AU740425B2 - Modulators of proteins with phosphotyrosine recognition units - Google Patents

Modulators of proteins with phosphotyrosine recognition units Download PDF

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AU740425B2
AU740425B2 AU15667/97A AU1566797A AU740425B2 AU 740425 B2 AU740425 B2 AU 740425B2 AU 15667/97 A AU15667/97 A AU 15667/97A AU 1566797 A AU1566797 A AU 1566797A AU 740425 B2 AU740425 B2 AU 740425B2
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Farid Bakir
Xiaodong Cao
Adnan Mjalli
Sepehr Sarshar
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Ontogen Corp
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Description

WD 98/27065 PCT/US96/20508 Modulators of Proteins with Phosphotyrosine Recognition Units Field of the Invention The present invention relates to novel protein tyrosine phosphatase modulating compounds, to methods for their preparation, to compositions comprising the compounds, to their use for treatment of human and animal disorders, to their use for purification of proteins or glycoproteins, and to their use in diagnosis. The invention relates to modulation of the activity of molecules with phosphotyrosine recognition units, including protein tyrosine phosphatases (PTPases) and proteins with Srchomology-2 domains, in in vitro systems, microorganisms, eukaryoic cells, whole animals and human beings.
Background of the Invention Reversible phosphorylation of proteins is a prevalent biological mechanism for modulation of enzymatic activity in living organisms. Tonks et al., J. Biol. Chem., 263(14):6722-30 (1988). Such reversible phosphorylation requires both a protein kinase to phosphorylate a protein at a particular amino acid residue, and a protein phosphatase to remove the phosphate moieties. See generally, Hunter, Cell, 80:225-236 (1995). Recently, it has been estimated that humans have as many as 2000 conventional PK genes, and as many as 1000 PP genes. Id.
One major class of PK's/PP's the protein serine/threonine kinases and protein serine/threonine phosphatases have been shown to play critical roles in the regulation of metabolism. See generally, Cohen, Trends Biochem. Sci., 17:408-413 (1992); Shenolikar, Ann. Rev. Cell Biol., 10:55-86 (1994); Bollen et al., Crit. Rev.
Biochem. Mol. Biol., 27:227-81 (1992). As their name suggests, these enzymes phosphorylate and dephoshphorylate serine or threonine residues of substrate WO 98/27065 PCTIUS96/20508 2 proteins. Inhibitors of protein serine/threonine phosphatases and kinases have been described. See, MacKintosh and MacKintosh, TIBS, 19:444-448 (1994).
The protein tyrosine kinases/phosphatases comprise a second, distinct family of PK/PP enzymes of significant interest, and have been implicated in the control of normal and neoplastic cell growth and proliferation. See Fisher et al., Science, 253:401-406 (1991). Protein tyrosine kinase (PTK) genes are ancient in evolutionary origin and share a high degree of inter-species conservation. See generally Hunter and Cooper, Ann. Rev. Biochem., 54:897-930 (1985). PTK enzymes exhibit high specificity for tyrosine, and ordinarily do not phosphorylate serine, threonine, or hydroxyproline.
More than 75 members of the PTPase family have been identified in eukaryotes, prokaryotes, and even viruses. Tonks and Neel, Cell 87:365-368. Protein tyrosine phosphatases (PTPases) were originally identified and purified from cell and tissue lysates using a variety of artificial substrates, and therefore their natural functions and substrates were not obvious. However, their roles in cellular processes, including cell-cell contact and cell adhesion, and growth factor and antigen signaling events, have begun to be elucidated.
PTPases are generally grouped into two categories: those which have both an extracellular domain and an intracellular catalytic domain, the receptor PTPases (R- PTPases); and those which are entirely intracellular. For R-PTPases much effort has been directed at determining the function of the extracellular domain. Most of the R- PTPases contain extracellular domains which are structurally similar to domains found in known adhesion molecules; these domains include fibronectin type III repeats, immunoglobulin domains, and cadherin extracellular repeats. See generally Brady-Kalnay and Tonks, Curr. Opin. Cell. Biol. 7:650-657 (1995); Streuli, Curr.
Opin. Cell. Biol. 8:182-188 (1996). This homology with proteins known to be involved in adhesion suggested a role for these R-PTPases in regulating or mediating adhesion events. For several of the R-PTPases, this has now been demonstrated.
WO 98/27065 PCT/US96/20508 3 Cells form specialized structures at the sites of cell-cell contact (adherens junctions) and cell-extracellular matrix contact (focal adhesion). Multiple signal transduction molecules are recruited to these sites, including several PTK's; and these sites are characterized by increased protein tyrosine phosphorylation. These sites are impermanent, and are created and destroyed as required for cell mobility. As enhanced tyrosine phosphorylation is characteristic of the formation of adherens junctions and focal adhesions, it is likely that protein tyrosine dephosphorylation by PTPases serves to regulate the creation and destruction of the sites. Supporting this, several studies have shown that treatment with a general PTPase inhibitor (vanadate) resulted in increased focal adhesion formation and increased cell spreading. Volberg et al., The EMBO J. 11:1733-1742 (1992); Bennett et al., J. Cell Sci. 106:891-901 (1993). Importantly, the broadly-expressed LAR R-PTPase has been demonstrated to localize to focal adhesions, apparently via the LAR-interacting protein LIP. 1. Serra- Pages et al., The EMBO J. 14:2827-2838 (1995). As PTP5 and PTPo, both R- PTPases, also associate with LIP.1 [Pulido et al., Proc. Natl. Acad. Sci. 92:11686- 11690 (1995)], it is likely that these two phosphatases can also localize to focal adhesions. Most significantly, LAR only localized to the portion of the focal adhesion which is proximal to the nucleus, and is thought to be undergoing disassembly. Thus it is likely that these phosphatases act to negatively regulate focal adhesion formation, acting to enhance the destruction of the focal adhesion site.
R-PTPases may also act to positively regulate adhesion. Adherens junctions contain, among others, adhesion receptors termed cadherins which mediate cell-cell contact through homophilic binding; the cadherins associate with and ycatenins, intracellular proteins which interact with cortical actin. Association between cadherins and catenins serves to stabilize the adherens junction and to strengthen cellcell contact. See generally Cowin, Proc. Natl. Acad. Sci. 91:10759-10761 (1994).
Association of cadherin with p-catenin is decreased by tyrosine phosphorylation of pcatenin [Kinch et J. Cell. Biol. 130:461-471 (1995); Behrens et al., J. Cell. Biol.
120:757-766 (1993)]; moreover, treatment with the PTPase inhibitor vanadate inhibits WO 98/27065 PCTIUS96/20508 4 cadherin-dependent adhesion [Matsuyoshi et al., J. Cell. Biol. 118:703-714 (1992)].
Collectively, these data indicate that PTPase activity is critical in maintaining cadherin-mediated cell aggregation. The R-PTPases PTPR and PTPI associate intracellularly with cadherins, and colocalize with cadherins and catenins to adherens junctions [Brady-Kalnay et al., J. Cell. Biol. 130:977-986 (1995); Fuchs et al., J. Biol.
Chem. 271:16712-16719 (1996)]; thus PTP4l and PTPK are likely to enhance cadherin function by limiting catenin phosphorylation.
In addition to their catalytic function in regulating adhesion events, several R- PTPases have direct roles in mediating adhesion through their extracellular domains.
PTPK and PTPp mediate cellular aggregation through homophilic binding [Brady- Kalnay et al., J. Cell. Biol. 122:961-972 (1993); Gebbink et al., J. Biol. Chem.
268:16101-16104 (1993); Sap et al., Mol. Cell. Biol. 14:1-9 (1994)]. The neuronal PTP (which has also been called R-PTPP) binds to contactin, a neuronal cell recognition molecule; binding of PTP( to contactin increases cell adhesion and neurite outgrowth. Peles et al., Cell 82:251-260 (1995). A secreted splice variant of PTP (also known as phosphacan) binds the extracellular matrix protein tenascin [Barnea et al. J Biol. Chem. 269:14349-14352 (1994)], and the neural cell adhesion molecules N-CAM and Ng-CAM [Maurel et al., Proc. Natl. Acad. Sci. 91:2512-2516 (1994)]. As the expression of PTP is restricted to radial glial cells in the developing central nervous system, which are though to form barriers to neuronal migration during embryogenesis, it is likely that the interaction of PTP( with contactin, tenascin, N-CAM, and/or Ng-CAM acts to regulate neuronal migration. This has been demonstrated for a related R-PTPase, DLAR, in Drosophila [Krueger et al. Cell 84:611-622 (1996)].
Because tyrosine phosphorylation by PTK enzymes usually is associated with cell proliferation, cell transformation and cell differentiation, it was assumed that PTPases were also associated with these events. For several of the intracellular PTPases, this function has now been verified.
WO 98/27065 PCT/US96/20508 SHP1 (which has also been called SHPTP1, SHP, HCP, and PTP-1C [see Adachi et al., Cell 85:15 an intracellular PTPase which contains two aminoterminal phosphotyrosyl binding Src Homology 2 (SH2) domains followed by the catalytic PTPase domain, has been demonstrated to be an important negative regulator of growth factor signaling events. See generally Tonks and Neel, supra; Streuli, supra. In mice, loss of SHP1 function (the motheaten and viable motheaten phenotypes) causes multiple hematopoietic defects resulting in immunodeficiency and severe autoimmunity; culminating in lethality by 2-3 weeks or 2-3 months depending on the severity of SHPI deficiency. Although these mice have reduced numbers of hematopoietic cells, suggesting defects in development and maturation, those cells which survive and enter the periphery are characterized by hyper-responsiveness to growth factors and antigen. This observation suggested a role for SHPI in negative regulation of hematopoietic signaling events.
This has now been well-established for the erythropoietin receptor (EpoR), a member of the cytokine receptor family (which also includes the receptors for interleukins 2, 3, 4, 5, 6, 7; granulocyte-macrophage colony stimulating factor, and macrophage colony stimulating factor). SHPI associates via its SH2 domains with tyrosine-phosphorylated EpoR, causing dephosphorylation and inactivation of the EpoR-associated Janus kinase 2 and termination of the cellular response to erythropoietin. Klingmuller et al., Cell 80:729-738 (1995). Mutation of the tyrosine on the EpoR to which SHPI binds results in enhanced cell proliferation to erythropoietin in vitro [Klingmuller, supra]. In humans, mutation of the EpoR resulting in loss of association with SHPI causes autosomal dominant benign erythrocytosis, which is characterized by increased numbers of erythrocytes in the periphery and increased hematocrit. de la Chapelle et al., Proc. Natl. Acad. Sci.
90:4495-4499 (1993).
SHP1 also appears to be a negative regulator of the cellular response to colony stimulating factor-1 (CSF-1, a major macrophage mitogenic cytokine), as cells from viable motheaten and motheaten mice, which have reduced or absent SHP1 function, WO 98/27065 PCTIUS96/20508 6 are hyper-responsive to CSF-1 in vitro. Reduced SHP1 expression also results in increased cellular response to interleukin 3 [Yi et al., Mol. Cell. Biol. 13:7577-7586 (1993)]. Collectively, these observations suggest that SHP1 functions to limit the cellular response to cytokines and growth factors by reversing the tyrosine phosphorylation of key signaling intermediates in these pathways.
PTPases appear to play a homologous role in the insulin signaling pathway.
Treatment of adipocytes with the PTPase inhibitor vanadate results in increased tyrosine phosphorylation and tyrosine kinase activity of the insulin receptor (InsR), and enhances or mimics the cellular effects of insulin including increased glucose transport. See, Shisheva and Shechter, Endocrinology 133:1562-1568 (1993); Fantus, et al., Biochemistry 28:8864-8871 (1989); Kadota, et al., Biochem. Biophys.
Res. Comm. 147:259-266 (1987); Kadota, et al., J. Biol. Chem. 262:8252-8256 (1987). Transiently induced reduction in expression of two PTPases, the intracellular PTPase PTP- B and the R-PTPase LAR, resulted in similar increases in the cellular response to insulin. Kulas, et al., J. Biol. Chem. 270:2435-2438 (1995); Ahmad et al., J. Biol. Chem. 270:20503-20508 (1995). Conversely, increased cellular expression of several PTPases (PTPa, PTPE, CD45) in vitro has been demonstrated to result in diminished InsR signaling [see, Moller, et al., J. Biol. Chem. 271:23126-23131 (1995); Kulas et al., J. Biol. Chem. 271:755-760 (1996)]. Finally, increased expression of LAR was observed in adipose tissue from obese human subjects [Ahmad, et al., J. Clin. Invest. 95:2806-2812 (1995)]. These data provide clear evidence that PTPases negatively regulate the insulin signaling pathway.
While many of the PTPases function to negatively regulate cellular metabolism and response, it is becoming increasingly evident that PTPases provide important positive signaling mechanisms as well. Perhaps the best example of such a positive regulator is the hematopoietic R-PTPase CD45. See generally Streuli, supra; Okumura and Thomas, supra; Trowbridge, Annu. Rev. Immunol. 12:85-116 (1994).
is abundantly expressed on the cell surface of all nucleated hematopoietic cells, in several alternative splice variants. T and B lymphocytes which lack WO 98/27065 PCTIUS96/20508 7 expression are incapable of responding normally to antigen, suggesting that CD45 is required for antigen receptor signaling. Genetically engineered mice which lack expression of CD45 exhibit severe defects in T lymphocyte development and maturation, indicating an additional role for CD45 in thymopoiesis. The major substrates for CD45 appear to be members of the Src family of PTK's, particularly Lck and Fyn, whose kinase activity is both positively and negatively regulated by tyrosine phosphorylation. Lck and Fyn isolated from CD45-deficient cells are hyperphosphorylated on negative regulatory tyrosine residues, and their PTK activity is reduced. As CD45 can dephosphorylate and activate purified Lck and Fyn in vitro, these data suggest that CD45 maintains the activity of Lck and Fyn in vivo through dephosphorylation of these negative regulatory tyrosines and that this is an important mechanism for maintaining lymphocyte homeostasis.
A second PTPase which is now believed to play an important positive role in signal transduction is the intracellular, SH2-domain-containing SHP2 (which has also been called SHPTP-2, SHPTP-3, syp, PTP2c, and PTP-1D [Adachi, et al., supra]).
See generally Saltiel, Am. J. Physiol. 270:E375-385 (1996); Draznin, Endocrinology 137:2647-2648. SHP2 associates, via its SH2 domains, with the receptor for plateletderived growth factor (PDGF-R), the receptor for epidermal growth factor (EGF-R), with the insulin receptor, and with the predominant substrate of the InsR, insulin receptor substrate 1 (IRSI). Bennett, et al., Proc. Natl. Acad. Sci. 91:7335-7339 (1994); Case, et al., J. Biol. Chem. 269:10467-10474 (1994); Kharitonenkov, et al., J.
Biol. Chem. 270:29189-29193 (1995); Kuhne, et al., J Biol. Chem. 268:11479-11481 (1993). SHP2 PTPase activity is required for cellular response to EGF and insulin, as competitive expression of inactive forms of SHP2 results in diminished signaling events and reduced cellular responses to EGF and insulin. Milarski and Saltiel, J.
Biol. Chem. 269:21239-21243 (1994); Xiao et al., J. Biol. Chem. 269:21244-21248 (1994); Yamauchi et al., Proc. Natl. Acad. Sci. 92:664-668 (1995). The relevant substrate(s) for the PTPase domain of SHP2 is not known.
WO 98/27065 PCTfUS96/20508 8 Due to the fundamental role that PTPases play in normal and neoplastic cellular growth and proliferation, a need exists in the art for agents capable of modulating PTPase activity. On a fundamental level, such agents are useful for elucidating the precise role of protein tyrosine phosphatases and kinases in cellular signalling pathways and cellular growth and proliferation. See generally MacKintosh and MacKintosh, TIBS, 19:444-448 (1994).
More importantly, modulation of PTPase activity has important clinical significance. For example, PTP-1B overexpression has been correlated with breast and ovarian cancers [Weiner et al., J. Natl. Cancer Inst., 86:372-8 (1994); Weiner et al., Am J. Obstet. Gynecol., 170:1177-883 (1994)], and thus agents which modulate PTP-1B activity would be helpful in elucidating the role of PTP-1B in these conditions and for the development of effective therapeutics against these disease states. The important role of CD45 in hematopoietic development and T lymphocyte function likewise indicates a therapeutic utility for PTPase inhibitors in conditions that are associated with autoimmune disease, and as a prophylaxis for transplant rejection. The antibiotic suramin, which also appears to possess anti-neoplastic indications, has recently been shown to be a potent, irreversible, non-competitive inhibitor of CD45. See Ghosh and Miller, Biochem. Biophys. Res. Comm. 194:36-44 (1993). The negative regulatory effects of several PTPases on signaling through receptors for growth factors and cytokines, which are implicated in normal cell processing as well as disease states such as cancer and atherosclerosis, also indicate a therapeutic potential for PTPase inhibitors in diseases of hematopoietic origin.
The PTPase Yop2b is an essential virulence determinant in the pathogenic bacterium Yersinia, responsible for bubonic plague. Bliska et al., Proc. Natl. Acad Sci. USA, 88:1187-91 (1991), and thus an antimicrobial indication exists for PTPase inhibitor compounds, as well.
PTPases have been implicated in diabetic conditions. Experiments with one family of PTPase inhibitors, vanadium derivatives, indicate a therapeutic utility for such compounds as oral adjuvants or as alternatives to insulin for the treatment of WO 98/27065 PCr/US96/20508 9 hyperglycemia. See Posner et al., J. Biol. Chem., 269:4596-4604 (1994). However, such metal-containing PTPase inhibitors act in a fairly non-specific fashion and act with similar potencies against all PTPase enzymes.
In addition to vanadium derivatives, certain organic phosphotyrosine mimetics are reportedly capable of competitively inhibiting PTPase molecules when such mimetics are incorporated into polypeptide artificial PTPase substrates of 6-11 amino acid residues. For example, a "natural" (phosphorylated tyrosine) PTPase substrate, which may be depicted by the Formula: 0
P
HO I
OH
H
N-
N
H
0 has been mimicked by eleven-mer oligopeptides containing phosphonomethyl phenylalanine (Pmp), as depicted by the schematic Formula: 0
P
HO I
OH
H
N-
"N
N
H
0 See Chatterjee et al., "Phosphopeptide substrates and phosphonopeptide inhibitors of protein tyrosine phosphatases," in Peptides: Chemistry and Biology (Rivier and Smith, Eds.), 1992, Escom Science Publishers: Leiden, Netherlands, pp. 553-55; Burke et al., Biochemistry, 33:6490-94 (1994). More recently, Burke et al., Biochem.
