium chloride (2 × 50 ml), dried (MgSO ₄ ), filtered and the solvent was evaporated in vacuo. Using a mixture of ethyl acetate and heptane (1: 1) as eluent,
The residue (3.8 g) was purified on silica gel (800 ml). The pure fractions were collected and the solvent was evaporated in vacuo, yielding 0.9 g (18%) of 1-benzoyl-3- (ethoxyoxalylamino) 1H-pyrazole-4-carboxylic acid ethyl ester as a solid. .

[0108] The impure fractions were collected and the solvent was evaporated in vacuo. The residue (1.0 g) was crystallized from diethyl ether (30 ml), filtered off, dried in vacuo at 50 ° C. for 2 hours and 0.9 g (18%) of 1-benzoyl-3- (ethoxy) was obtained. Oxalyl-amino) 1H-pyrazole-4-carboxylic acid ethyl ester was obtained as a solid. The total yield 1.8g (36%) has been recovered.

The above 1H-pyrazole-4-carboxylic acid ethyl ester (0.9 g, 2
Sodium hydroxide (0.26 g, 6.51 mmo) in ethanol (50 ml) solution
l) in water (25 ml) was added. The resulting reaction mixture was stirred at room temperature for 60 hours. The volatiles were evaporated in vacuo and the residue was dissolved in water (100 ml). Concentrated hydrochloric acid was added to the aqueous phase to reach pH = 1. The precipitate was filtered off and dried in vacuo at 50 ° C. for 18 hours to give 0.55 g (73%) of the title compound as a solid. _{Mp: 189 ~191 ℃ C 13 H} 11 N 3 O 5, 1.75 x H 2 O Calculated: C, 48.68%; H, 4.56%; N, 13.10% Found: C, 48.81%; H, 4.17% N, 12.84% Example 3

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4-Cyclohexyl-2- (oxalylamino) thiophene-3-carboxylate 4-cyclohexyl-2- (ethoxyoxalylamino) thiophene-3
-To a solution of carboxylic acid (60 mg, 0.18 mmol) in ethanol (10 ml) was added a solution of 1N sodium hydroxide (0.5 ml) in water (5 ml). The resulting reaction mixture is allowed to
Stirred for hours. Concentrated hydrochloric acid was added to the reaction mixture to adjust the pH to 1. The precipitate was filtered off and dried in vacuo at 50 ° C. for 18 hours to give 30 mg (55%) of the title compound as a solid. _{Mp:> 250 ℃ C 13 H} 15 NO 5 S, 1.5 x H 2 O Calculated: C, 48.14%; H, 5.59%; N, 4.32% Found: C, 47.84%; H, 9.92%; N , 4.21% Example 4

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Ethyl 2- (oxalylamino ) -4 -phenylthiophene -3-carboxylate 4-phenyl-2- (ethoxyoxalylamino) thiophene-3-carboxylate (2.2 g, 6.33 mmol) in ethanol (50 ml) solution, a solution of sodium hydroxide (630 mg, 15.83 mmol) in water (25 ml) was added. The resulting reaction mixture was stirred at room temperature for 18 hours and the volatiles were evaporated in vacuo. The residue was dissolved in water (100 ml) and washed with diethyl ether (2 × 100 ml). Concentrated hydrochloric acid was added to the aqueous phase to reach pH = 1. The mixture was extracted with diethyl ether (2 × 100 ml). The combined organic phases were washed with a saturated aqueous solution of sodium chloride (100 ml), dried (MgSO ₄ ), filtered and the solution was evaporated in vacuo. According to NMR, a mixture of monoethyl ester and the title compound in 0.8 g was obtained. The product mixture is ethanol (
40 ml), water (20 ml) and sodium hydroxide (400 mg). The resulting mixture was stirred at room temperature for 18 hours, volatiles were evaporated in vacuo, the residue was dissolved in water (50 ml) and washed with diethyl ether (50 ml). The aqueous phase was adjusted to pH = 1 by adding concentrated hydrochloric acid, the precipitate was filtered off, washed with diethyl ether,
It was dissolved in 2-propanol (25 ml). The insoluble material was filtered off and the organic phase was evaporated in vacuo to give 180 mg (10%) of the title compound as a solid. _{Mp: 196 ~198 ℃ C 13 H} 9 NO 5 S, 0.5H 2 O Calculated: C, 52.00%; H, 3.36%; N, 4.66% Found: C, 52.21%; H, 3.44%; N , 4.50% Example 5

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[0115] 5- (4-Furorofueniru) -3- (oxalyl amino) thiophene-2-Cal Bonn acid 5- (4-Furorofueniru) -3-Amino-2-carboxylic acid methyl esters (1.0 g, 4.0 mmol) And triethylamine (11.1, 80 mmol)
Ethyl oxalyl chloride (40 ml) in ice-cold solution of dry tetrahydrofuran (40 ml)
1.2 g, 9.0 mmol) was added dropwise. After stirring the reaction mixture for 2 hours, it was filtered and the solvent was evaporated in vacuo. Dissolve the residue in dichloromethane and add 0.1 N HCl
(2 x dicared). The organic phase was dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was flash chromatographed using toluene / ethyl acetate (19: 1) as eluent to give 1.19 g (85%) of 5- (4-fluorophenyl) -3- (ethoxyoxalylamino) thiophene-2-. The carboxylic acid ethyl ester was obtained.

Ethyl 5- (4-fluorophenyl) -3- (ethoxyoxalylamino) thiophene-2-carboxylate (1.19 g, 3.4 mmol) in methanol (150
ml) solution was added 2N sodium hydroxide (20 ml). The reaction mixture is
Stirred for hours. The volatiles were evaporated in vacuo and the residue was brought to pH = 1 by adding water and 1N hydrochloric acid. The aqueous phase was extracted with a mixture of dichloromethane / 2-propanol. The organic phase was dried (MgSO _4), filtered and the solvent was evaporated in vacuo. The residue was recrystallized from methanol / water to give 619 mg (67%) of the title compound as a solid. _{C 13 H 8 FNO 5 S,} 0.5H 2 O Calculated: C, 49.06%; H, 2.83%; N, 4.40% Found: C, 49.06%; H, 2.72%; N, 4.31% Example 5 The following compounds were prepared by procedures analogous to those described in Example 6

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Calculated value for 5- (4-isobutylphenyl) -3- (oxalylamino) thiophene-2- carboxylic acid C ₁₇ H ₁₇ NO ₅ S, 0.33 × H ₂ O: C, 57.79%; H, 5.00 %; N, 3.96% Found: C, 57.79%; H, 5.08%; N, 3.89% Example 7

[0119]

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[0120] 5- (4-chlorophenyl) -3- (oxalyl-amino) thiophene-2-Cal Bonn acid, monosodium salt _{Mp:> 250 ℃ C 13 H} 7 ClNO 5 SNa, 1 x H 2 O Calculated: C, 42.63%; H, 2.52%; N, 3.55% Found: C, 42.69%; H, 2.48%; N, 3.83% Example 8

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4- (oxalylamino)-[2.3] -bithiophenyl-5-carboxylic acid Mp: 220-222 ° C. Calculated for C ₁₁ H ₇ NO ₅ S ₂ : C, 44.44%; H, 2.37%; N, 4.71% Found: C, 44.17%; H, 2.43%; N, 4.54% example 9

[0123]

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[0124] 3- (oxalyl-amino) -5-phenylalanine-2-carboxylic acid, one sodium salt _{Mp:> 250 ℃ C 13 H} 8 NO 5 SNa, 1.6 x H 2 O Calculated: C, 45.64 %; H, 3.30%; N , 4.09% Found: C, 45.25%; H, 2.93%; N, 3.92% example 10

[0125]