Biophys. Res. Comm. 204(1):129-134 (1994) reported that a particular hexameric peptide sequence comprising a Pmp moiety or, more preferably, a phosphonodifluoromethvl phenvlalanine (F 2 Pmp, moiety. as depicted by the schematic Formula: F F 0 p
HO'I
OH
H
N
competitively inhibited PTP-113. However. such hexapeptude inhibitor-, nonetheless possess drawbacks for PTPase m odulation in nw More particularly, the hcxapeptide inhibitors described by Burke et al. are sufficiently large and anionic to potentially a:...:inhibit efficient. migration across cell membranes. for interaction with the catalytic domains of transmembrane and intracellular PTPase enzvmes which liewihnacl a.membrane. A need exists for small. orLanic -molecule based PTPase inhibitors havingz fewer anionic moieties, to facilitate migration across cell membranes.
For all of the foreizoing reasons. a need exists in the art for nlovel compounds effective for modulatingz. and especially inhibiting. the Phosphatase activity of protein tyrosine phosphatase molecules.
Any discussion of the prior art throughout the specification shoulId in no way be, considered as an admission that such prior art is widely known 'or forms part of common general knowledge in the field.
SUMMarv of the Invention Tihe invention provides compounds and derivatives. thereof useful for modulating. and especially inhibiting, the phosphatase activity of* one or more protein tyrosine phosphatase (PTPase) and'or dual specificity phosphatase enzymes. In one embodiment, the present invention relates to compounds having the general structure shown in Formula (Al):
PAQ
lkT O 11 (Al) wherein X and Y are defined below. The invention further provides salts, esters, prodrugs, solvates, and the like of the compounds, and compositions comprising these compounds.
According to a first aspect, the present invention provides a protein tyrosine phosphatase activity-modulating compound with the structure depicted in Formula
X-C(R')=C(R")COOR..
10 wherein R'and R" are independently selected from the group consisting of hydrogen, halo, cyano, itro, trihalomethyl, C 111 Ialky1, optionally substituted aryl C 111 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, itro, cyano, trihalomethyl, hydroxypyronyl, CI- 11 alkyl, aryl C 111 alkyl, CO- 15 ,alkyloxyC,,_,alkyl, aryl C 0 11 alkyloxy C 011 alkyl, C 0 11 alkylthioC 011 alkyl, arylC 0 i 1 alkylthioC 011 alkyl, C 011 alkylaminoC 11 alkyl, arylC 011 alkylaminoC.
11 alkyl, di(arylCj_ 11 alkyl)aminoC.
11 atkyl, C 111 alkylcarbonylC.
11 alkyl, arylC 111 alkylcarbonylC 11 alkyl, C,.
I
1 alkylcarboxyC 11 alkyl, arylCl-, 1 alkylcarboxyC 11 ,alkyl, C 1 11 alkylcarbonylaminoC 0 11 alkyl, arylC 1 ,alkylcarbonylaminoC 1 1 alkyl, C 011 alkylCOOR 1
-C
0 11 alkylCONR 2
R
3 wherein R 2 and R, are independently selected from hydrogen, C 1 -C,,alkyl, aryl Co- C,,allcyl, or R 2 and R 3 are taken together -Ilawith the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 alkyl, arylC 0 -C I Ialkyl substituent.
(ii) is selected from the group consisting of hydrogen
C
1 1 alkyl, substituted alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofluryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO- 11 alkyloxy, arylC 011 ,alkyloxy, C 0 1 1 alkylthio, arylC 0 1 1 alkylthio, C 011 alkylamino, arylC 0 11 alkylamino, di(arylC., 1 alkyl)amino, C 1 11 alkylcarbonyl, arylC 1 alkylcarbonyl, C,~ ,alkylcarboxy, arylC,- 1 alkylcarboxy, C 1 11 alkylcarbonylamino, arylC 1 1 alkylcarbonylamnino, -C 0 1 alkylCOOR 4
-C.
11 alkylCOR 5 R wherein R 5 and R 6 are independently selected from hydrogen, C,-C,,alkyl, arylC,-C 11 aikyl, or R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, 1 ,alkyl, arylC 0 -C 1 ,alkyl substituent.
i mono-, di- and tri-substituted arylC 0 -C,,alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted. aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fluryl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, 'PR A L hT -Ilb pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinoliz inyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl., acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a second aspect, the present invention provides a compound with the structure depicted in Formula (A2): 0
R
2 w h r i t l a t o e o R n 3 (A 2) whri alesonof RI, RanR3substituents has the general structure depicted in Formula (B)
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 111 alkyl, optionally substituted aryl C 1 11 .alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 1 alkyl, aryl Cl-, 1 alkyl, Co- 1 alkyloxyC 01 1 ialkyl, aryl Co- 1 allcyloxy Co- 1 alkyl, C 0 i 1 alkylthioCo 11 alkyl, arylC.
11 alkylthioC 01 1 alkyl, C 011 alkylaminoC 0 1 1 alkyl, arylC 0 1 alkylaminoC.
1 alkyl, di(arylC.
1 1 allcyl)aminoC..
1 alkyl, Cl- 1 alkylcarbonylC.
1 ailkyl, arylC 111 alkylcarbonylC.
11 alkyl, C 1 1 allcylcarboxyC..
11 alkyl, arylC 1 1 alkylcarboxyC 0 l 1 alkyl, C 1 allcylcarbonylaminoC 0 1 1 allcyl, aryiC 1 alkylcarbonylaminoC,, 1 alkyl, C,, lalkylCOOR 4
-C
0 11 alkylCONR 5
R
6 wherein R 4 R, and R 6 are independently selected from hydrogen, C,-C,,alkyl, arylC 0
-C
11 alkyl, or R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-C 11 alkyl, arylC 0 -C,,allcyl substituent.
(ii) is selected from the group consisting of hydrogen
C
111 alkyl, substituted CI 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, Co- 15 1 alkyloxy, arylC 011 alkyloxy, C 0 11 alkylthio, arylC 0 11 alkylthio, C 011 alkylamino, arylC 0 .1 1 alkylarnino, di(arylC.
11 alkyl)amino, C 111 alkylcarbonyl, aryiC,-,,alkylcarbonyl, C, 1 1 alkylcarboxy, arylC,- 1 alkylcarboxy, C,, 1 alkylcarbonylamino, arylC, I ,alkylcarbonylamino, 1 alkylCOOR 7 IalkylCONR 8
R
9 wherein R 7 R, and P.9 are independently selected from hydrogen, C 1
-C,
1 alkyl, arylC 0
-C
1 1 alkyl, or R, and R.
9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C, 1 alkyl, arylC 0 -C,,alkyl substituent.
0*
C..
0.
0 0 000000 0 0 *000 *0 0 0 0 *0 0*0* 0 0 9 0 *0 0 ~0 9* ldmono-, di- and tni-substituted arylC 0 ,-C,,alkyl wherein the aryl sub stituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, 10 cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, 15 and wherein the remaining of R 2 and R 3 are independently selected from the group consisting of: hydrogen; (ii) C 111 alkyl, substituted C,- 11 alkyl wherein the alkyl substituents are defined as above, (iii) arylC,.
11 alkyl, (iv) mono-, di- and tni-substituted aryl C 0 ,-C,,alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof Ile According to a third aspect, the present invention provides a compound with the structure depicted in Formula (A3): 0 RI 1 I NHR2 0 wherein at least one of R 1
R
2 and R 3 sub stituents has the general structure depicted in 5 Formula (B)
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, 10 halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted aryl C 1 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 11 alkyl, aryl C 1 11 alkyl, Co- ,,alkyloxyC.
1 1 alkyl, aryl C 0 1 alkyloxy C 01 alkyl, Co 1 alkylthioC.
1 alkyl, arylC 0 11 alkylthioC.
1 alkyl, C 0 1 alkylaminoC.
1 alkyl, arylC.
1 1 alkylaminoC.
1 1 alkyl, di(arylC,.
11 akyl)aminoC.
11 alkyl, C 1 11 alkylcarbonylC.
11 alkyl, arylC.
11 alkylcarbonylC.
11 alkyl, C, 11 alkylcarboxy 0 11 alkyl, arylC.
11 alkylcarboxyC.
11 alkyl, C 11 1 allcylcarbonylaminoC 0 ,,alkyl, arylC,.
1 alkylcarbonylaminoC.
11 alkyl, C 0 1 1 alkylCOOR 4
-C
0 11 atkylCONkRR 6 wherein R, and R, are in dependently llfselected from hydrogen, C, -C alkyl, arylC 0
,-C
11 alkyl, or R, and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
-C
1 1 alkyl, arylC 0 -Cl 1 alkyl substituent.
(ii) is selected from the group consisting of hydrogen alkyl, substituted alkyl wherein the substituents are 66. independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, ~*'tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0
I
1 alkyloxy, arylC 0 11 alkyloxy, C 011 ,alkylthio, arylC 0 11 Ialkylthio, C 011 alkylamnino, arylC 0 1 alkylamino, di(arylC 0 11 ,alkyl)amino, C 1 1 alkylcarbonyl, arylC 1 1 alkylcarbonyl, C,_ 11 alkylcarboxy, arylC.
11 alkylcarboxy, C 111 alkylcarbonylamino, arylC,_ 1 alkylcarbonylamino, -C 011 alkylCOjR 7
-C
01 1 jalkylCONR 8 R, wherein R7 R. n R 8 r independently selected from hydrogen, CI-C 11 allcyl, arylC 0 -Clialkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system 15 containing 3 to 8 carbon atoms with at least one C,-C 11 alkyl, arylC 0 -C,,alkyl substituent, mono-, di- and tri-substituted arylC 0
-C
1 1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuiryl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuiranyl, pyrrolyl, hgindolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, and wherein the remaining of R 2 and R 3 are independently selected from the group consisting of: hydrogen; (ii) C,, 1 alkyl, substituted C 111 alkyl, C 111 alkylcarbonyl, substituted C 1 1 alkylcarbonyl wherein the alkyl substituents are defined as above, (iii) arylC 011 alkyl, arylC 11 alkycarbonyl, mono-, di- and tni-substituted aryl C 0 ,-C,,alkyl, mono-, di- and tnisubstituted arylC 0
-C
1 1 alkylcarbonyl wherein the aryl substituents are defined as above, its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof According to a fourth aspect, the present invention provides a compound with the structure depicted in Formula (A4): 0
OH
(AM)
llhwherein at least one of R 1 R, substituents has the general structure depicted in Formula
(B)
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl., C 1 1 alkyl, optionally substituted aryl C,-,,alkyl wherein the aryl sub stituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, Cl- 11 alkyl, aryl C 111 alkyl, Co- 0 1 akloyC 1 alkyl, aryl C 011 ,alkyloxy C 011 ,alkyl, C 011 ,alkylthioC 01 1 alkyl, arylC 0 0 HalkylthioC 011 alkyl, C 0 1 1 alkylaminoC 01 1 alkyl, arylC 011 ,alkylaminoC.
11 alkyl, di(arylC 1 lialkyl)aminoC 0 11 alkyl, alkylcarbonylCo 11 alkyl, arylC 1 11 alkylcarbonylC 11 Ialkyl, C, 11 alkylcarboxyC 11 alkyl, arylC 111 alkylcarboxyC 11 alkyl, C 1 11 alkylcarbonylaminoC 0 1 alkyl, arylC 1 ,alkylcarbonylaminoC 11 ,alkyl, C 0 11 alkylCOOR 3
-C
01 1 alkylCONR 4
R
'00000 15 wherein R 3
R
4 and R, are in dependently selected from hydrogen, C,-C,,alkyl, arylC 0 0: C I ,alkyl, or R 4 and R, are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C, alkyl, arylC 0
,-C
1 1 alkyl substituent.
(ii) is selected from the group consisting of hydrogen, alkyl, substituted C,, 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, liitetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO- 11 alkyloxy, arylC 0 1 1 alkyloxy, C 01 alkylthio, arylC 01 alkylthio, C 0 11 alkylamino, arylC 0 11 alkylamino, di(arylC 01 1 ,alkyl)amino, 1 alkylcarbonyl, arylC 11 1 alkylcarbonyl, C 1 ,,alkylcarboxy, aryiC,, alkylcarboxy, C 1 1 alkylcarbonylamino, aryiC 1 lalkylcarbonylamino, -C 0 11 alkylCOOR 6
-C
01 1 alkylCONR 7
R
8 wherein R 6 R7, and R 8 are independently selected from hydrogen, C,-C,,alkyl, arylC 0 -Cl 1 alkyl, or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic system **containing 3 to 8 carbon atoms with at least one C 1 alkyl, arylC 0 -C 1 ,alkyl substituent, mono-, di- and tni-substituted arylC 0
-C
1 1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofiiranyl, isobenzofuiranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, llj and wherein the remaining of R 1
R
2 is selected from the group consisting of: hydrogen; (ii) C,,alkyl, substituted C,-,alkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 alkyl, (iv) mono-, di- and tri-substituted aryl Co-C, alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a fifth aspect, the present invention provides a compound with the 10 structure depicted in Formula 0 SRI_ R 2
O
S(A5) o S:o: wherein at least one of R 2 substituents has the general structure depicted in Formula
(B)
')COOR
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 ,,,alkyl, optionally substituted aryl C.,,alkyl wherein the aryl substituents are independently selected from the group consisting of -ilkhydrogen, halo, nitro, cyano, trihalomnethyl, hydroxypyronyl, C,_ 11 alkyl, aryl C 1 11 ,alkyl,
C,-
1 alkyloxyC 01 1 ,alkyl, aryl C 011 alkyloxy C 01 1 alkyl, C 011 ,alkylthioC 11 jalkyl, arylC 0 l 1 alkylthioC 011 alkyl, C 011 alkylamninoCQ 1 1 alkyl, arylC 11 alkylaminoC 11 jalkyl, di(arylC 1 11 alkyl)aminoC 11 alkyl, C,, 1 alkylcarbonylC 11 ~aikyl, aryiC 1- 1 alkylcarbonylC 1 1 alkyl, C,- 1 alkylcarboxyC 01 1 alkyl, arylC 1 l alkylcarboxyC.
11 alkyl, C 111 alkylcarbonylamninoC 0 1 alkyl, arylC 111 alkylcarbonylaminoC 1 1 alkyl, C 011 alkylCOOR 3
-C
0 1 1 alkylCONRR wherein R 3 R, and R 5 are in dependently selected from hydrogen, C 1 alkyl, arylC 0 I I 1 alkyl, or R, and R, 5 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 1 1 alkyl, arylC 0 -C I Ialkyl substituent.
(ii) is selected from the group consisting of hydrogen,
CI
1 alkyl, substituted C,-,,alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamnoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, Co- 11 alyoy arC 1 1 alkyloxy, C 0 1 1 alkylthio, arylC.
1 1 alkylthio, C 01 alkylamnino, arylC 0 Ialkylarnino, di(arylC.
11 alkyl)amnino, C 1 11 alkylcarbonyl, arylC 1 alkylcarbonyl, C, Ilalkylcarboxy, arylC.
11 alkylcarboxy, C 1 11 alkylcarbonylamino, arylC 1 1 alkylcarbonylamino, -C 0 1 1 alkylCOOR 6
-C
0 1 alkylCONRR 8 wherein R 6
P.
7 and R 8 are independently selected from hydrogen, C,-C, 1 alkyl, arylC 0
-C
1 1 alkyl, or R 7 and R. are taken together with the nitrogen to which 111they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
I-C
1 alkyl, arylC,-C 1 alkyl sub stituent.
mono-, di- and tri-substituted arylC 0
-C
11 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaplithyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuaryl, pyranyl, benzoturanyl, isobenzoturanyl, 2,3-dihydrobenzottiranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, beuzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, 15 benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, and wherein the remaining of R 1
R
2 is selected from the group consisting of: hydrogen; (ii) C 1 11 alkyl, substituted C 1 11 alkyl wherein the alkyl substituents are defined as above, (iii) arylC.-.
1 alkyl, urn- (iv) mono-, di- and tni-substituted aryl C 0 ,-C,,alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a sixth aspect, the present invention provides a compound with the structure depicted in Formula (A6): 1R 2 (A6) wherein at least one of R 1
R
2
R
3 and R 4 substituents is a 1 ,4-benzodioxanyl or has the general structure depicted in Formula (B) ~wherein Eis -0or-H
(B)
~e :wherein R' and R' are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 111 alkyl, optionally substituted aryl C,-,,alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 11 1 ,alkyl, aryl CI- 11 alkyl, CO- ,,alkyloxyC.
11 alkyl, aryl C 011 alkyloxy C 0 11 alkyl, C 011 ,alkylthioC.
11 alkyl, arylC 0 ,,alkylthioC.
11 alkyl, C 011 alkylaminoC 0 1 1 ialkyl, arylC 11 alkylaminoC 0 1 1 alkyl, di(arylC,- 11 alkyl)aminoC.
11 alkyl, C 1 1 1 alkylcarbonylC 0 jjalkyl, arylCl-, 1 alkylcarbonylC 11 ,alkyl, C,.
1 alkylcarboxyC 0 11 alkyl, aryiC 1 alkylcarboxyC 1 1 alkyl, C 11 alkylcarbonylaminoC 0 I Ialkyl, llnarylC 11 1 alkylcarbonylaminoC.
11 alkyl, C 011 allcylCOOR 5
-C
0 1 alkylCONR 6
R
7 wherein
R
5
R
6 and R, are independently selected from hydrogen, C,-C,,alkyl, arylCO-Cl 1 alkyl, or
R
6 and R 7 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C I Ialkyl, arylC 0
C
1 1 alkyl substituent.
(ii) "is selected from the group consisting of hydrogen,
C,-C
1 1 alkyl, substituted C,-C 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomnethyl, carbamoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO_ I, alkyloxy, arylC.
11 alkyloxy, C 011 Ialkylthio, arylC 01 1 alkylthio, C 0 11 alkylamnino, arylC 0 1 ,alkylamino, di(arylCO 1 -,alkyl)amino, C 111 alkylcarbonyl, arylC,- 1 alkylcarbonyl, C, I I alkylcarboxy, arylC, ,alkylcarboxy, C 11 I alkylcarbonylamino, aryiCI
-C
0 11 alkylCOOR 8 IalkylCONR 9
R
0 wherein R 8
R
9 and RIO are independently selected firom hydrogen, 1 alkyl, arylC 0 Ialkyl, or R 9 and RIO are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -C,,alkyl, arylCO-C,,alkyl substituent, mono-, di- and tri-substituted arylC 0
,-C
1 1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, lbfluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobeuzofuranyl, 2,3-dihydrobenzofuiranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl., phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxanyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl, or hydroxyl, 2 3 adR r neednl eetdfo h wherein the remaining of R, R2R3adRarinenetlslcedfoth group consisting of: hydrogen; (ii) C 1 1 1 alkyl, substituted C,- 11 alkyl wherein the alkyl substituents are defined *as above, (iii) arylC 0 11 ,alkyl, mono-, di- and tni-substituted aryl C 0 ,-C,,alkyl wherein the aryl substituents are defined as above, with the proviso that when R 3 and R 4 are selected from substituted phenyl or substituted fliryl then the phenyl and furyl substituents exclude hydroxy, halo, trifluoromethyl, CI- 6 alkyl, C 1 6 alkyloxy, C 1 6 alkylthio, amino, C, 6 alkylamino, di(C 1 6 alkyl)amino, phenyl C 1 6 alkylamnino and di(phenyl CI- 6 alkyl)amino, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a seventh aspect, the present invention provides a compound with the structure depicted in Formula (A6): liP (A6) wherein R 4 is selected from -COR., -COOR 6
-CONR
7
R
8 wherein R 5 thru R. are independently selected from hydrogen, C,-C 1 lkyl, substituted C 1 1 alkyl where the alkyl.
substituents are as defined below, optionally substituted aryl C 0
,-C
11 alkyl where the aryl substituents are as defined below, or R 7 and R. are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C, 1 alkyl, arylC 0 alkyl substituent, and wherein at least one of R 2 and R, substituents has the general structure depicted in Formula (B) 10 (B) .99. wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C,- 11 alkyl, optionally substituted aryl C 14 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, Cl- 11 alkyl, aryl C 1 11 alkyl, Co- IlalkyloxyC- 1 1 alkyl, aryl C 011 alkyloxy C 011 alkyl, C 0 1 1 alkylthioC 0 11 alkyl, arylC 0 11 alkylthioC 011 alkyl, C 0 1 alkylaminoC.
1 ailkyl, arylC 0 1 alkylaminoC 11 alkyl, di(arylC,- 11 allcyl)aminoC 011 alkyl, C 1 11 alkylcarbonylC.
1 alkyl, arylC.
11 alkylcarbonylC 11 alkyl, C 1 ,,alkylcarboxyC.
1 1 alkyl, arylC.
11 alkylcarboxyC.
1 1 alkyl, C,.
llq lallylcarbonylaminoC 11 lalkyl, arylC 1 1 alkylcarbonylaminoC., 1 1alkyl, C 0 11 alkylCOOR 9
-C
0 1 alkylCONR 0
R
1 I wherein R 9
R
10 and are independently selected from hydrogen, C, ,alkyl, arylC 0 -C I Ialkyl, or R, 0 and are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C,,alkyl, arylC 0
,-C
11 alkyl substituent.
(ii) R...is selected from the group consisting of hydrogen
C
1 1 alkyl, substituted alkyl wherein the substituents are .independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO- 1 alkyloxy, arylC 0 .,,alkyloxy, C 0 1 ,alkylthio, arylC 0 .,,alkylthio, C 011 alkylaino, arylC 0 1 alkylamino, di(arylC.
11 alkyl)amino, C 1 alkylcarbonyl, aryiC 1 alkylcarbonyl, C,.
1 alkylcarboxy, arylC 1 1 alkylcarboxy, C,-I alkylcarbonylamino, arylC, ,alkylcarbonylamino, alkylCOOR 2
-C
0 1 alkylCONR1 3
RI
4 wherein R,2 R, 3 and R4 are independently selected from hydrogen, Cl-Cl 1 alkyl, arylC 0
-C
11 atkyl, or R1 3 and R 14 *.:are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C, alkyl, arylC 0 -C I, alkyl substituent.
mono-, di- and tni-substituted arylC 0
-C,
1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, 4* C
C
C
4* C
C.
*0 C Cc.
C.
C C
C
CCCII
C C C
C
C
*9*C@e C C
C
C
CCC.
C
C
*C
C S C
C.
CC..
C
C
C.
C C C C
C.
CC C C C 6 CC 6 lir fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, 10 and wherein the remaining of R 2 and R 3 are independently selected from the group consisting of: hydrogen; (ii) 1 alkyl, substituted C,- 11 alkyl wherein the alkyl substituents are defined as above, 15 (iii) arylC 0 11 ,alkyl, (iv) mono-, di- and tri-substituted aryl C 0 ,-C,,alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to an eighth aspect, the present invention provides a compound with the structure depicted in Formula (A6): us- (A6) wherein either R(3 or R(4 is independently selected from -C0R 5
-COOR
6
-CONRR
8 wherein R, thru R 8 are independently selected from hydrogen, Cl-C,,alkyl, substituted C,-,,alkyl where the alkyl. substituents are as defined below, optionally substituted aryl
C
0
,-C
11 alkyl where the aryl substituents are as defined below, or R 7 and R8 are taken *..together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 11 alkyl, arylC 0 -C,,alkyl substituent, and wherein at least one of R2 and R(4 substituents has the general structure depicted in ash.:Formula (B) 10 )COOR..
(B)
~.wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 11 1 alkyl, optionally substituted aryl C 11 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, Cl-,,alkyl, aryl C 1 11 alkyl, Col 1 alkyloxyC 011 Ialkyl, aryl C 01 1 alkyloxy C 011 alkyl, C 0 11 alkylthioC 11 alkyl, arylC 0 11 alkylthioC 011 alkyl, C 011 ,alkylaminoC 0 11 alkyl, arylC 011 alkylaminoC.
1 1 alkyl, di(arylC,- ,alkyl)aminoCO- 11 alkyl, C 11 alkylcarbonylC 11 alkyl, arylC 111 alkylcarbonylC 11 ,alkyl, C,.
1 alkylcarboxyC.
11 alkyl, arylCl- 1 alkylcarboxyC..
1 1 alkyl, C.lit 1 alkylcarbonylaminoC 1 1 ,alkyl, arylC 1 11 lalkylcarbonylaminoC.
11 alkyl, C 011 alkylCOOR 9 alky1CONR 0
R
1 wherein R 9
R
10 and are independently selected from hydrogen,
C
1
-C
11 alkyl, arylC 0
-C
11 alkyl, or R 10 and R 11 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 1 1 alkyl, arylC 0 ,-Cl 1 alkyl substituent.
(ii) R...is selected from the group consisting of hydrogen,
C
11 1 alkyl, substituted C 11 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamnoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, COlalkyloxy, arylC- 1 1 alkyloxy, C 01 1 Ialkylthio, arylC 01 1 alkylthio, C 01 1 alkylamino, arylC 0 1 alkylamino, di(arylC 1 1 alkyl)amino, C 111 alkylcarbonyl, arylCl-,,alkylcarbonyl, C, 1 alkylcarboxy, arylC 1 1 1 ,alkylcarboxy, C,.
1 alkylcarbonylamino, arylC,_ li jalkylCOOR12 -C 11kyCORTR, wherein RI R13adR, are independently selected from hydrogen, C,-C,,alkyl, arylC 0 -Cl 1 alkyl, or R, 3 and R 14 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 1 1 alkyl, arylC 0
-C
1 1 alkyl substituent.
mono-, di- and tni-substituted arylC 0
-C
11 alkyl wher ein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, llufluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuiryl, pyranyl, benzofuiranyl, isobenzofuranyl, 2,3-dihydrobenzofuiranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or .::thiadiazolyl, and wherein the remaining of R 2 and either R 3 or Rare independently selected from the group consisting of: hydrogen; (ii) C 1 1 alkyl, substituted C,-,,alkyl wherein the alkyl substituents are defined as above, arylC 0 11 ,alkyl, mono-, di- and tri-substituted aryl C 0
-C
11 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a ninth aspect, the present invention provides a compound with the structure depicted in Formula (A7): liv- (A7) wherein R 2 is selected from -COR 5 -COOR,, -CONR 7 R, wherein R, thni R 8 are V. independently selected from hydrogen, C,-C,,alkyl, substituted C 111 ,alkyl where the alkyl 2:5 substituents are as defined below, optionally substituted aryl C 0
-C
1 1 alkyl where the aryl substituents are as defined below, or R 7 and R, are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 alkyl, arylC 0 ,alkyl substituent, and wherein at least one of R, and R 3 substituents has the general structure depicted in Formula (B)
(B)
*wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted aryl C 1 11 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 111 alkyl, aryl C 11 1 alkyl, Co- 11 alkyloxyC 011 alkyl, aryl Co-.
1 alkyloxy Co- I ,alkyl, Co- I IalkylthioC.
1 I alkyl, arylC 1 11 alkylthioC.
11 alkyl, C 011 alkylaminoC 01 1 alkyl, arylC.
1 alkylaminoC 11 alkyl, di(arylC 1 11 alkyl)aminoC 11 'alkyl, C 1 1 alkylcarbonylC 11 alkyl, arylC 1 ,,alkylcarbonylC 1 1 alkyl, C, -11w- 11 alkylcarboxyC.
11 alkyl, arylC 111 alkylcarboxyC 11 alkyl, C 1 11 alkylcarbonylaminoC 0 11 alkyl, arylCl.
1 alkylcarbonylaminoC 1 1 lalkyl, CO 11 allcylCOOR 9 -CcO.iialkylCONR 0 wherein R 9 and are independently selected from hydrogen, CI-Cl 1 alkyl, arylC 0 C 1 ,alkyl, or RI, and are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 1 1 alkyl, arylC 0 1 alkyl substituent.
(ii) is selected from the group consisting of hydrogen,
()C
1 alkyl, substituted C 1 11 alkyl wherein the substituentsar independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, terhdotrl .*rldnl ieiiymrhlnypprznl yrxprnl o ,etakydrmio, prdinaC,,lyl ipriinl, moaronyl, piperazin, hlydcrxponyl, C 1 alkylcarboxy, arylCl- 1 alkylcarboxy, C,, 1 alkylcarbonylamino, arylC,_ 0 00 1 alkylcarbonylamino, -C 0 11 alkylCOOR 12
-C~
1 alkylCONR,,R,, wherein RID ,3 andR1 are independently selected from hydrogen, C,-C,,alkyl, arylC 0 -Cilalkyl, or R 13 and R, 4 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, ,alkyl, arylC 0 -C 11 ,alkyl substituent.
mono-, di- and tni-substituted arylC 0 -C 1 ,alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, lxdihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofliranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or 10 thiadiazolyl, and wherein the remaining of R, and R 3 are independently selected from the group consisting of: hydrogen; (ii) C 11 alkyl, substituted C, 1 alkyl wherein the alkyl substituents are defined
S
S S S S S
S
S.
15 as above, (iii) aryl C 0
-C
1 1 alkyl, (iv) mono-, di- and tri-substituted aryl C 0
-C
11 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a tenth aspect, the present invention provides a compound with the structure depicted in Formula (A8): ly- N N (A8) wherein at least one of R, and R, sub stituents has the general structure depicted in Formula (B)
)COOR..
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C,-,,alkyl, optionally substituted aryl C 1 1 1 alkyl wherein 9. the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C, 1 alkyl, aryl C, 11 alkyl, C 0 1 alkyloxyC.
1 I alkyl, aryl C 0 1 alkyloxy Co., alkyl, Co, 1 alkylthioC.
1 1 alkyl, arylC 0 11 ,alkylthioC.
11 alkyl, C 0 11 alkylaminoC.
11 alkyl, arylC.
11 alkylaminoC.
1 1 ailkyl, di(arylC,- 11 alkyl)aminoC.
11 alkyl, C,.
11 alkylcarbonylC.
11 alkyl, arylC 1 alkylcarbonylC., 1 alkyl, C 1 11 alkylcarboxyC., 1 alkyl, arylC,.,,alkylcarboxyC., 1 alkyl, C, 1 1 alkylcarbonylaminoC 0 11 alkyl, arylC 1 .,,alkylcarbonylaminoC., 1 alkyl, C 0 1 ,alkylCOOR 4 alkylCONR 5
R
6 wherein R 4
R
5 and R 6 are independently selected from hydrogen, C, 1 alkyl, arylC 0
C
1
I
1 Ialkcyl, or R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 11 alkyl, arylC 0
-C
1 1 alkyl substituent.
liz- (ii) is selected from the group consisting of hydrogen
C,.
1 1 alkyl, substituted C 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamnoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 11 alkyloxy, arylC.
11 alkyloxy, C 0 11 alkylthio, arylC.
1 1 alkylthio, C 011 alkylamnino, arylC 0 1 alkylamino, di(arylC.
11 alkyl)amino, C 1 11 alkylcarbonyl, arylC.
11 alkylcarbonyl, C,.
1 ,alkylcarboxy, arylC,- 11 alkylcarboxy, C 1 1 1 alkylcarbonylamino, arylC 1 1 ,alkylcarbonylamino, -CO-, 1 alkylCOOR 7
-C
0
,-C
11 alky1CONRR 9 wherein R 7 R, and R 9 are independently selected from hydrogen, C 1 I-C I ,alkyl, arylC 0 -C I 1 ,alkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 I-C I 1 ,alkyl, arylC 0 11 alkyl substituent, mono-, di- and tri-substituent arylC 0
-C
11 alkyl wherein the aryl V V substituents are defined as above for R' and (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuiryl, pyranyl, benzofuranyl, isobenzofuiranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, la(i) carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, and wherein the remaining of R, and R 2 are independently selected from the group consisting of: hydrogen; (ii) C,- 11 alkyl, substituted C 1 1 alkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 11 alkyl, (iv) mono-, di- and tri-substituted aryl C 0 ,-C,,alkyl wherein the aryl substituents are defined as above, and wherein m is an integer between 0 and 4 and each R 3 is independently selected from the group consisting of hydrogen, halo, itro, cyano, trihalomethyl, hydroxypyronyl, C,.
15 1 akyl, C 011 alkyloxyC 11 alkyl, arylC 011 IalkyloxyC.
11 alkyl, C 011 jallylthioC.
11 alkyl, ~~arylC 011 alkylthioC 1 1 alkyl, C 0 11 alkylaminoC 11 alkyl, arylC.
11 alkylaminoC.
1 1 alkyl, di(arylC 1 alkyl)aminoC.
11 alkyl, C 1 11 alkylcarbonylC(,, 1 alkyl, C 1 1 1 alkylcarboxyC 0 11 alkyl, C 1 11 alkylcarbonylaminoC.
11 alkyl, aiylC alkylcarbonylC 11 alkyl, arylC 1 lialkylcarboxyC.
11 alkyl, arylC.
11 alkylcarbonylaminoC 1 1 alkyl, -CH=CHCOOR 0
-CH=CHCONIR
12
-C
0 1 1 alkylCOOR 13
-C
0 11 alkylCONR 14
R,
5 wherein Rio thru are independently selected from hydrogen, C, -C 11 alkyl, aryl C 0 Ialkyl, or and R, 12 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -Cl 1 alkyl, aryl C 0
-C
11 alkyl substituent, llb(i)or R 4 and R, 1 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-C,,alkyl, aryl Co- Clialkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to an eleventh aspect, the present invention provides a compound with the structure depicted in Formula (A8): RI R2 N N '^:V(R3)m (A8) wherein R, is selected from -COR 16 -COOR, -CONRiR 9 wherein Ri 6 thru R, 9 are independently selected from hydrogen, C,-C,,alkyl, substituted C 1 ,,alkyl where the alkyl *o* 10 substituents are as defined below, optionally substituted arylCo-C ,alkyl where the aryl substituents are as defined below, or R 8 and R, 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -C,,alkyl, arylCo-C alkyl substituent, and wherein R 2 has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR'"
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 ,,alkyl, optionally substituted aryl C.,,alkyl wherein the aryl substituents are independently selected from the group consisting of lc(i) hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 alkyl, aryl C 1 alkyl,
C
011 alkyloxyC 11 alkyl, aryl C 011 alkyloxy C 011 alkyl, C 0 11 alkylthioC 11 alkyl, arylCO- 1 ,alkylthioC 0 11 alkyl, C 011 alkylaminoC, 1 jalkyl, arylC 011 IalkylaminoC 1 1 alkyl, di(arylC 1 ,alkyl)aminoC 11 alkyl, alkylcarbonylC.
11 alkyl, arylC,.
1 alkylcarbonylC 1 1 alkyl, C 1 j 1 alkylcarboxyC 11 alkyl, aryiC 1 alkylcarboxyC 11 alkyl, C 111 alkylcarbonylaminoC 0 11 alkyl, aryiC 1 alkylcarbonylamninoC 0 1 alkyl, C 01 alkylCOOR 4 -CO-I 1 alkyICONR 5
R
6 wherein R 4
R
5 and R 6 are in dependently selected from hydrogen, C,-C,,alkyl, arylC 0 V C 1 alkyl, or R, and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C,,alkyl, 5:.
10 arylC 0 -Cl 1 alkyl substituent.
(ii) is selected from the group consisting of hydrogen, Cl-,,alkyl, substituted Cl- 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hyctroxypyronyl, Co- 11 ,alkyloxy, arylC 0 1 alkyloxy, C 0 1 alkylthio, arylC- 1 1 alkylthio, C 0 1 1 alkylamino, arylC 0 ,alkylamino, di(arylC 011 alkyl)amino, C 1 11 alkylcarbonyl, arylC allcylcarbonyl, C 1 ,allylcarboxy, arylC 1 ,alkylcarboxy, C 1 11 alkylcarbonylamino, arylC,
I
1 ,allylcarbonylamino, 1 alkylCOOR 7
-CO-,
11 alkylCONRR, wherein R7,, R 8 and R 9 are independently selected from hydrogen, C 1
-C
11 alkyl, arylC 0
-C
11 alkyl, or R 8 and R 9 are taken together with the nitrogen to which ld(i) they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
-C
11 alkyl, arylC,-C 1 alkyl substituent, mono-, di- and tri-substituent arylC 0
,-C
1 1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naplithyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofiiranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, and wherein R 3 is selected from the group consisting of: hydrogen; (ii) C 1 ,,,alkyl, substituted C,, 1 alkyl wherein the alkyl substituents are defined as above, (iii) arylC 011 alkyl, Ille(i) (iv) mono-, di- and tni-substituted aryl C 0
-CI
1 alkyl wherein the aryl substituents are defined as above, and wherein m is an integer between 0 and 4 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C,.
11 alkyl, C 0 11 alkyloxyC 11 alkyl, arylC 0 1 1 alkyloxyC.
11 alkyl, C 011 alkylthioC., 1 akyl, arylC.
11 alkylthioC 11 alkyl, C 0 11 alkylaminoC.