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3- (oxalylamino) thiophene-2-carboxylic acid, monosodium salt Mp:> 250 ° C. Calculated for C ₇ H ₇ NO ₅ SNa, 1.5 × H ₂ O: C, 31.83%; H, 2.67% N, 5.30% Found: C, 32.23%; H, 3.14%; N, 5.15% Example 11

[0127]

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[0128] 4-methyl-3- (oxalyl-amino) thiophene-2-carboxylic acid, one sodium Umushio _{Mp: 232 ~234 ℃ C 8 H} 6 NO 5 SNa, 1.5 x H 2 O Calculated: C, 34.54 %, H, 3.26%; N, 5.03% Found: C, 34.58%; H, 3.30%; N, 4.81% Example 12

[0129]

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3- (oxalylamino) -5- (4-phenoxyphenyl) thiophene-2- carboxylic acid Mp: 230 ° C. (decomposition) Calculated for C ₁₉ H ₁₃ NO ₆ S, 1.25 × H ₂ O: C, 56.22%; H, 3.85%; N, 3.45% Found: C, 56.00%; H, 3.57%; N, 3.39% example 13

[0131]

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5- (4-Benzyloxyphenyl) -3- (oxalylamino) thiophene- 2-carboxylic acid Mp: 210 ° C. (decomposition) Calculated for C ₂₀ H ₁₅ NO ₆ S: C, 60.45%; H , 3.80%; N, 3.52% Found: C, 59.94%; H, 3.79%; N, 4.45% example 14

[0133]

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[0134] 5- (4- (4-methoxyphenoxy) phenyl-3- (oxalyl-amino) Chi thiophene-2-carboxylic acid Mp: 215 ° C. _{(decomposition) C 20 H 15 NO 7 S} , 1.5H 2 O calculations Value: C, 54.54%; H, 4.12%; N, 3.18% Found: C, 54.80%; H, 3.88%; N, 3.15% Example 15

[0135]

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5- (4-Hydroxyphenyl) -3- ( oxalylamino ) thiophene-2- carboxylic acid, monosodium salt Mp: 205-206 ° C. C ₁₃ H ₉ NO ₆ SNa ₁ , calculation of 0.75 × H ₂ O Value: C, 45.42%; H, 3.08%; N, 4.07% Found: C, 45.11%; H, 3.16%; N, 3.98% Example 16

[0137]

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[0138] 5- (3-nitrophenyl) -2- (oxalyl-amino) thiophene-3-Cal Bonn acid 3-nitro phenethyl alcohol (102 mg, 0.61 mmol) in dichloromethane (2.2 ml) solution of room temperature, a nitrogen atmosphere In which Dess-Martin's periodinane reagent (285 mg, 0.67 mmol) in dichloromethane (
2.7 ml) solution was added. The reaction mixture was stirred at room temperature under a nitrogen atmosphere for 45 minutes. At this time, TLC analysis (hexane / ethyl acetate, 50/50) indicated that the reaction was complete. Diethyl ether (5.0 ml) was added, followed by a solution of 10% sodium sulfite / saturated sodium bicarbonate (5.0 ml, 1: 1). The emulsion gradually changed and upon standing for 10 minutes became a clear and heterogeneous solution. More dichloromethane is added and the organic phase is washed with water (5 ml), dried (MgSO ₄ ), filtered and evaporated in vacuo to give 100 mg (100%) of 3-nitrophenylacetaldehyde as a clear oil Obtained. The aldehyde was used in the next step without further purification. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 3.90 (s, 2H), 7.65 (d, 2H), 8.20 (s, 1H), 8.25 (m
Tert-butyl cyanoacetate (67 mg, 0.48 mmol), 3-nitrophenylacetaldehyde (86 mg, 0.52 mmol), triethylamine (73 μl, 0.52 mmol) and N, N-dimethyl Elemental sulfur (17 mg, 0.52 mmol) in formaldehyde (0.5 ml)
)) Was stirred at 60 ° C. for 1.5 hours. Upon cooling to room temperature, the dark solution was diluted with ethyl acetate and washed with water (3 × 5 ml). The organic layer was dried (MgSO _4), filtered and the solvent was evaporated in vacuo, the crude 2-amino-5- (3-nitrophenyl) thiophene-3-carboxylic acid tert-butyl ester (191 mg) Obtained. Purification by preparative TLC (hexane / ethyl acetate, 80/20) gave 74 mg (49%) of 2-amino-5- (3-nitrophenyl) thiophene-3-carboxylic acid tert-butyl ester as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.56 (s, 9H), 6.05 (s, 2H), 7.20 (s, 1H),
7.40 (t, 1H), 7.68 (d, 1H), 7.90 (d, 1H), 8.25 (s, 1H). 2-amino-5- (3-nitrophenyl) thiophene-3-carboxylic acid tert-butyl ester (66 mg, 0.21 mmol), imidazol-1-yl-oxoacetic acid tert-butyl ester (202 mg, 1.03 mmol) and triethylamine (40.4 μl,
(0.21 mmol) in tetrahydrofuran (0.5 ml) was stirred at room temperature for 3 hours. The volatiles are evaporated in vacuo, the residue is dissolved in ethyl acetate and the water (3
x 5 ml) and brine (5 ml). The organic layer was dried (Na ₂ SO _4), filtered, and the solvent was evaporated in vacuo to give a crude material. Preparation 9 by purification by TLC
1 mg (98%) of 2- (tert-butoxyoxalylamino) -5- (3-nitrophenyl) thiophen-3-carboxylic acid tert-butyl ester was obtained as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 1.54 (s, 9H), 1.62 (s, 9H), 7.5 (s, 1H), 7
.55 (t, 1H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.4 Hz), 8.16 (d, 1H, J = 8.4 Hz)
MS m / z: 447 (M-1). Dissolve the above 3-nitrophenylthiophene (85 mg, 0.19 mmol) in a 20% solution of trifluoroacetic acid in dichloromethane (3.0 ml). And stirred at room temperature for 6 hours. The solution was co-evaporated in vacuo with toluene to give the title of compound of 64mg (100%). ¹ H-NMR (400 MHz, CD ₃ OD) δ 7.71 (t, 1H, J = 8.25 Hz), 7.8 (s, 1H), 8
.1 (d, 1H, J = 7.5 Hz), 8.2 (d, 1H, J = 9 Hz), 7.86 (m, 1H). MS m / z: 335 (M-1). Described in Example 16. The following compounds were prepared in a similar manner to Example 17

[0139]

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Mp of 2- ( oxalylamino ) -5- (phenylmethyl) thiophene-3-carboxylic acid : 230-231 ° C. Calculated for C ₁₄ H ₁₁ NO ₅ S: C, 54.89%; H, 3.63%; N , 4.40% Determined: C, 54.94%; H, 3.63%; N, 4.43% example 18

[0141]

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[0142] 5- (naphthalen-2-yl) -2- (oxalyl-amino) thiophene-3-Ca carboxylic acid ^{1 H-NMR (400 MHz,} CD 3 OD) δ 7.42-7.49 (m, 2H), 7.66 ( d, 1H, J = 4.5 H
z), 7.75 (m, 1H ), 7.8-7.9 (m, 3H), 8.04 (d, 1H, J = 7.5 Hz) MS m / z:.. 340 (M-1) Example 19

[0143]

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2- (oxalylamino) -5-phenylthiophene-3-carboxylic acid Mp: 238-240 ° C. ¹ H-NMR (400 MHz, CD ₃ OD) δ 7.3 (t, 1H, J = 4.5 Hz), . 7.38 (t, 1H, J = 4.5 Hz), 7.54 (s, 1H), 7.61 (m, 3H) C 13 H 9 NO 5 S, 1 x H 2 O calculated: C, 47.13%; H, 3.04%; N, 4.23% Found: C, 47.34%; H, 3.53%; N, 4.20% Example 20

[0145]