11 alkyl, arylC 011 lalkylaminoC 11 ,alkyl, di(arylC 111 alkyl)aminoC 1 1 ,alkyl, C 111 alkylcarbonylC 1 1 alkyl, C 1 11 alkylcarboxyC 0 11 alkyl, C 111 alkylcarbonylaminoC 11 alkyl, aryiC _1 lalkylcarbonylC.
11 Ialkyl, arylC I* 1 lycroy 0 11 alkyl, arylC 1 ,alkylcarbonylaminoC.
1 1 alkyl,-C=HOR, -CH=CHCONR,,R,,, -CO.
11 alkylCOORI 1
-C.
11 alkylCON 14
R
5 wherein RIO thru RI, are independently selected from hydrogen, C,-Cl 1 alkyl, aryl C 0 -Cl 1 alkyl, or RI 1 and R, 2 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C I Ialkyl, aryl C 0 -C I Ialkyl substituent,
R
14 and are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C, -C I Ialkyl, aryl CO-
C
11 alkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a twelfth aspect, the present invention provides a compound with the structure depicted in Formula (A9): R, lfi) N N Nt (A9) wherein at least one of RI and R, substituents has the general structure depicted in Formula (B)
)COOR..
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C ,alkyl, optionally substituted aryl C, 11 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C,-,,alkyl, aryl C 1 11 alkyl, Co-
O
1 lkyloxyQ 11 jalkyl, aryl C 0 11 alkyloxy C 011 alkyl, C 011 alkylthioC 11 alkyl, arylC 0 11 alkylthioC.
11 alkyl, C 0 11 alkylaminoC 11 alkyl, arylC 01 alkylaminoC 11 alkyl, di(arylC 1 j 1 alkyl)aminoC, 11 alkyl, C 1 11 alkylcarbonylC.
11 alkyl, arylCl- 11 allcylcarbonylC 11 ,alkyl, C, 1 alkylcarboxyC.
11 alkyl, arylCl- 1 alkylcarboxyC.
1 1 alkyl, C 111 alkylcarbonylaminoC 0 1 Ialkyl, arylC 1 alkylcarbonylaminoC 0 1, alkyl, C 0 1 1 alkylCOOR 4
-C
0 11 alkylCONR 5
R,
wherein R 4 R, and R 6 are independently selected from hydrogen, C, -C, 1 ,alkyl, arylC 0
C,
1 alkyl, or R 5 and R 6 are taken together Ilg(i) with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C,,alkyl, arylC 0
-C
11 alkyl substituent.
(ii) R...is selected from the group consisting of hydrogen, C,-,,alkyl, substituted C 1 11 ,alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamnoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 4* 11 alkyloxy, arylC.
11 alkyloxy, C 0 1 1 alkylthio, arylCo 11 alkylthio, C 0 11 alky1amino, arylC..
,alkylamino, di(arylC 011 alkyl)amino, C 1 11 alkylcarbonyl, arylC,- 1 alkylcarbonyl, C, 10 1 alkylcarboxy, arylC,-, alkylcarboxy, alkylcarbonylamnino, arylCl- 1 alkylcarbonylamnino, alkylCOOR 7 alkylCONR 8
R
9 wherein R 7
R
8 and R, are independently selected from hydrogen, C,-C, 1 alkyl, arylC 0
-C
11 alkyl, or R, and R, are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
-C
1 1 alkyl, arylC 0
-C
1 1 alkyl substituent.
mono-, di- and tni-substituted arylC 0 -C,,alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuiryl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, a.
S.
SS6 S. S .5 @6 0 0000
S.
SS S 0 0 6 5 S 0
S
SSeS*O 0
S
S.O.S.
S
*S*S
5@ 0 5 S
SO
5O55
S
S
*500 S 0O S *5 S 55 5* S 5O
S.
0 I1lh(i) pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, l,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, and wherein the remaining of R 1 and R 2 is independently selected from the group consisting of: hydrogen; 10 (ii) C, 1 ,alkyl, substituted C 1 alkyl wherein the alkyl substituents are defined as above, (iii) arylC 01 1 alkyl, (iv) mono-, di- and tri-substituted aryl C 0
-C
11 alkyl wherein the aryl substituents are defined as above, 15 and wherein m is an integer between 0 and 3 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C, 11 alkyl, C 011 alkyloxyC 0 11 alkyl, arylC 0 11 lalkyloxyC- 1 1 alkyl, C 011 alkylthioC 11 alkyl, arylC.
11 alkylthioC 11 alkyl, C 011 alkylaminoC.
1 1 alkyl, arylC.
11 alkylaminoC 11 jalkyl, di(arylC 1 alkyl)aminoC 11 alkyl, C 1 1 1 alkylcarbonylC 11 alkyl, C 1 11 alkylcarboxyC 0 11 alkyl, C 111 alkylcarbonylaminoC.
11 alkyl, arylC 11 1 ,alkylcarbonylC 11 alkyl, arylC, 11 alkylcarboxyC- 11 alkyl, arylQ 1 1 ,alkylcarbonyl-aminoC 11 alkyl, -CH=CHCOOR 0
-CH=CHCONR
1
R
12 alkylCOOR 1 3 alkylCONR 1 4
R,
5 wherein R 10 thru R, 5 are independently selected from hydrogen, CI-C, 1 alkyl, aryl C 0 -C,,alkyl, or and R, 2 lli(i) are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C,,alkyl, aryl Co-C,,alkyl substituent, or R 14 and Rs 5 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C, 1 alkyl, aryl Co- C,,alkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a thirteenth aspect, the present invention provides a compound Shaving the structure depicted in Formula (A9): S R
AN
N N
N
(R3)m (A9) 10 wherein R, or R 2 is selected from -CORs, -COORI 7 -CONRisRi 9 wherein R, 6 thru RI 9 are independently selected from hydrogen, C 1 -C,,alkyl, substituted C,-Cllalkyl where the alkyl substituents are as defined below, optionally substituted arylCo-C ,alkyl where the aryl substituents are as defined below, or R 18 and are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one Ci-CIalkyl, arylCo-C,,alkyl substituent, and wherein the remainder of R, or
R
2 has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"'
(B)
wherein Illj(i) R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, Cl- 11 alkyl, optionally substituted aryl C, 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 11 1 alkyl, aryl CI- 11 alkyl, Co- 11 alkyloxyC 011 alkyl, aryl C 0 1 1 alkyloxy C 011 alkyl, C 0 1 1 alkylthioC.
1 1 alkyl, arylC 0 ilalkylthioC.
11 alkyl, C 0 11 alkylaminoC.
11 alkyl, arylC.
11 alkylaminoC.
11 alkyl, di(arylC ,,alkyl)aminoC.
11 alkyl, C, 11 alkylcarbonylC.
11 alkyl, arylC 1 alkylcarbonylC.
1 1 alkyl, C,.
i 1 alkylcarboxyC- 11 alkyl, aryl 1
-C
11 alkylcarboxyC 11 alkyl, C,.
11 alkylcarbonylaminoC 0 11 alkyl, arylC 1 ,alkylcarbonylaminoC.
1 1 alkyl, C 0 11 alkylCOOR 4
-C
0 11 alkylCONR 5
R'
6 10 wherein R(5 and R 6 are in dependently selected from hydrogen, C 1
-C
11 alkyl, arylC 0 C I ,alkyl, or R5 and R6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
-C
1 alkyl, arylC,-C 1 alkyl substituent.
(ii) is selected from the group consisting of hydrogen,
C
1 alkyl, substituted C 1 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, pipenidinyl, morpholinyl, piperazinyl, hydroxypyronyl, Co- 11 alkyloxy, arylCO-1 1 alkyloxy, C 0 1 alkylthio, arylC 0 11 Ialkylthio, C 0 11 alklamino, arylC 0 1 1 alkylamino, di(arylC.
1 1 alkyl)amino, C 1 11 alkylcarbonyl, arylC 1 1 1 ,alkylcarbonyl, C 1 1 1 alkylcarboxy, arylC.
11 alkylcarboxy, C 1 11 alkylcarbonylamino, arylC 1 lalkylcarbonylamino, -C 0 11 alkylCOOR 7
-CO-
Illk(i) I ,alky1CONR 8
R
9 wherein R 7
R
8 and R9 are indepdently selected from hydrogen, C- C I ,alkyl, arylC 0 -C I Ialkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,- C,,alkyl, arylC 0 ,-C,,alkyl substituent.
mono-, di- and tni-substituted arylC 0 ,-C,,alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, .::dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuiryl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, and wherein R 3 is selected from the group consisting of: hydrogen; (ii) C 111 alkyl, substituted alkyl wherein the alkyl substituents are defined as above, 111(i) (iii) arylC 01 1 alkyl, (iv) mono-, di- and tni-substituted aryl CO-C, Ialkyl wherein the aryl substituents are defined as above, and wherein m is an integer between 0 and 3 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C,_ 11 alkyl, CO_,,alkyloxyCO 1 1 alkyl, ary1CO 11 alkyloxyCO 1 1 alkyl, C 011 alkylthioCO 11 alkyl, arylCO 1 alkylthioC 01 alkyl, C 0 1 1 alkylaminoCO_, 1 alkyl, arylC.
1 1 alkylaminoC 01 1 ,alkyl, di(arylC 1 alkyl)aminoC 1 1 alkyl, C 1 11 alkylcarbonylC 0 _I alkyl, C 1 11 alkylcarboxyC 0 11 alkyl, C 111 alkylcarbonylaminoC 11 alkyl, aryiC 1 I- IalkylcarbonylCO_, alkyl, arylC,_ ialkylcarboxyC 11 alkyl, arylC 11 1 alkylcarbonyl-aminoC 1 1 ~alkyl, -CH=CHCOOR,,
-CH=CHCONR
1 1
R
1
-C
0 1 aklOR 3
-CO
1 aylO R,R 1 wherein RIO thru are independently selected from hydrogen, C alkyl, aryl C 0 -C I Ialkyl, or R, I and R, 2 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, Ialkyl, aryl C 0 -C I Ialkyl substituent, or R, 4 and RI, are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-C,,alkyl, aryl CO-
C
1 1 alkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a fourteenth aspect, the present invention provides a compound with the structure depicted in Formula (A1O):
Z,
R
1
R
(A1O) l lm(i) wherein Z, and Z, are independently selected from the group consisting of 0, OR3 SR 4
NR
5
R
6 ,whri R 3 R4 R5, R~r independently selected from: hydrogen; (ii) C 1 11 alkyl, substituted C 1 11 alkyl, C 11 1 alkylcarbonyl, substituted C, 1 ,alkylcarbonyl wherein the alkyl substituents are defined as below, (iii) arylC,, alkyl, arylC,-,,alkylcarbonyl; (iv) mono-, di- and tni-substituted aryl C 0
-C
1 alkyl; mono-, di- and trisubstituted arylC,-, 1 alkylcarbonyl wherein the aryl substituents are defined as in below, *~:and wherein at least one of R, and R 2 substituents has the general structure depicted in ormla B)X-C(R')=C(R")COOR..
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, 15 halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted aryl C,.
1 alkyl wherein :the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 11 alkyl, aryl C 111 alkyl, Q_ lialkyloxyC 0 11 alkyl, aryl C 011 alkyloxy C 0 11 alkyl, C 011 alkylthioC 11 alkyl, arylC 0 11 alkylthioC 011 alkyl, C 0 11 alkylaminoC.
11 alkyl, arylC.
11 alkylaminoC 11 alkyl, di(arylC 1 1 alkyl)aminoC 11 alkyl, C,.
1 1 alkylcarbonylC.
1 1 alkyl, arylC 1 alkylcarbonylC 11 alikyl, C 1 l 1 alkylcarboxyC.
11 alkyl, arylC 1 alkylcarboxyC.
11 alkyl, C 1 1 alkylcarbonylaminoC 0 ,alkyl, arylC.
11 alkylcarbonylaminoC 0 11alkyl, C 011 alkylCOOR 7
-C
011 alkylCONR 8
R,
wherein R 7 R, and R, 9 are independently 1 ln(i) selected from hydrogen, C, Ialkyl, arylC 0 -C I Ialkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C, alkyl, arylCO-C, I alkyl substituent.
(ii) is selected from the group consisting of hydrogen,
C
1 1 alkyl, substituted C 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO_ I Ialkyloxy, arylC..
11 alkyloxy, C 0
_.I
1 I alkylthio, arylC.
1 alkylthio, Co, 1 alkylamino, arylC..
Ialkylamino, di(arylC,- 1 alkyl)amino, C 111 alkylcarbonyl, arylC.
11 alkylcarbonyl, C,.
1 alkylcarboxy, aryiC 11 1 ,alkylcarboxy, C 1 11 alkylcarbonylamino, arylC..
1 alkylcarbonylamino, -C 0 1 alkylCOOR 10
-C
0 1 alkylCONR 1 1
R
1 2 wherein RIO, R 1 1 and R, 2 are indepdently selected from hydrogen, C 1
-C
11 alkyl, arylC 0 -CIalkyl, or R 11 and R, 2 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
-C
11 alkyl, arylC 0
-CI
1 alkyl substituent.
mono-, di- and tni-substituted arylC 0
-C
1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naplithyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, 9
S
S* *5*S S S S S
S
S
1lo00) indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 411-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl. or thiadiazolyl, and wherein the remaining of and R 2 is independently selected from the group consisting of: 10 hydrogen; (ii) C, 11 alkyl, substituted C, 1 alkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 1 1 alkyl, (iv) mono-, di- and tni-substituted aryl C.-C,,alkyl wherein the aryl 15 sub stituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a fifteenth aspect, the present invention provides a compound with the structure depicted in Formula (Al 1): N S
S
S
55
S
S S
S
S.
S S S S S. S S S 55 (All1) Illp(i) wherein at least one of RI, R 2 and R 3 sub stituents has the general structure depicted in Formula (B)
)COOR...
(B)
wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 1 alkyl, optionally substituted aryl C 111 ,alkyl wherein :9*9 the aryl substituents are independently selected from the group consisting of hydrogen, 6% halo, nitro, cyano, trihalomethyl, hydroxypyronyl, 1 alkyl, aryl C 11 1 alkyl, C, 10 11 alkyloxyC.
11 alkyl, aryl C 011 alkyloxy C 011 alkyl, C 0 1 1 alkylthioC 11 alkyl, arylC 0 0:.0 1 alkylthioC,.
1 ,alkyl, C 0 11 alkylaminoC.
1 1 alkyl, arylC 01 1 alkylaminoC.
11 alkyl, di(arylC,- 11 alkyl)aminoC.
11 alkyl, C,, 1 alkylcarbonylC.
11 alkyl, arylC.
11 alkylcarbonylC.
11 alkyl, C,.
11 alkylcarboxyC.
11 alkyl, arylC.
11 alkylcarboxyC 01 1 alkyl, C 111 laroylmno, 11 alkyl, arylC 1 ,alkylcarbonylaminoC 11 alkyl, C 0 1 alkylCOOR 5
-C
0 11 alkylCONR 6
R
7 wherein R 5
R
6 and 7 are independently selected from hydrogen, C, -C 1
I
1 alkyl, arylC 0 C Ialkyl, or R 6 and R 7 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one Ialkyl, arylC 0 1 alkyl substituent.
(ii) is selected from the group consisting of hydrogen,
C
1 1 1 alkyl, substituted C 11 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbomoyl, Illq(i) tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperzainyl, hydroxypyronyl, Co- 11 alkyloxy, arylC 01 1 alkyloxy, C 0 11 alkylthio, arylCO.
1 alkylthio, C 0 11 alky1amino, arylC 0 11 alkylamino, di(arylC 011 alkyl)amino, 1 alkylcarbonyl, arylC.
11 alkylcarbonyl, C,.
1 alkylcarboxy, arylC, 11 alkylcarboxy, C,-,,alkylcarbonylamino, arylC 1 ,alkylcarbonylamino, -C 0 11 alkylCOOR 8
-C
011 alkylCONRR wherein R, and R 10 are independently selected from hydrogen, C 1 -C,,alkyl, arylC 0
-C
11 alkyl, or R 9 and RIO are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C, ,alkyl, arylC 0
-C
1 1 alkyl substituent.
mono-, di- and tri-substituted arylC 0 -C,,alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fuiryl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, ptenidinyl, carbazolyl, acnidinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiozolyl or thiadiazolyl, I lr(i) and wherein the remaining of R 2 and R 3 are independently selected from the group consisting ofhydrogen; (ii) C I -IlIalkyl substituted C alkyl wherein the alkyl substituents are defined as above,
V.,
(iii) arylC0.-11alkyl, (iv) mono-, di- and tri-substituted aryl Co,-C Ialkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a sixteenth aspect, the present invention provides a compound with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
According to a seventeenth aspect, the present invention provides a compound with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
1 s(i) According to an eighteenth aspect, the present invention provides a pharmaceutical composition comprising as active component a compound according to any one of the first to seventeenth aspects together with a pharmaceutically acceptable carrier or diluent.
According to a nineteenth aspect, the present invention provides a pharmaceutical composition suitable for modulating the activity of PTPases or other molecules with tyrosine phosphate recognition unit(s) comprising an effective amount of a compound according to any one of the first to seventeenth aspects together with a pharmaceutically 9..
acceptable carrier or diluent.
10 According to a twentieth aspect, the present invention provides a method of modulating the activity of PTPases or other molecules with phosphotyrosine recognition unit(s) in a subject in need of such treatment comprising administering to said subject an 999999 effective amount of a compound or composition according to any one of the first to 9999 9 99 ninteenth aspects.
15 According to a twenty-first aspect, the present invention provides the use of a compound according to any one of the first to seventeenth aspects for preparing a medicament.
According to a twenty-second aspect, the present invention provides the use of a compound according to any one of the first to seventeenth aspects for preparing a medicament for modulating the activity of PTPases or other molecules with phophotyrosine recognition unit(s).
According to a twenty-third aspect, the present invention provides the use of a compound according to any one of the first to seventeenth aspects for preparing a medicament for treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and lIt(i) AIDS, diseases with dysfunctions of the coagulation system, allergic disease, osteoporosis, proliferative disorders including cancer and psoriosis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.
According to a twenty-fourth aspect, the present invention provides the use of a compound according to any one of the first to seventeenth aspects for preparing a medicament for treating a subject in need of such treatment.
••co 9.
10 According to a twenty-fifth aspect, the present invention provides the use of a compound according to any one of the first to seventeenth aspects for preparing a medicament for use as an immunosuppressant.
According to a twenty-sixth aspect, the present invention provides an immobilized 99 compound comprising a suitable solid-phase coupled with a compound according to any 9 one of the first to seventeenth aspects.