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[0146] 5- (2-fluorophenyl) -2- (oxalyl-amino) thiophene-3-Cal Bonn acid ^{1 H-NMR (400 MHz,} CD 3 OD) δ 7.18-7.23 (m, 2H), 7.30 (m , 1H), 7.63-7.
69 (m, 2H) MS m / z:.. 340 (M-1) Example 21

[0147]

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[0148] 5- (3-fluorophenyl) -2- (oxalyl-amino) thiophene-3-Cal Bonn acid. ^{Yield: 99% 1 H-NMR (} 400 MHz, CD 3 OD) δ 7.28 (m, 1H), 7.38 (m, 1H), 7.52-7.61 (m, 3H) MS m / z:.. 324 (M-1) example 22

[0149]

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5- (2,4-dichlorophenyl) -2- (oxalylamino) thiophene-3 -carboxylic acid ¹ H-NMR (400 MHz, CD ₃ OD) δ 7.37 (m, 1H), 7.39 (m, 1H) ), 7.52-7.58 (m,
3H) MS m / z:. . 358 (M-1) Example 23

[0151]

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[0152] 5- (4-bromophenyl) -2- (oxalyl-amino) thiophene-3-Cal Bonn acid ^{1 H-NMR (400 MHz,} CD 3 OD) δ 7.51 (s, 4H), 7.54 (s, 1H ) MS m / z:.. 370 (M-1) example 24

[0153]

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5-Ethyl-2- (oxalylamino) thiophene-3-carboxylic acid ¹ H-NMR (400 MHz, CD ₃ OD) δ 1.35 (t, 3H, J = 3.75), 2.95 (q, 2H), 7.0
5 (s, 1H) .MS m / z: 170.2 (M-73) (-COCOOH), 228.1 (M-1) .Example 25

[0155]

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5-Methyl-2- (oxalylamino) thiophene-3-carboxylic acid ¹ H-NMR (400 MHz, CD ₃ OD) δ 2.6 (s, 3H), 7.05 (s, 1H). MS m / z : 228 (M-1) Example 26

[0157]

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[0158] 5- (3-methylphenyl) -2- (oxalyl-amino) thiophene-3-Cal Bonn acid ^{1 H-NMR (400 MHz,} CD 3 OD) δ 2.39 (s, 3H), 7.12 (d, 1H , J = 8 Hz), 7.
25 (t, 1H, J = 7.5 Hz), 7.4 (m, 2H), 7.5 (s, 1H) MS m / z:.. 304, 232 (M-1) Example 27

[0159]

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[0160] 5-dibenzofuran-2-yl-2- (oxalyl-amino) thiophene-3-Ca carboxylic acid ^{1 H-NMR (400 MHz,} CD 3 COCD 3) δ 7.4 (t, 1H, J = 2 Hz), 7.52 (t, 1H, J = 2 Hz), 7.7 (m, 3H), 7.9 (t, 1H, J = 2 Hz), 8.25 (d, 1H, J = 2 Hz), 8.5 (s,
1H) .MS m / z: 380.5 (M-1) .Example 28

[0161]

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[0162] 5- (2- (4-chlorophenyl) ethyl) -2- (oxalyl-amino) Chiofu E down-3-carboxylic acid, monosodium salt _{Mp:> 250 ℃ C 15 H} 11 N 1 Cl 1 O 5 S Calculated for ₁ Na ₁ , 0.75 x H ₂ O: C, 46.28%; H, 3.24%; N, 3.60% Found: C, 46.17%; H, 3.38%; N, 3.40% Example 29

[0163]

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Mp of 2- (oxalylamino) thiophene-3-carboxylic acid : 225-228 ° C. Calculated for C ₇ H ₅ N ₁ O ₅ S ₁ , 1.25 × H ₂ O: C, 35.37%; H, 3.18% N, 5.89% Found: C, 35.53%; H, 2.82%; N, 5.72% Example 30

[0165]

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5- (1,3-dioxo-1,3-dihydroisoindol-2-ylmethyl) -2- (oxalylamino) thiophene-3-carboxylate 2- (3-hydroxypropyl) isoindole-1, 3-dione (0.2
g, 0.97 mmol), 0.7 M sodium bromide (0.70 ml, 0.46 mmol) and TEMPO
A mixture of (3.0 mg, 0.02 mmol) in dichloromethane (1 ml) at 0 ° C. was stirred and a solution of bleach (2.1 ml, 4.9 mmol) and sodium bicarbonate (117 mg, 1.4 mmol) was added dropwise. . After the addition was complete, the mixture was stirred at 0 ° C. for 2 hours. The mixture was extracted with ethyl acetate (3 × 20 ml). The combined organic extracts were washed with 10% sodium thiosulfate (3 × 10 ml), brine (10 ml), dried (MgSO ₄ ), filtered,
The solvent was evaporated in vacuum. The residue was washed with ethyl acetate (2 × 1 ml), dried and 161 mg (81%) of 3- (1,3-dioxo-1,3-dihydroisoindol-2-yl) propionaldehyde was solid. As obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 9.82 (s, 1H), 7.85 (dd, 2H, J = 5.6, 2.8
Hz), 7.73 (dd, 2H, J = 5.6, 2.8 Hz), 4.04 (t, 2H, J = 7.2 Hz), 2.89 (t, 2H,
J = 7.2 Hz). The above aldehyde (150 mg, 0.74 mmol), triethylamine (113 ml, 0.
To a solution of 81 mmol) and sulfur (24 mg, 0.81 mmol) in dichloromethane (10 ml) at room temperature was added tert-butyl cyanoacetate (114 mg, 0.81 mmol). The mixture was stirred and heated at reflux under a nitrogen atmosphere for 2 hours. The mixture was cooled to room temperature, the precipitate was filtered off and 189 mg of 2-amino-5- (1,3-dioxo-1
, 3-Dihydroisoindol-2-ylmethyl) thiophen-3-carboxylic acid tert-butyl ester was obtained as a solid.

The filtrate was evaporated in vacuo and the residue was taken up in ethyl acetate (50 ml).
5N hydrochloric acid (2 x 10 ml), saturated sodium bicarbonate (2 x 10 ml), brine (10 m
washed with l), dried (MgSO _4), and filtered. The solvent was evaporated in vacuo and the residue was washed with cold ethyl acetate (2 x 1 ml) and 52 mg of 2-amino-5- (1,
3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) thiophene-3-carboxylic acid tert-butyl ester was obtained as a solid. A total yield of 241 mg (91%) was obtained. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 7.86 (dd, 2H, J = 7.2, 4 Hz), 7.72 (dd, 2
H, J = 7.2, 4 Hz ), 6.97 (s, 1H), 5.83 (s, 2H, NH 2), 4.78 (s, 2H), 1.56 (s, 9
H). A solution of the above thiophene (100 mg, 0.28 mmol) in tetrahydrofuran (2 ml) was stirred, and imidazol-1-yloxoacetic acid tert-butyl ester (
60 mg, 0.31 mmol) in tetrahydrofuran (1 ml) was added. The mixture was stirred at room temperature for 3 hours. The solvent was evaporated in vacuum. The residue was treated with ethyl acetate (50 ml
), 0.5N hydrochloric acid (2 x 5 ml), saturated sodium hydrogen carbonate solution (2
x 5 ml), washed with brine (5 ml), dried (MgSO _4), and filtered. The solvent was evaporated in vacuo and 130 mg (96%) of 2- (tert-butoxyoxalylamino)
-5- (1,3-Dioxo-1,3-dihydroisoindol-2-ylmethyl) thiophen-3-carboxylic acid tert-butyl ester was obtained as a solid. ¹ H-NMR (400 MHz, CDCl ₃ ) δ 12.23 (s, 1H), 7.87 (dd, 2H, J = 7.2, 4 H
z), 7.73 (dd, 2H, J = 7.2, 4 Hz), 7.24 (s, 1H), 4.93 (s, 2H), 1.60 (s, 9H),
1.57 (s, 9H). To a solution of trifluoroacetic acid (1 ml) in dichloromethane (1 ml) was added the above ditertiary butyl ester (100 mg, 0.21 mmol). The solution was stirred at room temperature for 1 hour. The solvent was evaporated in vacuum. The residue was washed with dichloromethane (3 x 1 ml) and 6
3 mg (82%) of the title compound were obtained as a solid. ¹ H-NMR (400 MHz, DMSO-d ₆ ) δ 12.05 (s, 1H), 7.89 (m, 2H), 7.87 (m, 2
H), 7.10 (s, 1H), 4.83 (s, 2H). MS m / z: 373 (M-1) Example 31