_According to a twenty-seventh aspect, the present invention provides a method for coupling a compound according to any one of the first to seventeenth aspects to a suitable solid-phase matrix, said method comprising contacting said compound with said matrix under conditions sufficient for said coupling to occur.
According to a twenty-eighth aspect, the present invention provides a method for isolating a protein or a glycoprotein with affinity for a compound according to any one of the first to seventeenth aspects from a biological sample, comprising contacting an immobilized compound according to the twenty-sixth aspect with said biological sample in order for said immobilized compound to form a complex by binding said protein or glycoprotein llu(i) removing unbound material from said biological sample and isolating said complex extracting said protein or glycoprotein from said complex.
According to a twenty-ninth aspect, the present invention provides a method for isolating a protein-tyrosine phosphatase with affinity for a compound according to any one of the first to seventeenth aspects from a biological sample, comprising contacting an immobilized compound according to the twenty-sixth aspect with said biological sample in order for said immobilized compound to form a complex by binding said protein-tyrosine phosphatase 10 removing unbound material from said biological sample and isolating said complex
G
extracting said protein-tyrosine phosphatase from said complex.
According to a thirtieth aspect, the present invention provides a method for isolating a Src-homology 2 domain containing protein or a phosphotyrosine binding l 15 domain containing protein with affinity for a compound according to any one of the first
S@
to seventeenth aspects from a biological sample, comprising oS contacting an immobilized compound according to the twenty-sixth aspect with said biological sample in order for said immobilized compound to form a complex by binding said Src-homology 2 domain containing protein or a phosphotyrosine binding domain containing protein removing unbound material from said biological sample and isolating said complex extracting said Src-homology 2 domain containing protein or a phosphotyrosine binding domain containing protein from said complex.
llv(i) According to a thirty-first aspect, the present invention provides a compound according to any one of the first to seventeenth aspects coupled to a fluorescent or radioactive molecule.
According to a thirty-second aspect, the present invention provides a method for detecting a protein-tyrosine phosphatase or other molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound according to the thirtysecond aspect comprising: contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a o 0 **0 10 complex with said protein-tyrosine phosphatase or said other molecules with G o. phosphotyrosine recognition unit(s) detecting said complex, thereby detecting the presence of said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s).
.According to a thirty-third aspect, the present invention provides a method for 0 15 quantifying the amount of protein-tyrosine phosphatase or other molecules with 0 0 phosphotyrosine recognition unit(s) in a cell or in a subject using a compound according 00 to the thirty-second aspect comprising: contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a complex with said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s) measuring the amount of said complex, thereby detecting the presence of said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s).
llw(i)- According to a thirty-fourth aspect, the present invention provides a method for determining the function of a given protein-tyrosine phosphatase or group of proteintyrosine phosphatases or said molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound according to the thirty-second aspect comprising: contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a complex with said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s) measuring the biological effects induced by said complex.
According to a thirty-fifth aspect, the present invention provides a method of "i treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic disease, osteoporosis, proliferative disorders including cancer and psoriosis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases comprising administering a therapeutically effective amount f a compound according to any one of the first to seventeenth aspects to a subject in need thereof.
llx(i)- According to a thirty-sixth aspect, the present invention provides a method of treatment comprising administering a therapeutically effective amount of a compound according to any one of the first to seventeenth aspects to a subject in need thereof.
Unless the context clearly requires otherwise, throughout the description and the claims, the words 'comprise', 'comprising', and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to".
Definitions In the specification and claims, the term "derivatives" means: aryl acrylic acids 10 with structure depicted in Formula (Al) having substitution (with e.g, hydrogen, hydroxy, halo, amino, carboxy, nitro, cyano, methoxy, etc.) at one or more atoms of the aryl ring. Moreover, "derivatives" includes compounds of the Formula (Al) having substitution at the alkene carbons with, e.g. an electron withdrawing group Cl, F, Br, CF 3 phenyl) or an electron donating group CH 3 alkoxy).
Y-X-C(R')=C(R")COOR'"
i "(Al) As used herein, the term "attached" signifies a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art.
The terms "halogen" or "halo" include fluorine, chlorine, bromine, and iodine.
The term "alkyl" includes C 1 straight chain saturated and C 2
-C
1 unsaturated aliphatic hydrocarbon groups, C 1 branched saturated and C 2 unsaturated aliphatic hydrocarbon groups, C 2
-C
8 cyclic saturated and C 5 unsaturated aliphatic hydrocarbon groups, and straight chain or branched saturated and C 2
-C
1 straight chain or branched unsaturated aliphatic hydrocarbon groups substituted with C 3
-C
8 cyclic A4 5 saturated and unsaturated aliphatic hydrocarbon groups having the specified number of lly(i) carbon atoms. For example, this definition shall include but is not limited to methyl ethyl propyl butyl pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, ethenyl, propenyl, butenyl, 6*
I
WO 98/27065 PCTIUS960508 12 penentyl, hexenyl, heptenyl, octenyl, nonenyl, decenyl, undecenyl, isopropyl (i-Pr), isobutyl tert-butyl sec-butyl isopentyl, neopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, methylcyclopropyl, ethylcyclohexenyl, butenylcyclopentyl, and the like.
The term "substituted alkyl" represents an alkyl group as defined above wherein the substitutents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, Co.- 11 alkyloxy, arylCo- 1 1 alkyloxy, Co- 1 1 alkylthio, arylCo-.
11 alkylthio, Co-.alkylamino, arylCo- 1 1 alkylamino, di(arylCo-.
1 alkyl)amino, Cl.
lIalkylcarbonyl, arylC 1 alkylcarbonyl, Cl.- 1 alkylcarboxy, arylC 11 alkylcarboxy, CI.
lialkylcarbonylamino, aryl Ci.- 1 alkylcarbonylamino, tetrahydrofuryl, morpholinyl, piperazinyl, hydroxypyronyl, alkylCOOR 1 alkylCONR 2
R
3 wherein RI,
R
2 and R 3 are independently selected from hydrogen, CI-C, 1 alkyl, arylCo-C, alkyl, or
R
2 and R 3 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1
-C
1 1 alkyl, arylCo- Cl alkyl substituent.
The term "alkyloxy" methoxy, ethoxy, propyloxy, allyloxy, cyclohexyloxy) represents an alkyl group as defined above having the indicated number of carbon atoms attached through an oxygen bridge. The term "alkyloxyalkyl" represents an alkyloxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylthio" methylthio, ethylthio, propylthio, cyclohexenylthio and the like) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a sulfur bridge. The term "alkylthioalkyl" represents an alkylthio group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylamino" methylamino, diethylamino, butylamino, Npropyl-N-hexylamino, (2-cyclopentyl)propylamino, hexenylamino, pyrrolidinyl, piperidinyl and the like) represents one or two alkyl groups as defined above having WO 98/27065 PCT/US96/20508 13 the indicated number of carbon atoms attached through an amine bridge. The two alkyl groups maybe taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 11 carbon atoms with at least one CI- Cl alkyl, arylCo-C 1 alkyl substituent. The term "alkylaminoalkyl" represents an alkylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylcarbonyl" cyclooctylcarbonyl, pentylcarbonyl, 3hexenylcarbonyl) represents an alkyl group as defined above having the indicated number of carbon atoms attached through a carbonyl group. The term "alkylcarbonylalkyl" represents an alkylcarbonyl group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylcarboxy" heptylcarboxy, cyclopropylcarboxy, 3pentenylcarboxy) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through an oxygen. The term "alkylcarboxyalkyl" represents an alkylcarboxy group attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "alkylcarbonylamino" hexylcarbonylamino, cyclopentylcarbonyl-aminomethyl, methylcarbonylaminophenyl) represents an alkylcarbonyl group as defined above wherein the carbonyl is in turn attached through the nitrogen atom of an amino group. The nitrogen group may itself be substituted with an alkyl or aryl group. The term "alkylcarbonylaminoalkyl" represents an alkylcarbonylamino group attached through an alkyl group as defined above having the indicated number of carbon atoms. The nitrogen group may itself be substituted with an alkyl or aryl group.
The term "aryl" represents an unsubstituted, mono-, di- or trisubstituted monocyclic, polycyclic, biaryl and heterocyclic aromatic groups covalently attached at any ring position capable of forming a stable covalent bond, certain preferred points of attachment being apparent to those skilled in the art 3-indolyl, 4imidazolyl). The aryl substituents are independently selected from the group W-0 98/27065 PCT/US96/20508 14 consisting of halo, nitro, cyano, trihalomethyl, hydroxypyronyl, CI- 1 alkyl, arylC 1 11 alkyl, Co..
1 alkyloxyCo- 1 allcyl, arylCo-.
1 alkyloxyC..
1 alkyl, CO- 1 1 alkylthioC 0 1 1 alkyl, arylCo.
1 alkylthioC.
1 1 alkyl, C 0 1 alkylaminoC.
1 1 alkyl, arylC 0 j alkylaminoCo-lialkyl, di(arylC..
1 alkyl)aminoCO.
1 1 a1k y I, C 1 1 lalkylcarbonylC 0 1 l Ialkyl, a r y ICl lialkylcarbonylC.
11 alkyl, C 1 11 alkylcarboxyC..
11 alkyl, ary IC 1 1 alkylcarboxyC 0 lialkyl, C 1 1 alkylcarbonylaminoC 01 1 alkyl, arylC 1 .llalkylcarbonylaminoC 0 11 alkyl, alkylCOOR 4 I alkylCONR 5
R
6 wherein R 4
R
5 and R 6 are independently selected from hydrogen, C I-C I Ialkyl, arylC 0 -C 1 alkyl, or R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 11 alkyl, aryl C 0
-C
11 alkyl substituent.
The definition of aryl includes but is not limited to phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazoly 1, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, pyrazolyl, triazoly 1, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazoly 1, benzoxazolyl, oxadiazolyl, thiadiazolyl.
The term "arylalkyl" (4-hydroxyphenyl)ethyl, (2-aminonaphthyl)hexenyl, pyridylcyclopentyl) represents an aryl group as defined above attached through an alkyl group as defined above having the indicated number of carbon atoms.
The term "arylcarbonyl" g. 2 -thi op henylIc arbonyl1, 3methoxyanthrylcarbonyl, oxazolylcarbonyl) represents an aryl group as defined above attached through a carbonyl group.
The term "arylalkylcarbonyl" 2 3 -dimethoxyphenyl)propylcarbonyl, (2chloronaphthyl)pentenylcarbonyl, imidazolylcyclopentylcarbonyl) represents an W-0 98/27065 PCT/US96/20508 arylalkyl group as defined above wherein the alkyl group is in turn attached through a carbonyl.
The term "signal transduction" is a collective term used to define all cellular processes that follow the activation of a given cell or tissue. Examples of signal transduction include but are not in any way limited to cellular events that are induced by polypeptide hormones and growth factors insulin, insulin-like growth factors I and II, growth hormone, epidermal growth factor, platelet-derived growth factor), cytokines interleukines), extracellular matrix components, and cell-cell interactions.
Phosphotyrosine recognition units/tyrosine phosphate recognition units/phosphotyrosine recognition units are defined as areas or domains of proteins or glycoproteins that have affinity for molecules containing phosphorylated tyrosine residues (pTyr). Examples of pTyr recognition units include but are not in any way limited to: PTPases, SH2 domains and PTB domains.
PTPases are defined as enzymes with the capacity to dephosphorylate pTyrcontaining proteins or glycoproteins. Examples of PTPases include but are not in any way limited to: intracellular PTPases PTP-lB, TC-PTP, PTP-lC, PTP-1D,PTP- Dl, PTP-D2), receptor-type PTPases PTPa, PTPe, PTPP, PTPy, CD45, PTPK, PTPg), dual specificity phosphatases VH1, VHR, cdc25) and other PTPases such as LAR, SHP-1, SHP-2, PTP-1H, PTPMEGI, PTP-PEST, PTP PTPS31, IA-2 and HePTP and the like.
Modulation of cellular processes is defined as the capacity of compounds of the invention to 1) either increase or decrease ongoing, normal or abnormal, signal transduction, 2) initiate normal signal transduction, and 3) initiate abnormal signal transduction.
Modulation of pTyr-mediated signal transduction/modulation of the activity of molecules with pTyr recognition units is defined as the capacity of compounds of the invention to 1) increase or decrease the activity of proteins or glycoproteins with pTyr recognition units PTPases, SH2 domains or PTB domains) or to 2) decrease or WAD 98/27065 PCTIS9/20508 16 increase the association of a pTyr-containing molecule with a protein or glycoprotein with pTyr recognition units either via a direct action on the pTyr recognition site or via an indirect mechanism. Examples of modulation of pTyr-mediated signal transduction/modulation of the activity of molecules with pTyr recognition units, which are not intended in any way limiting to the scope of the invention claimed, are: a) inhibition of PTPase activity leading to either increased or decreased signal transduction of ongoing cellular processes; b) inhibition of PTPase activity leading to initiation of normal or abnormal cellular activity; c) stimulation of PTPase activity leading to either increased or decreased signal transduction of ongoing cellular processes; d) stimulation of PTPase activity leading to initiation of normal or abnormal cellular activity; e) inhibition of binding of SH2 domains or PTB domains to proteins or glycoproteins with pTyr leading to increase or decrease of ongoing cellular processes; f) inhibition of binding of SH2 domains or PTB domains to proteins or glycoproteins with pTyr leading to initiation of normal or abnormal cellular activity.
A subject is defined as any mammalian species, including humans.
WO 98/27065 PCT/US96/20508 17 Detailed Description This application relates to compounds having the general structure shown in Formula (Al):
Y-X-C(R')=C(R")COOR"
(Al) wherein R and R are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, alkyl, arylalkyl, (ii) is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl (iii) X is aryl, (iv) Y is selected from hydrogen or 0 0 0
O
OH z, N *N :4
Y
NYO
Y
wherein indicates a potential point of attachment to X and all other positions are substituted as described below.
WO 98/27065 PCTIUS96/20508.
18 According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A2): 0
R
3 O0
R
1 R2 0 (A2) wherein at least one of RI, R2 and R3 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"
(B)
wherein R, R R and X are defined as above in Formula and wherein the remaining of RI, R 2 and R 3 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl.
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A3): 0
R
3 0 /RL NHR 2 0 (A3) wherein at least one of RI, R 2 and R3 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"
(B)
WO 98/27065 PCTIUS96/20508 19 wherein R, and X are defined as above in Formula and wherein the remaining of R 1
R
2 and R 3 are independently selected from the group consisting of:hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, arylalkylcarbonyl.
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A4): 0 R, y R2
OH
(A4) wherein at least one of RI, R 2 substituents has the general structure depicted in Formula (B)
X-C(R)=C(R")COOR"
(B)
wherein R, R" and X are defined as above in Formula and wherein the remaining ofRI, R 2 is defined as above in Formula (A2).
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in 0 R1 R2 0 WO 98/27065 PCT/US96/20508 wherein at least one of RI and R 2 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"'
(B)
wherein R, R" and X are defined as above in Formula and wherein the remaining of R and R2 is defined as above in Formula (A2).
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A6):
R
3 R4
R,
(A6) wherein at least one of RI, R2, R 3 and R4 substituents has the general structure depicted in Formula (B)
X-C(R)=C(R")COOR"'
(B)
wherein R" and X are defined as above in Formula and wherein the remaining of RI, R 2 R3 and R 4 have the same definition as RI, R2 and R 3 in Formula with the proviso that when R 3 and R4 are selected from substituted phenyl or substituted furyl then the phenyl and furyl substituents exclude hydroxy, halo, trifluoromethyl, Cl-6alkyl, Ci.
6 alkyloxy, Ci-.alkylthio, amino, Ci-.alkylamino, di(Ci.
6 alkyl)amino, phenylC i.alkylamino and di(phenylCi.
6 alkyl)amino.
WO 98/27065 PCTIUS96/2008 21 According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A6):
R
3 R 4 NY N- N R
R
2 (A6) wherein R 4 is selected from -CORs, -COOR 6
-CONR
7
R
8 wherein R 5 thru R 8 are selected from hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one alkyl, aryl, arylalkyl substituent, and wherein at least one of R R 2 and R 3 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"
(B)
wherein R, R and X are defined as above in Formula and wherein the remaining of R, R 2 and R 3 are defined as above in Formula (A2).
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A6): R4 R3 N N.
R,
R2 (A6) WO 98/27065 PCTIUS96/20508 22 wherein RI, R2, R 3 and R4 are defined as above in According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A7):
R
3
R
2 N O
RI
(A7) wherein R 2 is selected from -CORs, -COOR 6
-CONR
7
R
8 wherein R5 thru Rs are defined as above in and wherein at least one of RI and R 3 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"
(B)
wherein R, R R and X are defined as above in Formula and wherein the remaining of R, and R 3 are defined as above in Formula (A2).
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A8): RI
R
2 N N (R3)m (A8) WO 98/27065 PCTIUS96/20508 23 wherein at least one of R, and R 2 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"
(B)
wherein R, R, R' and X are defined as above in Formula and wherein the remaining of R, and R 2 is defined as above in Formula and wherein m is an integer between 0 and 4 and each R 3 is independently selected from the group consisting of halo, nitro, cyano, trihalomethyl, hydroxypyronyl, alkyl, arylalkyl, COlialkyloxyC 0 11 alkyl, arylC o-l 1 alkyloxyC 0 11 alkyl, C 0 11 alkylthioC..
11 alkyl, ary IC 0 lialkylthioC..
11 alkyl, C 0 11 alkylaminoC 0 1 alkyl, ary ICo-llalkylaminoCo-li 1 alkyl, di(arylC 1 11 lalkyl)aminoC.
1 1 a 1ky 1, C 1 1 alkylcarbonylC 0 1 1 alkyl, a ry IC 1 I IalkylIcarbonylC 0 11 alkyl, C 1 1 lalkylcarboxyC.
1 1 alkyl, ary 1C 1 11 alkylcarboxyC 0 11 alkyI, C 1 1 1 alkylcarbonylaminoC..
11 alkyl, arylC 1 l alkylearbonylaminoC.
11 alkyl, alkylCOOR 4 alkylCONR 5
R
6 wherein R 4
R
5 and R 6 are independently selected from hydrogen, C I-C 1 alkyl, arylC 0
-C
1 alkyl, or R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 1 alkyl, arylCO-C I Ialkyl substituent.
According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A8): Ri R 2 N N
R
3 )m (A8) WO 98/27065 PCTfUS96t2O58 24 wherein R, is selected from -CORs, -COOR 6
-CONR
7
R
8 wherein R 5 thru Rs are defined as above in and wherein R 2 has the general structure depicted in Formula
(B)
X-C(R')=C(R")COOR"
(B)
wherein R R and X are defined as above in Formula and wherein m is an integer between 0 and 4 and each R 3 is defined as above in (11) According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A9): R, R 2 N N N I I (R 3 )m (A9) wherein m is an integer between 0 and 3 and wherein RI, R 2 each R 3 is defined as above in (12) According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (A9): Ri
R
2 N N
N
2(R 3 )m (A9) WO 98/27065 PCTIUS96/20508 wherein either R, or R 2 is selected from -CORs, -COOR 6
-CONR
7 Rs wherein R 5 thru
R
8 are defined as in and wherein the remainder of R, and R 2 is defined as above in and wherein m is an integer between 0 and 3 and each R 3 is defined as above in (13) According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in
R
1
R
2
Z
2 wherein Z, and Z 2 are independently selected from the group consisting of OR 3
SR
4
NR
5
R
6 and wherein at least one of R 1
R
2 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"
(B)
wherein R, R, and X are defined as above in Formula and wherein the remaining of RI, R 2 is defined as above in Formula and wherein R 3
R
4
R
5
R
6 are independently selected from hydrogen, alkyl, substituted alkyl, alkylcarbonyl, substituted alkylcarbonyl, aryl, arylalkyl, arylcarbonyl, arylalkylcarbonyl.
(14) According to the invention, a class of preferred PTPase activitymodulating compounds have the general structural Formula depicted in (All): WO 98/27065 PCTfUS96/20508 26
R
3 R 2
RI
(All) wherein at least one of RI R 2 and R 3 substituents has the general structure depicted in Formula (B)
X-C(R')=C(R")COOR"'
(B)
wherein R, R R and X are defined as above in Formula and wherein the remaining of R, R2 and R 3 are defined as above in Formula (A2).
Preferred compositions of the invention include compositions comprising compounds as defined above in structural formula (A6), (A10), (All) (or pharmaceutically acceptable salts, prodrugs, esters, or solvates of these compounds) in admixture with a pharmaceutically acceptable diluent, adjuvent, or carrier.
Provided according to the invention, therefore, are novel compounds which modulate the activity of PTPase or other molecules with pTyr recognition unit(s) as well as previously known aryl acrylic acid compounds which modulate the activity of PTPase or other molecules with pTyr recognition unit(s).
Another aspect of the present invention provides compositions comprising PTPase modulating compounds of the invention suitable for administration to a mammalian host.
WO 98/27065 PCT/US96/20508 27 In a preferred embodiment the compounds of the invention act as inhibitors of PTPases, e.g. protein tyrosine phosphatases involved in the regulation of tyrosine kinase signaling pathways. Preferred embodiments include modulation of receptortyrosine kinase signaling pathways via interaction with regulatory PTPases, e.g. the signaling pathways of the insulin receptor, the IGF-I receptor and other members of the insulin receptor family, the EGF-receptor family, the platelet-derived growth factor family, the nerve growth factor receptor family, the hepatocyte growth factor receptor family, the growth hormone receptor family and members of other receptortype tyrosine kinase families. Further preferred embodiments of the invention is modulation of non-receptor tyrosine kinase signaling through modulation of regulatory PTPases, e.g. modulation of members of the Src kinase family. One type of preferred embodiments of the invention relates to modulation of the activity of PTPases that negatively regulate signal transduction pathways. Another type of preferred embodiments of the inventions relate to modulation of the activity of PTPases that positively regulate signale transduction pathways.
In a preferred embodiment compounds of the inventions act as modulators of the active site of PTPases. In another preferred embodiment the compounds of the invention modulate the activity of PTPases via interaction with structures positioned outside the active sites of the enzymes, preferably SH2 domains. Further preferred embodiments include modulation of signal transduction pathways via binding of the compounds of the invention to SH2 domains or PTB domains of non-PTPase signaling molecules.
Other preferred embodiments include use of the compounds of the invention for modulation of cell-cell interactions as well as cell-matrix interactions.
As a preferred embodiment, the compounds of the invention may be used as therapeutics to inhibit PTPases involved in the regulation of the insulin recptor WO 98/27065 PCT/US96/2050B 28 tyrosine kinase signaling pathway in patients with type I diabetes, type II diabetes, impaired glucose tolerance, insuline resistance and obesity. Further preferred embodiments include use of the compounds of the invention for treatment of disorders with general or specific dysfunction of PTPase activity, e.g. proliferative disorders including neoplastic diseases and psoriosis. As another embodiment, the compounds of the invention may be used in pharmaceutical preparations for treatment of osteoporosis.
Preferred embodiments of the invention further include use of compounds of the invention in pharmaceutical preparations to increase the secretion or action of growth hormone and its analogs or somatomedins including IGf-I and IGF-2 by modulating the activity of PTPases or other signal transduction molecules with affinity for phosphotyrosine involved controlling or inducing the action of these hormones or any regulating molecule.
To those skilled in the art, it is well known that the current and potential uses of growth hormone in humans are varied and muti-tudinous. Thus, compounds of the invention can be administered for purposes of stimulating the release of growth hormone from the pituitary or increase its action on target tissues thereby leading to similar effects or uses as growth hormone itself. The uses of growth hormone maybe summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids; treatment of osteoporosis, stimulation of the immune system; treatment of retardation, accelaration of wound healing; accelerating bone fracture repair; treatment of growth retardation; treating renal failure or insufficiency resulting in growth retardation; treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness; treatment of obesity and growth retardation associated with obesity; treating growth retardation associated with the Pader-Willi syndrom and Turner's syndrom; accelerating the recovery and reducing WO 98/27065 PCTfUS96/20508 29 hospitalization of bur patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients; treatment of osteochondro-dysplasis, Noonans syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation; treatment of pulmonary dysfunction and ventilator dependency; attenuation of protein catabolic responses after major surgery; reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidio-blastosis; adjuvant treatment for ovulation induction; stimulation of thymic development and prevention of age related decline or thymic function; treatment of immunosuppresed patients; improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly; stimulation of osteoblasts, bone remodelling and cartilage growth; stimulation of the immune system in companion animals and treatment of disorder of aging in companion animals; growth promotant in livestock and stimulation of wool growth in sheep.
The compounds of the invention may be used in pharmaceutical preparations for treatment of various disorders of the immune system, either as stimulant or suppresor of normal or perturbed immune functions, including autoimmune reactions.
Further embodiments of the invention for treatment of allergic reactions, e.g. asthma, dermal reactions, conjunctivitis.
In another embodiment, compounds of the invention may be used in pharmaceutical preparations for prevention or induction of platelet aggregation.
In yet another embodiment, compounds of the invention may be used in pharmaceutical preparations for treatment of infectious disorders. In particular, the compounds of the invention may be used for treatment of infectious disorders caused WO 98/27065 PCTfUS96/20508 by Yersinia and other bacteria as well as disorders caused by viruses or other microorganisms.
Compounds of the invention may additionally be used for treatment or prevention of diseases in animals, including commercially important animals.
Also included in the present invention is a process for isolation of PTPases via affinity purification procedures based on the use of immobilized compounds of the invention using procedures well-known to those skilled in the art.
The invention is further directed to a method for detecting the presence of PTPases in cell or in a subject comprising contacting said cell or an extract thereof with labeled compounds of the invention.
detecting the binding of the compounds of the invention or measuring the quantity bound, thereby detecting the presence or measuring the quantity of certain PTPases.
The invention further relates to analysis and identification of the specific functions of certain PTPases by modulating their activity by using compounds of the invention in cellular assay systems or in whole animals.
The invention further provides methods for making compounds (A2), (A10), (All) of the present invention having PTPase-m6dulatory/inhibitory activity. In preferred methods, compounds of the invention are synthesized in a multi-component combinatorial array, which permits rapid synthesis of numerous, structurally related compounds for subsequent evaluation. In preferred synthesis protocols, the acrylic acid moiety of a compound is protected during synthesis by, esterification with a tert-butyl protecting group.
WO 98/27065 PCTIUJS96/20508 31 Thus, a preferred method of making compounds of the invention comprises use of a protected acrylic acid reagent and removal of the protective group by, treatment of a precursor ester compound with acid. Optionally, such a method includes further esterifying or salifying the acrylic acid product thereby obtained.
The compounds of formula (A8), (A10), (Al 1) may be prepared by procedures known to those skilled in the art from known compounds or readily preparable intermediates. General synthetic procedures and examples are as follow: General method for the removal of tert-butyl esters 0 50% TFA-CH 2 C1 2 R OtBu R OH Unless otherwise stated, tert-butyl esters were converted to their corresponding carboxylic acids via treatment with a solution of 50% trifluoroacetic acid in dichloromethane for 1 hour at 23 0 C. The solvent was removed in vacuo and the residue was azeotroped with toluene or acetonitrile to yield the corresponding carboxylic acid.
General method for the synthesis of compounds (Al) and Method 1 X LG C(R")CO 2 R" C(R")C02R'" 1 2 (Al) or By allowing a compound of formula wherein LG is a suitable leaving group such as bromo, iodo, or triflate to react with compound of formula wherein Z is hydrogen (Heck reaction: J. Org. Chem., 1977, 42, 3903), or trialkyltin (Stille reaction: J. Am. Chem. Soc., 1991, 113, 9585), or B(OH) 2 (Suzuki reaction: J. Am.
W-0 98/27065 PCr/US96/20508 32 Chem. Soc., 1989, 111, 314) and wherein and X are defined as above for formula (Al).
These reactions may be carried out neat or in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), or toluene, in the presence of a catalyst Pd(OAc) 2 Pd(PPh 3 4 Pd 2 dbaA) a ligand Ph 3 P, Ph 3 As, (o-tolyl) 3
P)
and a base K 2 C0 3 CsCQ3, Et 3 N) at temperatures ranging from 23 0 C to 1 30 0
C,
for I to 60 hours.
Examples
COH
COH Pd(OAC) 2 (o-TolYI) 3
P
C0 2 tBU Et 3 N DMF 100-C Br C0 2 tBU 3 Prepared according to Patel et al (J Org. Chem., 1977, 42, 3903).
1'H NMR of 3 (400 MHz, CDC1 3 8 1.5 9H), 6.4 IlH), 7.6 (in, 3 H), 8.05 211).
CHO
CHO Pd(OAc) 2 (o-ToI) 3 P N 11; t fC0 2 tBu Et 3 N DMF :ioo*C Br C0 2 tBu 4 Prepared according to Patel et al Org. Chem., 1977, 42, 3903).
1H NMR of 4 (400 MHz, CDC1 3 8 1.5 6.4 111), 7.55 111), 7.6 211), 7.8 2H), 9.95 1H1).
WO 98/27065PC/S/258 PCTIUS96/2050B COH
CO
2 tBU K~ Pd(OAc) 2 (o-TOI) 3
P
Et 3 N DMF 100-C C 2
H
C0 2 tBU Prepared according to Patel et al Org. Chem., 1977, 42, 3903).
1H NMR of 5 (400 MHz, CDCI 3 8 1.44 9H), 6.26 1H), 7.18 LH), 7.56 1H), 7.74 I H).
Br 0 0 CO~tBu Pd(OAc) 2 (o-TolyI) 3 P Et 3 N DMF 100'C r 0
CO
2 tBu Prepared according to Patel et al Org. Chem. 1977, 42, 3903).
'H NMR of 6 (400 MHz, CDC1 3 8 1.5 18H), 6.42 2H), 7.6 (in, 6H), 7.9 4H).
W-0 98127065 PCTIUS96/20508 34
CO
2 tBU Br 2 tBu 0Pd(OAC) 2 (o-Tolyl) 3 P 0\/ HO OH Et 3 N DMF 1lOOC HO OH o 0 7 Br
CO
2 tBu Prepared according to Patel et al (J1 Org. Chem. 1977, 42, 3903).
'H NMR of 7 (400 MHz, CDCl 3 8 1.5 1 8H), 6.2 211), 7.1 2H1), 7.35 2H1), 7.5 2H1), 7.7 2H).
Br Br 0 1. Pd(OAC) 2 (o-ToIY) 3
P
0 CO 2 tBU Et N DMF 100 0
C-
i 0 0 1 2 0 T F A -C H 2 C 2 08 Br/ C0 2
H
To I1I g of 4,4'-dibromobenzil (30mmol, I .Oequiv), 67mg of palladium (11) acetate (0.3mmol, 0.Olequiv), 365mg of tri-o-tolylphosphine (1.2mmol, 0.O4equiv) was added 200mL, of dimethylformamide followed by 4.2mL (30mmol, 1 .Oequiv) of triethylamine. The mixture was placed in a 100'C preheated bath and 4.4mL of tertbutylacrylate (3Ommol, 1 .Oequiv) in 3OmL, of dimethylforamide was added dropwise over 1 hour. The reaction mixture was heated at I 00 0 C for 12 hours, cooled to 23'C and the solvent was removed in vacuo. Ethyl acetate was added and the organic layer was washed with water and dried over sodium sulfate. The solvent was removed and the residue (mixture of dibromobenzil, mono and bis-tert-butylacrylate benzil) was recrystallized from hot 30% dichloromethane in hexane. The solid which crashed out WO 98/27065 PCTIUS96/20508 (mixture of dibromobenzil and mono-tert-butylacrylate benzil) was filtered off and treated with 20% trifluoroacetic acid in dichioromethane. After 20 minutes, the mono-tert-butylacrylate benzil 8 was filtered off and washed with 20% trifluoroacetic acid in dichioromethane (1 .4g isolated). The mother liquor (mixture of mono and bistert-butylacrylate benzil) was recovered and purified by flash chromatography (ethyl acetate-hexane eluant) to yield 2.4g of the mono-tert-butylacrylate dione which was treated with 20% trifluoroacetic acid in dichioromethane to give 2.2g of 8. The combined total yield of 8 was 3.6g 'H NMR of 8 (400 MHz, d 6 -DMSO) 8 6.7 IlH), 7.6 IlH), 7.8 4H), 7.9 4H).
BUt0 2 C HO 2
C
0 50%TFA-CH 2 C 2 0' 0 -0
CO
2 tBu COH 'H NMR of 9 (400 MHz, d 6 -DMSO) 8 6.7 2H), 7.6 2H), 7.9 8H).
H0 2
C
Br/ Et 3 N DMF 100 0' 0 0 -dO 0 oy) 0 8-tert-butyl ester
CO
2 tBU/
CO
2 tBu Prepared according to Patel et al (J1 Org. Chem., 1977, 42, 3903).
WO 98/27065 PCT/US96/20509 36 'H NMR of 10 (400 MHz, CDC1 3 -CD30D 9:1) 8 1.45 9H), 6.42 1H), 1H), 7.55 1H), 7.6 (dd, 4H), 7.68 1H), 7.92 (dd, 4H).
o HOC
O
CiCeHINH octyl amine S EDCI DMAP o O CH 2
C
2 0 11 COCtBu
CO
2 tBu
CO
2 tBu To a solution of 10 (1 equiv) in dichloromethane was added octylamine (1 equiv), EDCI (1.3 equiv) and 4-dimethylaminopyridine (0.5 equiv) at 23 0 C. The solution was stirred overnight, diluted with ethyl acetate, washed with 1N HCI and saturated sodium bicarbonate and dried over sodium sulfate. The residue was purified by flash chromatography (ethyl acetate-hexane eluant) and the solvent was removed in vacuo to yield compound 11. 'H NMR of 11 (400 MHz, CDCI 3 8 0.9 3H), 1.25 (s br, 10H), 1.5 9H), 1.55 (s br, 2H), 3.35 (dd, 5.6 (t br, 1H), 6.44 9d, 1H), 6.48 1H), 7.58 6H), 7.92 4H).
WO 98t27065 WO 9827065PCTIUS96/20508 PhCHCH 2
NH
PhCH 2
CH
2
NH
2 0 EDCI DMAP 0 CH 2
CI
2 0 120
CO
2 tBu
CO
2 tBU Same procedure as compound 11. 'H NMR of 12 (400 MHz, CDC1 3 8 1.5 (s, 9H), 2.83 2H), 3.62 (dt, 2H), 5.82 (t br, 1H), 6.4 (in, 2H), 7.18 (in, 5H), 7.6 (in, 6H), 7.9 (mn, 4H).
0 0
C
8
H
1 ,NH CH 17
NH
I/ S 2 C1 2 C0 2 tBu
C
2 C02H WO 98/27065 PCTLUS9620508 38 Method 2 o
O
X-LG C O O0 1 14 (Al) or Functionalized crosslinked polystyrene polymer By allowing a compound of formula as defined above to react with polymer bound compound of formula (14) wherein Z, R'and R" are defined as above in method 1.
These reactions may be carried out on functionalized cross linked polystyrene polymers such as Merrifield resin, Wang resin, Rink resin, TentagelTM resin, in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), or toluene, in the presence of a catalyst Pd(OAc) 2 Pd(PPh 3 4 Pd 2 dba 3 a ligand Ph 3 P, Ph 3 As, (o-tolyl) 3 P) and a base K 2 CO3, CsCO 3 Et 3 N) at temperatures ranging from 23°C to 130 0 C, for 1 to 60 hours.
Examples OH
CO
2 H OH^*0 V O DIC DMAP WANG Resin 23°C, 48 hrs For leading references see: a) Mathias (Synthesis 1979, 561). b) Sarantakis et al (Biochem. Biophys. Res. Commun. 1976, 73, 336). c) Hudson et al (Peptide Chemistry 1985 (Kiso, 1986, Protein Research Foundation, Osaka.). d) Wang Am. Chem. Soc. 1973, 95, 1328). e) Lu et al Org. Chem. 1981, 46, 3433.) e) Morphy et al (Tetrahedron Letters 1996, 37, 3209). e) Yedidia et al (Can. J. Chem.
1980, 58, 1144).