[0168]

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5- (3,4-Dimethoxyphenyl) -3- ( oxalylamino ) thiophene- 2-carboxylic acid Mp: 230-231 ° C. Calculation of C ₁₅ H ₁₃ N ₁ O ₇ S ₁ , 1 × H ₂ O Value: C, 48.78%; H, 4.09%; N, 3.79% Found: C, 49.01%; H, 3.75%; N, 3.79% Example 32

[0170]

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[0171] 5- (3-methoxyphenyl) -3- (oxalyl-amino) thiophene-2-mosquito carboxylic acid _{Mp: 217 ~218 ℃ C 14 H} 11 N 1 O 6 S 1, 0.75 x H 2 O Calculated : C, 50.22%; H, 3.76%; N, 4.18% Found: C, 50.02%; H, 3.73%; N, 4.16% Example 33

[0172]

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[0173] 5- (3,5-dimethoxy - phenyl-3- (oxalyl - amino) - thiophene-2-Cal Bonn acid; _{mp: 223 ~225 ℃ C 15 H 13} N 1 O 7 S 1, 1.25 x H ₂ O calculated: C, 48.19%; H, 4.18%; N, 3.75% Found:. C, 48.25%; H , 4.10%; N, 3.39% example 34

[0174]

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5- (3-nitro-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid ; melting point:> 250 ° C. C ₁₃ H ₇ N ₁ O ₇ S ₁ Na ₁ , 1.25 × H ₂ Calculated O: C, 41.01%; H, 2.51%; N, 7.36% Found: C, 41.03%; H, 2.38%; N, 7.17%. Example 35

[0176]

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5- (3-Amino-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid ; melting point:> 250 ° C. Calculation of C ₁₃ H ₁₀ N ₂ O ₅ S ₁ , 0.5 XH ₂ O Value: C, 49.52%; H, 3.52%; N, 8.88% found: C, 49.48%; H, 3.44%; N, 8.71% Example 36

[0178]

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5- (4-Methoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid ; melting point: 220-221 ° C. C ₁₄ H ₁₁ N ₁ O ₆ S ₁ , 0.4 × H ₂ O calculated: C, 51.19%; H, 3.62%; N, 4.62% Found: C, 51.29%; H, 3.53%; N, 3.96% example 37

[0180]

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5- (4-amino-phenyl) -3- (oxalyl-amino) -thiophene-2-carboxylic acid ; calculated for C ₁₃ H ₁₀ N ₂ O ₅ S ₁ , 0.5 × H ₂ O: C, 49.52%; H, 3.52%; N, 8.88% Found: C, 49.40%; H, 3.87%; N, 8.23% example 38

[0182]

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[0183] 5- (4- (2- (2-methoxy - phenyl) -2-oxo - ethoxy) - phenyl) -3- (oxa Lil - amino) - thiophene-2-carboxylic acid disodium salt; N, 3- (Ethoxyoxalylamino) using N-dimethylformamide (35ml) as solvent
) -5- (4-Hydroxyphenyl) thiophene-2-carboxylic acid methyl ester (524 mg
, 1.5 mmol) and potassium carbonate (275 mg, 2.0 mmol) in a nitrogen atmosphere under ω-
Brom-2-methoxyacetophenone (460 mg, 2.0 mmol) was added. After stirring for 3 hours, precipitated crude 3- (ethoxyoxalylamino) -5- (4- (2- (2-methoxyphenyl) -2-oxy-ethoxy) phenyl) -thiophen-2-carboxylic acid methyl ester
(1.0 g) was filtered off.

Crude 3- (ethoxyoxalylamino) -5- (4- (2- (2
To a solution of -methoxyphenyl) -2-oxy-ethoxy) phenyl) -thiophene-2-carboxylic acid methyl ester (0.5 g) was added 1N sodium hydroxide (10 ml). 65 ℃
After stirring at for 3 hours, the product was isolated by filtration and washed with a mixture of water and ethanol (1: 1), and after drying in vacuo, 290 mg of the title compound was obtained as a solid. _{Mp: 286 ~287 ℃ C 22 N 18} N 1 O 9 S 1 Na 2 Calculated: C, 50.19%; H, 3.42%; N, 2.66% Found: C, 51.18%; H, 3.42%; N , 2.58% Example 39

[0185]

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5- (4-carboxymethoxy-phenyl) -3- (oxalyl-amino) -thiophene-2 -carboxylic acid, trisodium salt; 3- (ethoxy, using N, N-dimethylformamide (5 ml) as a solvent Oxalylamino
) -5- (4-Hydroxyphenyl) thiophene-2-carboxylic acid methyl ester (307 mg
, 1.0 mmol) and potassium carbonate (166 mg, 1.2 mmol) in a solution of 2-bromoacetamide.
(165 mg, 1.2 mmol) was added. After stirring at 50 ° C. for 16 hours, the reaction mixture was quenched by adding water, and precipitated 5- (4-carbamoylmethoxy-phenyl) -3- (ethoxyoxalylamino) -thiophen-2-carboxylic acid methyl ester ( 70 mg) was isolated by filtration. The aqueous phase was acidified with 1N hydrochloric acid, adjusted to pH = 1-2, and semi hydrolysed product 5- (4-carbamoylmethoxy-phenyl) -3- (oxalylamino) -thiophene 2-Carboxylic acid methyl ester (300 mg) was isolated by filtration. To a suspension of 5- (4-carbamoylmethoxy-phenyl) -3- (oxalylamino) -thiophen-2-carboxylic acid methyl ester (295 mg, 0.78 mmol) in methanol (5 ml) and water (5 ml) , 1N sodium hydroxide (2 ml) was added. After stirring for 5 days, the precipitate was filtered to give 105 mg (88%) of the title compound as a solid.
Melting point:> 300 ° C. Calculated for _{C 15 H 12 N 1 O 10} S 1 Na 3: C, 38.56%; H, 2.59%; N, 3.00% Found: C, 38.73%; H, 2.74%; N, 3.06% Example 37 The following compounds were prepared in a similar manner to Example 40

[0187]

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[0188] 5- (4- (4-fluoro - benzyloxy) - phenyl) -3- (oxalyl - amino) - thiophene-2-carboxylic ^{acid; 1 H NMR (300 MHz,} DMSO-d 6) δ 5.15 (s, 2H), 7.1 (d, 2H), 7.25 (t, 2H), 7.55 (
q, 2H), 7.7 (d , 2H), 8.2 (s, 1H) SP / MS: 415 (M +, 12%), 372, 353, 299, 218, 190, 162, 109 (100%) Example 41

[0189]

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5-((2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -acetoamino ) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid 2- (t-butoxyoxalyl-amino) -5- (1) using dichloromethane (2 ml) as a solvent ;
, 3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl) -thiophen-3-
To a solution of carboxylic acid t-butyl ester (0.4 g, 0.82 mmol, prepared as described in Example 30) was added anhydrous hydrazine (28 ml, 0.9 mmol) and the mixture was allowed to stand at ambient temperature under nitrogen. Stirred for 19 hours. An additional portion of hydrazine (84 ml, 2.7 mmol) and dichloromethane (5.5 ml) was added and stirring was continued for a further 88 hours. Dichloromethane (50 ml) was added and the reaction mixture was placed in a sonicator for 20 minutes and filtered through celite. The filtrate was evaporated in vacuo to give 0.24 g of solid 5-aminomethyl-2- (t-butoxyoxalyl-amino) -thiophene-3-carboxylic acid t-butyl ester (0.24 g).
82%) which was used in the next step without further purification.

(1,3-Dioxo-1,3-dihydro-isoindol-2-yl) -acetic acid (0.17 g, 0.82 mmol) in anhydrous acetonitrile (10 ml) as a solvent, 1-hydroxybenzotriazole (0.133 g) , 0.98 mmol) and 2,6-lutidine (0.4 ml) under nitrogen with cooling in an ice bath under 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.2 ml).
1 g, 1.1 mmol) was added and the solution was stirred for 0.5 h. 5-aminomethyl-2- (
t-butoxyoxalyl-amino) -thiophene-3-carboxylic acid t-butyl ester (0
.24 g, 0.68 mmol) was added, the cooling bath was removed and the solution was stirred at ambient temperature for 20 hours. Volatiles were evaporated in vacuo and the residue was dissolved in dichloromethane, washed with saturated aqueous sodium hydrogen carbonate and 1N hydrochloric acid, dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo. The residue (0.18 g) was dissolved in anhydrous tetrahydrofuran (6 ml) under nitrogen, and imidazol-1-yl-oxo-acetic acid t-butyl ester (0.25 g, 1.3 mmol)
Was added and the solution was stirred at ambient temperature for 17 hours, the solvent was evaporated in vacuo and the residue was dissolved in a mixture of dichloromethane and saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried (Na ₂ SO ₄ ) and the solvent was evaporated in vacuo. The residue is chromatographed on silica gel to give 2- (t-butoxyoxalyl-amino) -5-((2- (1,3
-Dioxo-1,3-dihydro-isoindol-2-yl) -acetylamino) -methyl
0.1 g of) -thiophene-3-carboxylic acid t-butyl ester was obtained. ¹ H NMR (400 MHz, CDCl ₃ ), δ 12.3 (bs, 1H), 7.9 (m, 2H), 7.8 (m, 2H), 7.1
(s, 1H), 6.5 (m, 1H), 4.6 (m, 2H), 4.4 (s, 2H), 1.8 (s, 9H), 1.6 (s, 9H) 2- (t-butoxyoxalyl-amino) -5-((2- (1,3-dioxo-1,3-dihydro-
Isoindol-2-yl) -acetylamino) -methyl) -thiophen-3-carboxylic acid
20% of t-butyl ester (0.1g, 0.18mmol) in dichloromethane (4ml)
Trifluoroacetic acid was added and the reaction mixture was stirred at ambient temperature under nitrogen for 14 hours. Volatiles were evaporated in vacuo and the residue was chased with dichloromethane until a solid remained. The precipitate was filtered and dried under vacuum for 18 hours to give the title compound as a solid in quantitative yield.
Melting point: 243-244 ° C MS m / z: 430 (M-1) ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.1 (s, 1H), 8.9 (s, 1H), 7.8 -7.9 (m, 4H ),
7.1 (s, 1H), 4.4 (m, 2H), 4.2 (s, 2H) Example 42 Using a solid-phase chemistry method, a 64-member library was synthesized according to the following scheme.

[0192]

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5-Aminomethyl-2- (t-butoxyoxalyl-amino) -thiophene-3-carboxylic acid wang resin ester (1.8 mmol) was weighed out and mixed in a mixture of tetrahydrofuran and dichloromethane (90 ml, 1: 1). 1 ml of a suspension containing 20 μmol of this resin
Was dispensed into 64 wells (OntoBlock system). The wells were drained and dried under vacuum for 2 hours. Anhydrous N, N-dimethylformamide (1 ml) was dispensed into each well. The chemicals dispensed into each well are listed below: Urea Wells A1 to C8 and 24 μmol each of isocyanate were dispensed into the corresponding wells. Sulfonylurea wells D1 to D4 and 40 μmol each of sulfonyl isocyanate were dispensed into the corresponding wells. 7.0 μL (60 μmol) of carbamate wells D5 to F7,2,6-lutidine were added to each of these wells, followed by the addition of 40 μmol of the corresponding sulfonyl isocyanate. Sulfonamide wells F8 through H8, 8.4 μL (60 μmol) of triethylamine were added to each of these wells followed by the corresponding 40 μmol of sulfonyl chloride. After dispensing the chemicals (see below for a list of R-groups) into each well, the blocks were shaken at 500 rpm for 3 days, then drained, washed and dried under vacuum overnight. A 1 ml solution (200 μmol) of imidazol-1-yl-oxo-acetic acid t-butyl ester in dichloromethane as a solvent was dispensed to each well under nitrogen. The blocks were shaken at 500 rpm overnight, drained, washed and dried under vacuum. Dispense 1 ml of trifluoroacetic acid / dichloromethane (1: 1) into each well of these blocks,
Thirty minutes after dispensing, the solution was drained to a microtiter plate. Thereafter, 0.5 ml of trifluoroacetic acid / dichloromethane (1: 1) is dispensed into each well of these blocks, and 45 ml of the dispensed.
After one minute, the solution was drained to a microtiter plate. The microtiter plate containing the product cleaved from the resin was vacuum dried using a Gen-Vac to give the final product. These final products were analyzed by HPLC and MS.

X ₁ represents a binding site of the R-group. Percent means the peak area of the HPLC at 220 nm.

[0195]

[Table 2]

[0196]

[Table 3]

[0197]

[Table 4]

[0198]

[Table 5]

[0199]

[Table 6]

[0200]

[Table 7]

[Procedure amendment]

[Submission date] October 11, 2000 (2000.10.11)

[Procedure amendment 2]

[Document name to be amended] Abstract

[Correction target item name] Full text

[Correction method] Change

[Correction contents]

Abstract: The present invention relates to a compound comprising PTP1B, CD45, SHP-1, SHP-2, PTPα, LAR and HePTP.
Novel compounds, new compositions, methods of their use, and methods for their manufacture are provided as pharmaceutically useful inhibitors of protein tyrosine phosphatase (PTPase). These compounds are useful for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immunodeficiencies including autoimmune diseases, diseases involving clotting system dysfunction, allergic diseases including asthma, osteoporosis Proliferative disorders, including cancer and psoriasis, diseases due to reduced or increased growth hormone synthesis or action, diseases caused by reduced or increased synthesis of hormones or cytokines that control the release and / or response of growth hormone, Alzheimer's disease and division It is useful in treating brain diseases, including diseases, as well as infectious diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/422 A61K 31/422 A61P 3/04 A61P 3/04 3/10 3/10 7/00 7 / 00 11/06 11/06 17/06 17/06 19/10 19/10 25/18 25/18 25/28 25/28 31/00 31/00 35/00 35/00 37/02 37/02 37 / 08 37/08 43/00 111 43/00 111 C07D 231/38 C07D 231/38 B 333/38 333/38 333/40 333/40 409/04 409/04 409/06 409/06 409/12 409 / 12 (31) Priority claim number 9800939 (32) Priority date July 15, 1998 (July 15, 1998) (33) Priority claim country Denmark (DK) (31) Priority claim number 9801561 (32 ) Priority date November 26, 1998 (November 26, 1998) (33) Priority country Denmark (DK) (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI) FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM) , AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN , MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL , TJ, TM, TR, TT, UA, UG, UZ, VN, YU, ZW (72) Inventor Yeppesen, Rone, Denmark, DECO-2830 Birm, Malmosebay 121 (72) Inventor Andersen, Henrik Sne, Denmark, Decor-2800 Lynview, Gustav Adolfsvay 2 (72) Inventor Olsen, Ole Fbilstead Denmark, Decor-2700 Brensey, Beckeskovy 38 (72) Inventor Judge, Luke Milburn United States of America, California 92037, La Jolla, Bonaire Way 644 1/2 (72) Inventor Holsworth, Daniel Dale United States of America, California 92129, San Diego, Chabola Road 9462 (72) Inventor Baker, Farid United States of America, California 92120, San Diego, College Avenue 5 757, Apartment A (72) Inventor Axe, Frank Urban United States of America, California 92027, Escondido, Birch Avenue 1250 (72) Inventor J. You, United States of America, California 92129, San Diego, Briquera Street 12455 F-term (reference) 4C023 HA03 HA05 4C063 AA01 BB01 BB03 BB08 CC92 DD07 EE01 4C069 AC06 BD02 4C086 AA01 AA02 AA03 BB02 BC05 BC11 BC36 BC69 GA04 GA07 GA16 MA01 MA04 MA52 MA55 NA14 ZA16 ZA51 ZA59 ZA70 ZA90 ZA97 ZB07 ZB13 ZB21 ZB26 ZB31 ZC02 ZC03 ZC20 ZC35