WO 98/27065 PCT/US96/20508 39 To 10g (11.2mmol, lequiv) of Wang resin in 80mL of dry dichloromethane was added 33.6mmol (3equiv) of diisopropylcarbodiimide and the mixture was sonnicated under N 2 for 2 hours (final bath temperature was 40 0 Freshly distilled acrylic acid (33.6mmol, 3equiv) and 4-dimethylaminopyridine (11.2mmol, lequiv) were added and the mixture was magnetically stirred for 16 hours at ambient temperature. The resin was filtered and thoroughly washed with dichloromethane (500mL), methanol (500mL), dimethylformamide (500mL), dichloromethane (500mL) and methanol (500mL) and dried in vacuo (O.lmmHg) for 24 hours. The coupling was repeated and resin 15 was filtered, washed and dried as above, and used directly in the next step.
o 4,4'-dibromobenzil 0- o P o Pd(OAc) 2
PR
3 Et 3
N
5 DMF 100 0
C
1 5 16 o SBr To 8.2g of acrylate Wang resin 15 was added 10.4g (28.3mmol) of 4,4'dibromobenzil, 437mg of palladium (II) acetate (1.95mmol), 1.25g of tri-otolylphosphine (4.11mmol), 95mL of dimethylformamide followed by 3.3mL (23.7mmol) of triethylamine. The mixture was placed in a 100 0 C preheated bath and stirred magnetically at 200rpm for 2 hours. The resin was filtered hot and washed thoroughly with hot dimethylformamide (500mL), hot acetic acid (500mL), methanol (500mL), dichloromethane (500mL), dimethylformamide (500mL), dichloromethane (500mL) and methanol (500mL) and dried in vacuo (0.lmmHg) for 24 hours. The linker was cleaved from the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20min at ambient temperature. 'H NMR for monobromomonoacid linker (400 MHz, d 6 -DMSO) 8 6.7 2H), 7.6 2H), 7.8 4H), 7.9 (s, 4H).
W-0 98/27065 PCT/US96/20508 WO 982706 PCTUS962O40 00 0 0 0 tert-Butyl acrylate
S.
.~Pd(OAc) 2
PR
3 Et 3
N
16 0 0Br DMF 100 0 C 17 2OtB To 10.2g resin 16 was added 5.4 lmL (37rnnol) of tert-butylacrylate, 132mg of palladium (II) acetate (0.592mmo1), 0.
3 60g of tri-o-tolylphosphine (1.1 8mmol), 3 lmL of dimethylformamide followed by lmL (7.4mmol) of triethylamnine. The mixture was placed in a 1 00 0 C preheated bath and stirred magnetically at 200rpmn for 1 8 hours. The resin was filtered hot and washed thoroughly with hot dimethylformamide (500mL), hot acetic acid (500mL), methanol (500mL), dichloromethane (500mL), dimethylformamide (500mL), dichioromethane (500m.L) and methanol (500mL) and dried in vacuo 1 mniHg) for 24 hours. The linker was cleaved from the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20min at ambient temperature. 'H NMR for diacid linker (400 MHz, 46-DMSO) 8 6.7 2H), 7.6 2H), 7.9 8H).
Br0 00 00 Pd(OAc) 2
PR
3 DMF 100 0 C 0.- 8 18 COH
COH
To 1 g of acrylate resin 15 was added 1 .02g (2.8mmol) of mono-bromo-monotert-butylacrylate benzil 0.044g of palladium (11) acetate (0.l9mmol), 0.130g of tri-o-tolylphosphine (0.41minol), 1 OmL of dimethylformamide followed by a solution of 0.76mL (5.7mrnol) of triethylamnine in lOmL of dimethylformaniide. The mixture was placed in a I100 0 C preheated bath and stirred magnetically at 200rpm for 2 hours.
The resin was filtered hot and washed thoroughly with hot dimethylformamide water (5OmL), 10% sodium bicarbonate (S0rmL), 10% aqueous acetic acid WO 98/27065 PCT[US96/20509 41 water (50mL), methanol (50mL), dichloromethane (50mL), methanol dichloromethane (50mL) and dried in vacuo (0.1mmHg) for 24 hours. The linker was cleaved from the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20min at ambient temperature. 'H NMR for diacid linker (400 MHz, d 6 -DMSO) 8 6.7 2H), 7.6 2H), 7.9 8H).
18 co 18 19
COR
Resin 18 was treated with a 1.0M solution of oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide for 1 hour and filtered. The resin was subsequently treated with a dichloromethane solution containing the alcohol (ROH), pyridine and 4 -dimethylaminopyridine for 20 hours at 23 0 C to yield the monoester resin 19.
co, CONRIAr Resin 18 was treated with a 1.OM solution of oxalyl chloride in dichloromethane in the presence of a catalytic amount of dimethylformamide for 1 hour and filtered. The resin was subsequently treated with a dichloromethane solution containing the aromatic amine (ArN(Ri)H), pyridine and 4 -dimethylaminopyridine for 20 hours at 23 0 C to yield the monoamide resin WO 98/2065 PCT/US96/2050& 42 1. EDCI, DMAP I 1 0 CH2C12 0 2. RjR2NH 18 CO 2 H 21 CONRR, 18 21 Resin 18 was treated with a dichloromethane solution containing the amine
(RIR
2 NH), EDCI and 4-dimethylaminopyridine for 20 hours at 23 0 C to yield the monoamide resin 21.
General methods for the synthesis of compounds (A2) and Method 1
OH
R
1 CHO
R-
OH
(A10)-1 By allowing an aldehyde (RICHO) wherein RI is defined as above in formula to react with itself.
These reactions may be carried out in a solvent or combination of solvents such as tetrahydrofuran (THF), dichloromethane (CH 2 Cl 2 in the presence of a catalyst TiC1 3 and a base pyridine) at temperatures ranging from -78 0 C to 23 0 C, for 1 to 60 hours.
WO 98/27065 PCT/US96/20508- 43 Examples
CHO
TiCI 3 OH N CO~tBU N
THF-CH
2
CI
2 N
N
0,tBuO 2 C
O
22
CO
2 tBU 4 Prepared according to Araneo et al (Tetrahedron Let. 1994, 35, 2213). The reaction was stirred for 4hrs at 23'C. 'H NMR of 22 (400MHz, CDC1 3 8 1.55 (s, 1 8H), 4.65 2H), 6.27 2H), 7.05 4H), 7.31 4H), 7.5 2H).
IBUO
2 C H0 2
C
OH 50% TFA-CH 2
CI
2 OH HO -HO 22/ 23\ Co 2 tBu CO 2
H
'H NMR of 23 (400MHz, CD 3 OD) 8 4.65 2H), 6.4 2H), 7.15 4H1), 7.4 4H), 7.6 211). MS ESI (neg ion) for 353 (calculated 354).
Method 2 OH CR
CR
R,--Iy R, R 2
CO
2 H_ 7 -R NoR--7 R OH OH 0 (AIO)-l (AIO)-2 (A2) WO 98/27065 PCT/US96/20508 44 By allowing a compound of formula (Al0)-1 prepared as above to react with a acid chloride (R 2
CO
2 H) and by subsequently oxidizing (A10)-2 wherein R, and R2 are defined as in formula (A2).
The first step in this reaction may be carried out in a solvent such as tetrahydrofuran (THF), dichloromethane (CH 2 C2), in the presence of diisopropyl carbodiimide (DIC) and a base 4-dimethylaminopyridine) at temperatures ranging from 0°C to 23 0 C, for 1 to 60 hours. The second step in this reaction may be carried out in a solvent such as dichloromethane (CH 2 C1 2 in the presence of an oxidizing reagent tetrapropylammonium perruthenate (VII) (TPAP)) and activated 4A molecular sieves at temperatures ranging from 0°C to 23 0 C, for 1 to hours.
WO 98/27065 PCTfUS96/2050B Examples
CO
2 tBu
CO
2 tBu HO -H OH MeO CO,H0 0 2/ DIC DMAP 24 tBU0 2 C tBuO 2 C OMe To 50mg of diol 22 (1 equiv) in lmL of dichioromethane was added diisopropyl carbodiimide (0.4 equiv) and the reaction was stirred for 1 hour at 23'C.
To the solution was added 4-dimethylaminopyridine (0.1 equiv) followed by paramethoxybenzoic acid (0.4 equiv) in 5mL of tetrahydrofuran and the mixture was stirred for an additional 3 hours at 23'C. The reaction was diluted with ethyl acetate and washed with IN HCl, saturated sodium bicarbonate and the organic layer was dried over sodium sulfate. The crude mixture was separated using radial chromatography (ethyl acetate-hexane eluent). 111 NMR of 24 (400MHz, CDC1 3 6 1.55 18H), 3.8 3H1), 5.05 IH), 6.0 lH), 6.25 IH), 6.3 111), 6.9 (d, 2H), 7.1 4H), 7.32 (in, 4H), 7.45 IH), 7.48 111), 8.0 111).
OH N% COOtH N ~OH'%c 2 t~uO 2 C 50%TFA-CH 2 C1 2
NN
HO
2 CN 2C OMe OMe WO 98/27065 WO 9827065PCT1US96/20508 46 11H NMR of 25 (400MHz, CD 3 OD) 863.82 3H4) 5.08 I1H), 6.02 I1H), 6.4 211), 6.9 2H), 7.22 4H1), 7.42 4H), 7.6 2H), 8.03 2H).
MS ESI (neg ion) for 487 (calculated 488).
CO
2 tBU TPAP tBUO 2
C'
CH
2
CI
2 0= 26 OMe OMe Hydroxyester 24 (1 equiv) was oxidized to ketoester 26 at 23'C in CF1 2 C1 2 in the presence of catalytic amount of TPAP (0.1 equiv), N-methylmorpholine oxide (2 equiv) and 4A activated powdered molecular sieves (500mg/mol of substrate). 1H4 NMR of 26 (400MHz, CDCl 3 8 1.55 1811), 3.8 311), 6.25 1H), 6.29 lH), 6.9 211), 7.0 114), 7.5 (in, 1011), 7.95 111), 8.02 I1H).
Co 2 tBU
COH
tBUO 2
C
OMe 1H NMR of 27 (400MHz, CD 3 OD) 8 3.82 3H), 6.45 111), 6.55 1H), 6.95 211), 7.18 111), 7.65 (in, 1011), 8.0 111), 8.08 I1H).
WO 98/27065 PCT/US96/20508 Method 3 RICOC
R
2 CHO
OCOR
1
OCOR,
S
R
2 R2 R2 R OH 0 (A10)-3 (A2) By allowing an acid chloride (RICOCI) to react with an aldehyde (R 2
CHO)
wherein RI, R 2 are defined as above in formula (A2) and by subsequently oxidizing (A10)-3.
The first step in this reaction may be carried out in a solvent or a combination of solvents such as tetrahydrofuran (THF), dichloromethane (CH 2 C2), in the presence of a catalyst TiCI 3 and a base pyridine) at temperatures ranging from 78 0 C to 23 0 C, for 1 to 60 hours. The second step in this reaction may be carried out in a solvent such as dichloromethane (CH 2 C12), in the presence of an oxidizing reagent tetrapropylammonium perruthenate (VII) (TPAP)) and activated 4A molecular sieves at temperatures ranging from 0°C to 23 0 C, for 1 to 60 hours.
Examples
CHO
CH
3
O
2
C(CH
2 4
COCI
TiCI 3
THF-CH
2
CI
2 COtBu 4
O
HO O (CH 2 4
CO
2
CH
3
CO
2 tBu CO 2 tBu 28 Prepared according to Araneo et al (Tetrahedron Lett. 1994, 35, 2213). The reaction was stirred for 4hrs at 23 0 C, the crude mixture was separated by flash W-0 98/27065 PCTIUS96/20508 48 chromatography (ethyl acetate in hexane eluent) to yield hydroxyester 28. 'H NMR of 28 (400MHz, CDCl 3 5 1.55 18H1), 1.6 (in, 4H), 2.2-2.4 (in, 4H), 3.6 311), 4.9 111), 5.85 111), 6.25 111), 6.3 111), 7.07 (in, 4H), 7.3 (mn, 4H), 7.45 (mn, 2H1).
W~u0 2 1C
HOC
TR
C0 2 1' 'H NMR of 29 (400MHz, CD 3 OD) 8 1.5 (in, 4H1), 2.3 (mn, 2H1), 2.4 (in, 211), 3.6 3H), 4.95 1H), 5.85 111), 6.4 211), 7.2 (mn, 411), 7.42 411), 7.6 (d, 2H). MS ESI (neg ion) for 495 (calculated 496).
0 HO 0 <(CH)C 2
CH,
TPAP
-CH
2 C1 2 28
CO
2 tBu CO 2 tBU 0 0 (CH,),C0 2
CH
3
CO
2 tBU CO 2 tBu Hydroxyester 28 was oxidized to ketoester 30 as above. 1H NMR of (400MHz, CDCl 3 8 1.55 1811), 1.65 (s br, 411), 2.3 (in, 211), 2.5 (mn, 211), 3.6 (s, 311), 6.3 111), 6.35 111), 6.78 111), 7.4-7.6 (nm, 811), 7.9 211).
WO 98/27065 49 General method for the synthesis of compounds (A3) Method 1 PCT/US96/20508 R3
R
1
CO
2 H R 2 NC R 3 CHO
O
SR. NHR 2 O R, (A3)-1 By allowing a carboxylic acid (RICO 2 H) to react with an isocyanide (R 2
NC)
and an aldehyde (R 3 CHO) wherein RI, R 2 and R 3 are defined as above in formula (A3).
These reactions may be carried out in a solvent or a combination of solvents such as dichloromethane
(CH
2 C2), chloroform (CHCl 3 methanol (MeOH), tetrahydrofuran (THF) or acetonitrile (CH 3 CN), in the presence or absence of a catalyst ZnCl 2 MgBr 2 at temperatures ranging from -78 0 C to 80 0 C, for 1 to hours.
Examples
R
1
CO
2 H R 2 CHO R 3 NC
R
2 R. NHR 3 Prepared according to Passerini (Gazz. Chim. Ital. 1926, 56, 826).
A solution of the carboxylic acid, aldehyde and isocyanide in a given solvent selected from tetrahydrofuran, acetonitrile, ethyl ether or chloroform was stirred between 0° and 25 0 C for 1 to 3 days. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel chromatography.
WO 98/27065 CU96258 PCT/US96/20508- CO'H
HOC
HN COEt .9C 1.C 6
H
13 CHO,THF 0 2. 50% TFA-CH 2 Cl 2 C0 2 tBU 3 32 'H NMR of 32 (400 MHz, d 6 -acetone) 8 0.8 3H), 1.1-1.6 (in, 9H), 1.97 (in, 1 3.9 (in, 2H), 4.1 (in, 2H), 5.3 I1H), 6.62 I1H), 7.7 I1H), 7.8 2H), 8.0.5 2H).
Method 2 AdMINR 3
NC
R- 0
R
1
CO
2 H R1 3
CHO
(A3)-2 Functionalized crosslinked polystyrene polymer By allowing a carboxylic acid (RCO 2 H) and an aldehyde (R 3 CHO) to react with a polymer bound isocyanide (R 2 NC) wherein RI, R 2 and R 3 are defined as above in formula (A3).
These reactions may be carried out on functionalized cross linked polystyrene polymers such as Merrifield resin, Wang resin, Rink resin, TentagelTm resin, in a solvent or a combination of solvents such as dichioromethane
(CH
2 Cl 2 chloroform (CHCl 3 methanol (MeOH), tetrahydrofuran (THF), acetonitrile (CH 3 CN), in the presence or absence of a catalyst ZnCl 2 MgBr 2 at temperatures ranging from WO 98/27065 PCT/US96/20508- 51 78 0 C to 80 0 C, for 1 to 60 hours. The product maybe released from the polymer by conditions known to those skilled in the art.
Examples
HO
2 C NHCHO 1. n DIC DMAP NC OH -0 2. Ph 3 P CCI, Et 3
N
WANG Resin n 2 to 33 Prepared according to Zhang et al (Tetrahedron Letters 1996, 37, 751).
0
S
33 33 0 R Nn CO 2
H
S R 2 CHO 0 0 oz CO,tBu 1 34 2. 50%TFA-CH 2
CI
2 O OH A solution of the carboxylic acid 3 in tetrahydrofuran was added to a mixture of the aldehyde and isocyanide resin 33 in tetrahydrofuran or acetonitrile. The mixture was stirred at 25 0 C or 60 0 C for 1 to 3 days. The resin was filtered and washed with dichloromethane and methanol and dried. Compounds 34 were isolated after treatment of the resin with a solution of 50% trifluoroacetic acid in dichloromethane for 1 hour at 23 0 C and removal of the solvent in vacuo.
WO 98/27065 PCT/US96/20508 52
O
S NC OHC CO C COH -o jl Ri N 2. 50%TFA-CHCI 2 0 O H n 33 0 A solution of the carboxylic acid in tetrahydrofuran was added to a mixture of the aldehyde 4 and isocyanide resin 33 in tetrahydrofuran or acetonitrile. The mixture was stirred at 25 0 C or 60 0 C for 1 to 3 days. The resin was filtered and washed with dichloromethane and methanol and dried. Compounds 35 were isolated after treatment of the resin with a solution of 50% trifluoroacetic acid in dichloromethane for 1 hour at 23 0 C and removal of the solvent in vacuo.
WO 98/27065 WO 9827065PCT/US96/20508 0 N f C0 2
H
n 0
HO
2
C.
TABLE 1.
Compound R2 MWt IM-HI- (Found) 36 Br 2 475; 477 474; 476 37 519 518 Br 38 C 6
H
14 CHO 2 405 404 39 C 6
H
14 CHO 5 447 446 CqH 2 oCHO 2 447 446 41 CqH 2 oCHO 5 489 488 W-0 98/27065 WO 9827065PCT/US96/20508 54 HOC
HN
HOC 0 TABLE Compound R, n MWt (Calculated) (Found) 42 2427 426 43 5469 468 Me( 44 5~ 2 442 441 0 2
N
452 441 440 F -f 46 5 483 482 47 H,C, 2 419 418
C
3
H,
48 H 7 C, 519 518 49 2 417 416 5 459 458 W-0 98/27065 WO 9827065PCT/US96/20508 General method for the synthesis of compounds (A4) RjCOC1 R 2 CHO- 0 Ri -11YR 2
OH
(M4) By allowing an acid chloride (RICOCI) to react with an aldehyde (R 2
CHO)
wherein R I, R 2 are defined as above in formula (A4).
These reactions may be carried out in a solvent or combination of solvents such as tetrahydrofuran (THF), dichiorornethane (CH 2 Cl 2 in the presence of a catalyst TiCIA) and a base pyridine) at temperatures ranging from -78'C to 23'C, for 1 to 60 hours.
Example
CHO
CH
3
O
2
C(CHA)COCI
N. TiC1 3
THF-CH
2 C1 2 C0 2 tBU 4 C0 2 tBu 51 Prepared according to Araneo et al (Tetrahedron Lett. 1994, 35, 2213). 'H NMR of 51 (400MHz, CDCl 3 8 1.45 9H), 1.5 (in, 4H), 2.1-2.3 (in, 4H), 3.6 (s, 3 4.6 IlH), 6.25 I 6.97 2H), 7.25 7.5 I H).