Claims (37)

[Claims] 1. A compound of formula 1(Wherein A is, together with the double bond of formula 1, furanyl, thiophenyl, pyrrolyl,
Xazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, iso
Thiazolyl, 1,2,3-oxadiazolyl, flazanil or 1,2,3-triazolyl
R; R₁Is hydrogen, COR_Five, OR₆, CF_Three, Nitro, cyano, CH_TwoOH, SO_ThreeH, S0_TwoNR₇R₈, PO
(OH)_Two, CH_TwoPO (OH)_Two, CHFPO (OH)_Two, CF_TwoPO (OH)_Two, C (= NH) NH_Two, NR₇R₈Or below
Is selected from the following five-membered heterocycles:Or R₁Is(Where R₁₂, R₁₃, And R₁₄Is independently hydrogen, C₁-C₆Alkyl, aryl,
Aryl C₁-C₆Alkyl, and the alkyl and aryl groups are optionally substituted.
R)_TwoIs COR_Five, OR₆, CF_Three, Nitro, cyano, SO_ThreeH, SO_TwoNR₇R₈, PO (OH)_Two, CH_TwoPO (
OH)_Two, CHFPO (OH)_Two, CF_TwoPO (OH)_Two, C (= NH) NH_Two, NR₇R₈Or the following 5-membered heterocycle
Selected from:R_Three, R₁₆And R₁₇Is independently hydrogen, halo, nitro, cyano, trihalomethyl,
C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, hydroxy, oxo, mosquito
Ruboxy, carboxy C₁-C₆Alkyl, C₁-C₆Alkyloxycarbonyl, ant
Oxycarbonyl, aryl C₁-C₆Alkyloxycarbonyl, C₁-C₆Al
Killoxy, C₁-C₆Alkyloxy C₁-C₆Alkyl, aryloxy, aryl
C₁-C₆Alkyloxy, aryl C₁-C₆Alkyloxy C₁-C₆Alkyl, thio,
C₁-C₆Alkylthio, C₁-C₆Alkylthio C₁-C₆Alkyl, arylthio, ant
Rule C₁-C₆Alkylthio, aryl C₁-C₆Alkylthio C₁-C₆Alkyl, NR₇R₈ , C₁-C₆Alkylamino C₁-C₆Alkyl, aryl C₁-C₆Alkylamino C₁-C₆ Alkyl, di (aryl C₁-C₆Alkyl) amino C₁-C₆Alkyl, C₁-C₆Archi
Lecarbonyl, C₁-C₆Alkylcarbonyl-C₁-C₆Alkyl, aryl C₁-C₆Al
Kill carbonyl, aryl C₁-C₆Alkylcarbonyl C₁-C₆Alkyl, C₁-C₆A
Lucylcarboxy, C₁-C₆Alkyl carboxy C₁-C₆Alkyl, arylcarbo
Xy, aryl carboxy C₁-C₆Alkyl, aryl C₁-C₆Alkyl carboxy
, Aryl C₁-C₆Alkyl carboxy C₁-C₆Alkyl, C₁-C₆Alkyl carboni
Lumino, C₁-C₆Alkylcarbonylamino C₁-C₆Alkyl, -carbonyl NR₇C ₁ -C₆Alkyl COR₁₁, Aryl C₁-C₆Alkylcarbonylamino, aryl C₁-C ₆ Alkylcarbonylamino C₁-C₆Alkyl, CONR₇R₈Or C₁-C₆Alkyl CO
NR₇R₈Wherein the alkyl and aryl groups are optionally substituted; and R₁₁Is NR₇R₈;
Or C₁-C₆Alkyl NR₇R₈It is. ); Or R₁₆And R₁₇Is hydrogen
, R_ThreeIs A-B-C-D-C₁-C₆Alkyl, wherein A is C₁-C₈Alkyl, aryl or aryl C₁-C₆B is amino, thio, SO, SO_TwoOr oxo; C is C₁-C₈D is a chemical bond, amino or C₁-C₈Alkyl, where alkyl and aryl
The radical is optionally substituted. ); Or(Where R₁₂, R₁₃, And R₁₄Is independently hydrogen, C₁-C₆Alkyl, aryl,
Aryl C₁-C₆Alkyl and the alkyl and aryl groups are optionally substituted
R)_FourIs hydrogen, hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl
, NR₇R₈, C₁-C₆Alkyloxy; wherein the alkyl and aryl groups are
R_FiveIs hydroxy, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, C₁-C ₆ Alkyloxy, C₁-C₆Alkyloxy C₁-C₆Alkyloxy, aryloxy
Si, aryl C₁-C₆Alkyloxy, CF_Three, NR₇R₈Where alkyl and ally
R is optionally substituted; R₆Is hydrogen, C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl; here
Wherein the alkyl and aryl groups are optionally substituted; or R₇And R₈Is independently hydrogen, C₁-C₆Alkyl, adamantyl, aryl, ally
Le C₁-C₆Alkyl, C₁-C₆Alkylcarbonyl, arylcarbonyl, aryl
C₁-C₆Alkylcarbonyl, C₁-C₆Alkyl carboxy or aryl C₁-C₆A
Alkylcarboxy; wherein the alkyl and aryl groups are optionally substituted
R; R₇And R₈Is, together with the nitrogen to which they are attached, a saturated, partially saturated or aromatic monocyclic ring
Selected from nitrogen, oxygen or sulfur, 3 to 14 carbon atoms, bicyclic or tricyclic,
Form a ring system containing from 0 to 3 heteroatoms, wherein the ring system optionally has at least
1 C₁-C₆Alkyl, aryl, aryl C₁-C₆Alkyl, hydroxy, oki
S, C₁-C₆Alkyloxy, aryl C₁-C₆Alkyloxy, C₁-C₆Alkylo
Kiss C₁-C₆Alkyl, NR₉R_TenOr C₁-C₆Alkylamino C₁-C₆Substitute with alkyl
(Where R₉And R_TenIs independently hydrogen, C₁-C₆Alkyl, aryl
, Aryl C₁-C₆Alkyl, C₁-C₆Alkylcarbonyl, arylcarbonyl,
Aryl C₁-C₆Alkylcarbonyl, C₁-C₆Alkyl carboxy or aryl
C₁-C₆Alkyl and carboxyl); wherein the alkyl and aryl groups are
Optionally substituted; or R₇And R₈Is an independently saturated or partially saturated cyclic 5, 6 or 7 membered amine,
Imides or lactams; or their salts with pharmaceutically acceptable acids or bases, or racemic mixtures
Optical isomers or mixtures of optical isomers, or tautomers. 2. The compound according to claim 1, wherein A is furanyl. 3. The compound according to claim 1, wherein A is thiophenyl. 4. The compound according to claim 1, wherein A is pyrrolyl. 5. The compound according to claim 1, wherein A is oxazolyl. 6. The compound according to claim 1, wherein A is thiazolyl. 7. The compound according to claim 1, wherein A is imidazolyl. 8. The compound according to claim 1, wherein A is pyrazolyl. 9. The compound according to claim 1, wherein A is isoxazolyl. 10. The compound according to claim 1, wherein A is isothiazolyl. 11. The compound according to claim 1, wherein A is 1,2,3-oxadiazolyl. 12. The compound according to claim 1, wherein A is furazanil. 13. The compound according to claim 1, wherein A is 1,2,3-triazolyl. 14. The compound according to claims 2 to 13, wherein R ₁ and R ₂ are COR ₅ and R ₄ is hydrogen; wherein R ₅ is as defined above. 15. The compound according to claims 2 to 13, wherein R ₁ is 5-tetrazolyl and R ₂ is COR ₅ ; wherein R ₅ is as defined above. 16. The method of claim _{2, wherein} R ₁ and R ₂ are COOH and R ₄ is hydrogen.
13. The compound according to 13. 17. A compound selected from: 2-methyl-4- (oxalyl-amino) -1H-pyrrole-3-carboxylic acid; 1-benzyl-3- (oxalyl-amino) -1H-pyrazole-4 -Carboxylic acid; 3- (oxalyl-amino) -1H-pyrazole-4-carboxylic acid; 4-cyclohexyl-2- (oxalyl-amino) -thiophene-3-carboxylic acid; 2- (oxalyl-amino) -thiophene- 3-carboxylic acid; 2- (oxalyl-amino) -4-phenyl-thiophen-3-carboxylic acid; 3- (oxalyl-amino) -thiophen-2-carboxylic acid; 3- (oxalyl-amino) -5-phenyl -Thiophene-2-carboxylic acid; 4- (oxalyl-amino)-[2,3] -bithiophenyl-5-carboxylic acid; 4-methyl-3- (oxalyl-amino) -thiophen-2-carboxylic acid; 2- (Oxalyl-amino) -5-phenyl-thiophen-3-carboxylic acid; 5- (4-chloro-phenyl) -3- (o Salyl-amino) -thiophen-2-carboxylic acid; 5- (4-fluoro-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-isobutyl-phenyl) -3- ( Oxalyl-amino) -thiophen-2-carboxylic acid; 3- (oxalyl-amino) -5- (4-phenoxy-phenyl) -thiophen-2-carboxylic acid; 5- (4-benzyloxy-phenyl) -3- (Oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4- (4-methoxy-phenoxy) -phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-hydroxy -Phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl) -2- (oxalyl-amino)- Thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (phenyl-methyl) -thiophen-3-carboxylic acid; 5- (2- (4-chloro- Le) - ethyl) -2- (oxalyl - amino) - thiophene-3
Carboxylic acid; 5- (naphthalen-2-yl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-nitro-phenyl) -2- (oxalyl-amino) -thiophen-3- Carboxylic acid; 5- (2-fluoro-phenyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-chloro-phenyl) -2- (oxalyl-amino) -thiophen-3- Carboxylic acid; 5- (2,4-dichloro-phenyl) -2- (oxalyl-amino) -thiophene-3-carboxylic acid; 5- (4-bromo-phenyl) -2- (oxalyl-amino) -thiophene- 3-carboxylic acid; 5-ethyl-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-methyl-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-methyl- Phenyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-dibenzofuran-2-yl-2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5 -(3,4-dimethoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (3-methoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid 5- (3,5-dimethoxy-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (3-nitro-phenyl) -3- (oxalyl-amino) -thiophen-2- Carboxylic acid; 5- (3-amino-phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-methoxy-phenyl) -3- (oxalyl-amino) -thiophen-2- 5- (4- (2- (2-methoxy-phenyl) -2-oxo-ethoxy) -phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-carboxy) (Methoxy-phenyl) -3- (oxalyl-amino) -thiophene-2
-Carboxylic acid; 5- (4- (4-fluoro-benzyloxy) -phenyl) -3- (oxalyl-amino) -thiophen-2-carboxylic acid; 5- (4-amino-phenyl) -3- (oxalyl -Amino) -thiophen-2-carboxylic acid; 5- (4-carbamoylmethoxy-phenyl) -3- (oxalyl-amino) -thiophene
2-carboxylic acid; 5-((2- (1,3-dioxo-1,3-dihydro-isoindol-2-yl) -acetamino
) -Methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-ethoxycarbonylmethyl-ureidomethyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 5- (3-t-butyl-ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((3-ethyl-ureido) -methyl) -2 -(Oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (2-nitro-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3 -(3-methoxy-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (3-acetyl-phenyl) -ureidomethyl) -2- (oxalyl- Amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((3-propyl-ureido) -methyl) -thiophen-3-
Carboxylic acid; 5- (3- (3-bromo-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (2,6-diisopropyl-phenyl)- Ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (4-nitro-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid 5-((3-naphthalen-1-yl-ureido) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((3-biphenyl-2-yl-ureido) -methyl ) -2- (Oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (3,5-bis-trifluoromethyl-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophene- 3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (2-trifluoromethyl-phenyl) -ureidomethyl) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- ( 3- (3-trifluoromethyl-phenyl) -ureidomethyl) -thiophen-3-carboxylic acid; 5- (3-isopropyl-ureidomethyl) -2- (oxalyl-amino) -thiophene-3
-Carboxylic acid; 5-((3-cyclohexyl-ureido) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (2-methoxy-phenyl) -ureidomethyl)- 2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3-benzyl-ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (3- (2,4 -Dimethoxy-phenyl) -ureidomethyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 5-((3-adamantan-1-yl-ureido) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- ((3-phenyl-ureido) -methyl) -thiophen-3-
Carboxylic acid; 5- (3- (3-nitro-phenyl) -ureidomethyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (3- (3 , 4,5-Trimethoxy-phenyl) -ureidomethyl) -thiophen-3-carboxylic acid; 2-oxalyl-amino-5- (3- (phenylsulfonyl) ureidomethyl) -thiophen-3-carboxylic acid; 2-oxalyl -Amino-5- (3- (2-methyl-phenylsulfonyl) ureidomethyl
) -Thiophen-3-carboxylic acid; 2-oxalyl-amino-5- (3- (4-chloro-phenylsulfonyl) ureidomethyl
) -Thiophene-3-carboxylic acid; 5-((4-bromo-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((4-fluoro-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((2,2-dimethyl- Propoxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((2-nitro-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 2-oxalyl-amino-5- (3- (4-methyl-phenylsulfonyl) -ureidomethyl
) -Thiophen-3-carboxylic acid; 5-((2-ethyl-hexyloxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (benzyloxycarbonylamino-methyl ) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5- (propoxycarbonylamino-methyl) -thiophen-3-carboxylic acid; 5- (isopropoxycarbonylamino- Methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((4-nitro-phenoxycarbonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((4-nitro-benzyloxycarbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5-((4-methoxy-phenoxy) Carbonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (octyloxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 2- (Oxalyl-amino) -5- (prop-2-ynyloxycarbonylamino-methyl) -thiophen-3-carboxylic acid; 5- (ethoxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophene
-3-carboxylic acid; 5- (isobutoxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophene-3-carboxylic acid; 5- (allyloxycarbonylamino-methyl) -2- (oxalyl-amino) -Thiophen-3-carboxylic acid; 5- (but-3-enyloxycarbonylamino-methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((4-bromo-benzenesulfonylamino) -methyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 5- (methoxycarbonylamino-methyl) -2- (oxalyl-amino) -thiophene
-3-carboxylic acid; 2- (oxalyl-amino) -5- (phenoxycarbonylamino-methyl) -thiophene-3-carboxylic acid; 5-((2-nitro-phenylmethanesulfonylamino) -methyl) -2- (Oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((4-trifluoromethoxy-benzenesulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-(( 4-chloro-benzenesulfonylamino) -methyl) -2- (oxalyl-amino)-
Thiophene-3-carboxylic acid; 2- (oxalyl-amino) -5-((propane-2-sulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-((4-fluoro-benzenesulfonylamino)- Methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5- (methanesulfonylamino-methyl) -2- (oxalyl-amino) -thiophen-3
-Carboxylic acid; 5- (naphthalene-1-sulfonylamino) -methyl) -2- (oxalyl-amino) -thiophen-3-carboxylic acid; 5- (ethanesulfonylamino-methyl) -2- (oxalyl-amino) -Thiophene-3
-Carboxylic acid; 2- (oxalyl-amino) -5-((3-trifluoromethyl-benzenesulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-((4-acetylamino-benzenesulfonylamino) -Methyl) -2- (oxalyl-
Amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((propane-1-sulfonylamino) -methyl) -thiophen-3-carboxylic acid; 5-((4-t-butyl- (Benzenesulfonylamino) -methyl) -2- (oxalyl-amino
) -Thiophen-3-carboxylic acid; 5-((2-nitro-4-trifluoromethyl-benzenesulfonylamino) -methyl) -2-
(Oxalyl-amino) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((2,2,2-trifluoro-ethanesulfonylamino)-
Methyl) -thiophen-3-carboxylic acid; 2- (oxalyl-amino) -5-((2-phenyl-ethanesulfonylamino) -methyl)-
Thiophene-3-carboxylic acid; 5- (benzenesulfonylamino-methyl) -2- (oxalyl-amino) -thiophene
-3-carboxylic acid; or a pharmaceutically acceptable salt thereof. 18. The compound according to any one of claims 1 to 17, which acts as an inhibitor or modulator of protein tyrosine phosphatase. 19. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or an optical isomer including a racemic mixture thereof. A pharmaceutical composition comprising a mixture or tautomer together with one or more pharmaceutically acceptable carriers or diluents. 20. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or an optical isomer including a racemic mixture thereof. A pharmaceutical composition suitable for the treatment of type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity, comprising a mixture or a tautomer together with one or more pharmaceutically acceptable carriers or diluents. . 21. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or an optical isomer including a racemic mixture thereof. An immunodeficiency, including an autoimmune disease, a disease associated with dysfunction of the coagulation system, an allergic disease, including asthma, a bone, containing the mixture or tautomer together with one or more pharmaceutically acceptable carriers or diluents. Osteoporosis, proliferative disorders including cancer and psoriasis, diseases due to decreased or increased growth hormone synthesis or action, diseases due to decreased or increased synthesis of hormones or cytokines controlling growth hormone release and / or response, Alzheimer's disease And a pharmaceutical composition suitable for treating brain diseases including schizophrenia, and infectious diseases. 22. The pharmaceutical composition according to claim 19, 20 or 21, which is in an oral unit dosage form or a parenteral unit dosage form. 23. The method according to claim 14, wherein the compound is administered in a dose of about 0.05 to 1000 mg, preferably about 0.1 to 1000 mg.
22. Pharmaceutical composition according to claim 19, 20 or 21 which is administered in the range of 500 mg and in particular in the range of 50 to 200 mg. 24. A compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or a racemic mixture for use in therapy. An optical isomer, a mixture of optical isomers, or a tautomer. 25. The method according to claim 1, which is used therapeutically for treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity.
A compound according to claim 1, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or a mixture of optical isomers, including a racemic mixture, or a tautomer. 26. Immunodeficiency disorders including autoimmune disorders, disorders involving clotting system dysfunction, allergic disorders including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, reduced growth hormone synthesis or action. Or for treating or preventing diseases due to decreased or increased synthesis of hormones or cytokines controlling the release and / or response of growth hormone, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or an optical isomer including a racemic mixture. Mixtures or tautomers. 27. The compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, as a drug.
Or the use of an optical isomer or a mixture of optical isomers, including a racemic mixture, or a tautomer. 28. Use of a compound according to any one of claims 1 to 17 for preparing a medicament. 29. The method according to any one of claims 1 to 17, for preparing a drug suitable for treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance or obesity.
Use of a compound according to claim 1, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or a mixture of optical isomers, including a racemic mixture, or a tautomer. 30. Immunodeficiency disorders including autoimmune disorders, disorders involving clotting system dysfunction, allergic disorders including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, reduced growth hormone synthesis or action. Or drugs that are suitable for treating or preventing diseases caused by decreased or increased synthesis of hormones or cytokines that control the release and / or response of growth hormone, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases. For preparation, a compound according to any one of claims 1 to 17, or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable acid or base, or an optical isomer or an optical isomer comprising a racemic mixture. Use of mixtures or tautomers. 31. Type I diabetes, type II diabetes, decreased glucose tolerance, insulin resistance, which comprises administering an effective amount of the compound according to any one of claims 1 to 17 to a subject in need thereof. Treatment of gender or obesity. 32. An immunodeficiency, including an autoimmune disease, comprising administering an effective amount of a compound according to any one of claims 1 to 17 to a subject in need thereof.
Diseases involving coagulation system dysfunction, allergic diseases including asthma, osteoporosis, proliferative disorders including cancer and psoriasis, diseases due to reduced or increased growth hormone synthesis or action, growth hormone release and / or response. Methods for treating diseases due to decreased or increased synthesis of controlling hormones or cytokines, brain diseases including Alzheimer's disease and schizophrenia, and infectious diseases. 33. A method for preparing a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, in a galenic dosage form, in particular, type I diabetes, type II diabetes, impaired glucose tolerance, insulin. A method for producing a drug used in the treatment or prevention of resistance or obesity. 34. A process for preparing a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof in a galenic dosage form, in particular immunodeficiency including autoimmune diseases, function of the coagulation system. Diseases with insufficiency, allergic diseases including asthma,
Osteoporosis, proliferative disorders including cancer and psoriasis, diseases due to reduced or increased growth hormone synthesis or action, diseases due to reduced or increased synthesis of hormones or cytokines controlling growth hormone release and / or response, Alzheimer's disease A method for producing a drug used in the treatment or prevention of brain diseases including sickness and schizophrenia, and infectious diseases. 35. A novel feature or combination of features described herein. 36. A process for preparing a compound of formula 1 characterized by the following: a) Reacting the amino-substituted compound of formula (I) with an acid chloride of formula (II), wherein A, R ₁ , R ₂ , R ₃ , R ₄ , R ₁₆ and R ₁₇ are previously Defined)) or b) Reacting a carboxylic acid (I), a primary amine (II) and an aldehyde (Ill) with an isocyanide (IV), wherein R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are each independently Selected from the group consisting of hydrogen, C ₁ -C ₆ alkyl, aryl, aryl C ₁ -C ₆ alkyl, and wherein the alkyl and aryl groups are as defined above,
Optionally substituted or R ₁₂ , R ₁₃ , R ₁₄ and R ₁₅ are independently selected from: (Wherein Y represents the point of attachment of R ₁₂ , R ₁₃ , R ₁₄ , and R ₁₅ , and A ₁ , R ₁ , R _2, and R ₄ are as defined above): or c) The method wherein the four-component Ugi reaction described above (method b) proceeds by coupling any one of these components to a solid support, whereby synthesis is achieved in a combinatorial chemistry format. 37. Acts as a ligand, inhibitor or modulator of a molecule with a pTyr recognition unit, including a protein having an SH2 domain.
18. The compound according to any one of claims 17 to 17.