WO 98/27065 56 General methods for the synthesis of compounds (A6) Method 1 PCTIUS96/20508 0
SRINH
2
R
2
CHO
R
3 O NH 4 0Ac
R
4
R
3 R N N N R,
YY
R
2 (A6)-1
R
3
R
4 R1< N
N
R
2 (A6)-2 By allowing a compound of formula (A5) to react with an aldehyde (R 2
CHO),
a primary amine (RINH 2 and ammonium acetate wherein RI, R 2
R
3 and R 4 are defined as above in formula (A6).
These reactions may be carried out in a solvent such as acetic acid (AcOH) at temperatures ranging from 23 0 C to 120 0 C, for 1 to 60 hours.
Examples ButO 2 C ButO 2 C AcOH 100°C
CO
2 tBu Prepared according to Krieg et al (Z Naturforsch teil 1967, 22b, 132).
To 47mg of 6 (O.lmmol, l.Oequiv), R 2 CHO (0.lmmol, 1.Oequiv) in lmL of acetic acid was added 231mg of ammonium acetate (3.0mmol, 30equiv) in 0.5mL of acetic acid and the mixture was placed in 100 0 C preheated oil bath for 1 hour. The solution was then poured into ether and washed with saturated sodium bicarbonate.
WO 98/27065 PCT/US96/20508 57 The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to yield the desired imidazoles 52 which were purified by preparative thin layer chromatography with ethyl acetate-hexane or methanol-dichloromethane as eluent.
CO
2
H
Y
R,
TFA-CH
2
CI
2 23 0 C 1 h TABLE 3.
data not available.
WO 98/27065 WO 9827065PCTUS96/20508.
data not available.
WO 98/27065 WO 9827065PCTIUS96/20508 59 TABLE 3. (continued) Entry R2 MWt. NMt.
493 494 AcHN 54 (400MHz, CDC1 3
-CD
3 0D 10: 1) 8 6.23 2H), 7.3-7.48 (in, I OH), 7.88 2H), 8.02 2H).
(400MHz, CD 3 OD) 8 6.5 2H), 7.52 4H), 7.7 (in, 6H1), 9.1 (s,1IH).
56 (400MHz. CD 3 OD) 8 6.3 2H), 6.52 2H), 7.4-7.9 (in, 1211).
57 (400MHz, CD 3 OD) 8 6.52 2H), 7.50-8.36 (in, 1411).
58 (400MHz, CDC1 3
-CD
3 0D 10: 1) 8 3.7 3H), 6.3 2H), 6.85 2H), 7.4 (in, 811), 7.5 211), 7.85 2H).
59 (400MHz, CD 3 OD) 8 3.98 3H), 6.52 2H), 7.50-7.76 (mn, 1311).
(400MHz, CDC1 3
-CD
3 0D 10: 1) 586.3 2H), 6.5 (br s, 11H), 6.85 211), 7.3-7.6 (in, 1211).
61 di-tert-butyl ester (400MHz, CDC1 3
-CD
3 0D 6:1) 8 1.4 18H), 6.2 2H), 6.9 111), 7.2-7.42 (in, 111H), 7.5 8 11H), 7.62 I1H).
62 (400MHz, CD 3 OD) 8 6.50 2H), 7.30-8.70 (in, 1211).
63 (400MHz, CD 3 OD) 8 6.54 211), 7.46-8.60 (mn, 16H1).
WO 98/27065 PCTIUS9&20508 64 (400MHz, CD 3 OD) 8 3.90 311), 6.50 2H), 7.50-8.30 (in, 13H1).
di-tert-butyl ester (400MHz, CDC1 3
-CD
3 0D 6:1) 8 1.4 1 8H), 6.2 2H), 6.65 1H), 7.3-7.5 (in, 12H1).
66 di-tert-butyl ester (400MHz, CDC1 3
-CD
3 0D 6:1) 8 1.4 1811), 6.2 (dd, 211), 7.1 1iH), 7.3 -7.5 (mn, 10OH), 7.6 (br d, 111), 7.7 (dd, I1H).
67 di-tert-butyl ester (400MHz, CDC1 3
-CD
3 0D 6:1) 8 1.4 18H1), 6.2 211), 7.1 2H), 7.3-7.5 (mn, LOH), 7.75 (mn, 111).
68 (400M1-z, CD 3 OD) 8 1.2 6H), 3.48 4H), 6.52 2H), 7.3-8.02 (in, 1511).
69 (400MHz, CD 3 OD) 8 3.96 3H), 6.52 211), 7.04-7.70 (mn, 1311).
(400MHz, CD 3 OD) 8 6.46 211), 7.14 111), 7.50-7.80 (in, 1211).
71 (400MHz, CD 3 OD) 8 4.32 (in, 411), 6.52 211), 7.1-7.7 (in, 13H1).
72 (400MHz, CD 3 OD) 8 3.90-4.02 (3s, 9H), 6.50 211), 6.90-7.80 (in, 12H1).
73 (400MHz, CD 3 OD) 8 6.5 2H), 7.55 4H), 7.65 (in, 611), 7.95 211), 8.15 2H).
74 (400MHz, CD 3 OD) 8 3.95 311), 6.56 211), 6.9-7.82 (in, 14H1).
(400MHz, CDC1 3
-CD
3 0D 10: 1) 8 6.34 2H), 7.3-7.4 (mn, 1111), 7.52 211), 8.92 (d,2H).
WO 98/27065 PCTIUS96/20508 61 76 di-tert-butyl ester (400MHz, CDC1 3
-CD
3 0D 6: 1) 8 1.4 18H-), 6.2 (hr d, 2H), 6.9 (in, 1H), 7.05 (in, 1H1), 7.3-7.5 (in, 77 (400MHz, CDC1 3
-CD
3 0D 6:1) 860.9 (in, 5H), 1.3 (mn, 2H), 1.7 (in, 2H), 2.9 2H), 6.35 2H), 7.3-7.6 (mn, 1OH).
78 (400MHz, CD 3 OD) 6 6.50 2H), 7.40-7.9 (in, 14H).
79 di-tert-butyl ester (400MHz, CDCI 3 6 1.4 1 8H), 6.3 2H), 7.1 2H), 7.22 1H), 7.34 2H), 7.4-7.7 (in, 14H), 7.9 2H).
(400MHz, CD 3 OD) 6 6.54 2H), 7.6-8.0 (in, 19H).
81 (400MHz, CD 3 OD) 6 6.54 2H), 7.6-8.90 (mn, 19H).
82 (400MHz, CD 3 OD) 6 6.50 2H), 7.5 8-8.0 (in, 14H).
83 (400MHz, CD 3 OD) 6 3.96 3H), 6.52 2H), 7.3 6-7.90 (in, 13H).
84 (400MHz, CD 3 OD) 6 6.50 2H), 7.55-7.70 (in, 1 OH).
(400MHz, CD 3 OD) 6 6.12 2H), 6.56 2H), 7.10-7.60 (mn, 13H).- 86 (400MHz, CD 3 OD) 6 2.20 3H), 2.40 3H), 3.90 3H), 6.52 2H), 7.10-7.70 (in, 12H).
87 (400MHz, CD 3 OD) 6 5.20 2H), 6.56 2H), 7.22-7.98 (in, 19H).
W-0 98/27065 PCT/US96/20508 62 88 (400MHz, CD 3 OD) 8 1.52 (2s, 12H), 1.74 4H), 2.42 3H), 6.52 2H), 7.40-7.68 (in, 13H).
89 (400MHz, CD 3 OD) 8 1.12 2H), 3.0 (in, 4H), 6.56 2H), 7.52-7.62 (in, 13H).
(400MHz, CD 3 OD) 562.14 3 6.54 2H), 7.5 8-8.0 (in, 14H).
1. MO -a CHO OH NH 4 OAc AcOH 100*C N 2. 50% TFA-CH 2
CI
2 COH CO 2
H
HO 0 OH HN CF 3
COH
S91 OMe BUtO 2
C
Prepared according to Krieg et al (Z Naturforsch teil 1967, 22b, 132).
'H NMR of 91 (400 MHz, CD 3 OD) 6 3.9 (s,3 6.2 2H), 6.95 2H), 7.2 (d, 2H), 7.4-7.6 (mn, 6H), 7.9 2H).
BUtO 2 C ICO 2 tBu
R
1
NH
2
R
2
CHO
NH
4 OAc AcOH 100*C N NR,
R
2 92
CO
2 tBU WO 98/27065 WO 9827065PCTUS9620508 63 Prepared according to Krieg et al (Z Naturforsch teil 1967, 22b, 132).
Lt0 2 C Co~tBu H0 2 C \C2 TFA-CHZC1 2 R,N N -CF 3
COH
23 0 C 1 h
R
2 93 TABLE 4.
Entry RR2 MWt MWt (Caic.) (Obs.) 94 n-C 4
H
9 H 416 415 n-C 4
H
9 498 497 96 Ph Iij~ 518 517 97 n-C 4
H
9 522 521 98 Ph 542 541 99 Ph H 436 435 100 j< 582 581
M.I
M L~ WO 98/27065 PCTIUS96/20508 64 94(400MHz, CD 3 OD) 60.8 3H), 1.22 (in,2H), 1.62 2H), 4.10 2H), 6.42 111), 6.58 1H), 7.32-7.80 (in, 1011), 9.18 1H1).
(400MHz, CD 3 OD) 6 0.64 3H), 1.04 (in, 2H), 1.58 (in, 2H), 4.20 2H), 6.42 111), 6.62 111), 7.42-8.0 (in, 1311).
96 (400MHz, CD 3 OD) 6 6.42 (2d, 211), 7.12-7.68 (in, 18H).
97 (400MHz, CD 3 OD) 860.6 311), 1.0 (mn, 2H), 1.38 (mn, 2H), 4.12 2H), 3.84 3H), 6.42 111), 6.62 111), 7.22-7.8 (in, 1311).
98 (400MHz, CD 3 OD) 6 3.80 3H), 6.44 (2d, 2H), 6.94-7.68 (in, 1911).
99 (400MHz, CD 3 OD) 6 6.44 (2d, 2H), 7.20-7.60 (in, 1511), 9.2 111).
100 (400MHz, CD 3 OD) 6 1.22 911), 2.40 311), 6.36-6.44 (2d, 211), 7.26-7.60 (in, 1811).
Method 2 0 R4 R 3 R4 NH 2
R
2 CHO
H
R
3 NHOAc R<Nyr
+R
3
H-R
4 ~N N Riy (AS)-2 (A5)-2 (6 (A6)4 WO 98/27065 PCT/US96/2050B By allowing a polymer bound compound of formula (A5)-2 to react with an aldehyde (R 2 CHO), a primary amine (RiNH 2 and ammonium acetate wherein RI, R 2
R
3 and R 4 are defined as above in formula (A6).
These reactions may be carried out on functionalized cross linked polystyrene polymers such as Merrifield resin, Wang resin, Rink resin, TentagelTM resin, in a solvent such as acetic acid (AcOH) at temperatures ranging from 23°C to 120 0 C, for 1 to 60 hours. The product maybe released from the polymer using conditions known to those skilled in the art.
Examples HO,C
COH
A 1. R 2 CHO NH40Ac o I AcOH 100 0
°C
Nk 2.20% TFA-CH 2 C12 N NH CFCO2H 17 cotaBu R 101 To resin 17 were added excess NH40Ac and R 2 CHO and acetic acid and the mixture was heated at 100 0 C for 15 hours, cooled to 23 C and washed with methanol and dichloromethane and dried under vacuum. The trifluoroacetate salts of imidazoles 101 were isolated following treatment of the resin with a solution of trifluoroacetic acid in dichloromethane for 20 minutes at 23 0
C.
HOC
COOR,
1. R 2 CHO 0 AcOH 100°C N NH CFCO,H 2.20% TFA-CH 2 C1 2 0 1 R2
CO,R
19 102 Same procedure as imidazoles 101.
WO 98/27065 WO 9827065PCTIUS96/20509 TABLE W-0 98127065 WO 9827065PCTIUS96/20508 TABLE 5. (continued) Entry RR2 MWt. MWt.
I O,(Cale.) (Obs.) ill 2-propyl N2 553 554 112 2-indanyl 2 627 628 113 Mo 626 627 Ph I I 1. R 2 CHO NH 4 OAc AcOH 100 0 C -0
HCC
20% TFA-CH 2 C1 2 CON (R 1 )Ar Same procedure as imidazoles 101.
1. R 3 CHO NH 4 OAc 0 AcQH 100'C NNHCC2 N
-FI-
2 '2.20% TFA-CH 2 C1 2
Y
110 CONR 1
R,
Same procedure as imidazoles 101.
W-0 98/27065 PCTIUS96/20508 68
HOC.
.CONHR,
TABLE Entry R, R 2 MWt. MWt.
(Caic.) (Obs.) 116 CFM-o-( 559 560 117 meO 562 563 118 0sB 633 634 119 NO, 642 643 Ph OMe 120 EtNl( 592 593 121 0 579 580 122 n-propyl m.o 508 509 123 n-propyl Br S 562,564 563, 565 124 n-butyl F 528 529 125 n-heptyl IC 1NO 579 580 WO 98/27065 WO 987065PTIUS96/20508 TABLE 6. (continued)_____ Entry IIR 2 MWt. MWt.
(jCaic.) (Obs.) 126 n-octyl F2-. 566 567 127 n-octyl DkN1~ 619 620 128 0) 612 613 PhI Method 3 0 0 R4--YOR 3
R
1 NH7 R 2
CHO
R
1 N YN
R
2 0
OR
3
R
4 OR 3 (A6)-6 By allowing a compound of formula (129) Org. Chem., 1995, 60, 823 1; J Org. Chem., 1993, 58, 4785) to react with an aldehyde (R 2 CHO), a primary amine
(R
1
NH
2 and anmmoniumn acetate wherein RI, R 2
R
3 and R 4 are defined as above in formula (A6).
These reactions may be carried out in a solvent such as acetic acid (AcOH) at temperatures ranging from 23'C to 120'C, for I to 60 hours.
Examples
CO
2
IH
CO
2 tBu 3 Ph) PPh3 EDCI DMAP
CH
2
I
Ph o 0 P~h,
CO
2 tBU 131 WAO 98/27065 PCTIUS96/20508 Prepared according to Wasserman et al (J Org. Chem., 1995, 60, 823 1; Org. Chem., 1993, S8, 4785). Benzyl (triphenyiphosphoranylidene) acetate (130) was purchased from Aldrich chemical company and used directly. '11 NMR of 131 (400 MHz, CDC1 3 8 1.5 911), 4.62 2H), 6.3 111), 6.62 211), 7.05 211), 7.1 111), 7.38-7.8 (in, 2011). TLC: RjfO.5 (30% ethyl acetate-hexane).
Ph Oxone® THF-H 0 0 PPh 3 131
.CO
2 tBu Prepared according to Wasserman et al (J Org. Chem., 1995, 60, 823 1; J.
Org. Chem., 1993, 58, 4785). 'H1 NMR of 132 (400 MHz, CDC1 3 8 1.5 911), 5.1 (s, 211), 5.15 (br s, 211, 2 x 6.4 IH), 6.95 211), 7.1 211), 7.18 111), 7.4 211), 7.5 1H), 7.9 211). TLC: RTO.7 (30% ethyl acetate-hexane).
HO
OHI
132 0 0 2 C1 2 Z PNI HO OH 0 C0 2 1Bu Ph C0 2
H
133 'H NMR of 133 (400 MHz, CDC1 3 -CDOD, 8:1) 8 5 211), 6.4 (d 111), 6.9- 7.16 (in, 511), 7.35 211), 7.53 1H), 7.9 2H).
1. HCHO, NH 4 OAc 2.30% TFA-CH 2 Cl 2 C0 2 tBu COCHPh
~CF
3
CO
2
H
WO 98/27065 PCTIUS96/2008 71 Prepared according to Brackeen et al (Tetrahedron Letters 1994, 35, 1635).
For other approaches to imidazole-4-carboxylates see: a) Nunami et al Org. Chem.
1994, 59, 7635). b) Heindel et al (Tetrahedron Letters 1971, 1439). 'H NMR of 134 (400 MHz, 8:1 CDC1 3
-CD
3 OD) 8 5.2 2H), 6.4 1H), 7.25 (br s, 5H), 7.5 2H), 7.6 1H), 7.7 2H), 8.3 1H).
Method 4 0 O 0 0 RCHO R4 OR 3
R
4
OR
3 R RR2 4 OR 3
RINH
2 NH40Ac RN N Ny NR R2 R129 129 (A6)-7 (A6)-89 By allowing a compound of formula (129) to react with a polymer bound aldehyde (RICHO), a primary amine (R 2
NH
2 and ammonium acetate wherein RI, R 2
R
3 and R 4 are defined as above in formula (A6).
This reaction may be carried out on functionalized cross linked polystyrene polymers such as Merrifield resin, Wang resin, Rink resin, TentagelTM resin, in a solvent such as acetic acid (AcOH) at temperatures ranging from 23 0 C to 120 0 C, for 1 to 60 hours. The product maybe released from the polymer using conditions known to those skilled in the art.
Examples HOC- CH
O
OH -O DIC DMAP WANG Resin 23°C, 48 hrs 135 CHO WO 98/27065 PCTIUS96/0508 72 For leading references see: a) Mathias (Synthesis, 1979, 561). b) Sarantakis et al (Biochem. Biophys. Res. Commun. 1976, 73, 336). c) Hudson et al (Peptide Chemistry 1985 (Kiso, 1986, Protein Research Foundation, Osaka.). d) Wang Am. Chem. Soc. 1973, 95, 1328). e) Lu et al Org. Chem. 1981, 46, 3433). To 6mmol (lequiv) of Wang resin in 130mL of dry dimethylformamide was added 18mmol (3equiv) of diisopropylcarbodiimide and the mixture was sonnicated for 4 hours (final bath temperature was 37 0 4-Formylcinnamic acid (18mmol, 3equiv) and 4-dimethylaminopyridine (6mmol, lequiv) were added and the mixture was magnetically stirred for 48 hours at ambient temperature. The resin was filtered and thoroughly washed with dimethylforamide (500mL), methanol (500mL), dichloromethane (500mL) and methanol (500mL) and dried in vacuo (0.1mmHg) for 24 hours. A coupling yield of 80% was established by cleaving 100mg of the resin with a solution of 20% trifluoroacetic acid in dichloromethane for 20min at ambient temperature.
o
HO
2
C
135 CHO 1. NH4OAc o S AcOH 100 0 C N F HN N CF 3
COH
0 2. 50%TFA-CH 2 C1 2 HO OH Ph H
CO
2 tBu 1 132 136
CO
2
H
To 60mg (0.048mmol, 1.0equiv) of 135 was added 40mg (0.097mmol, of 132 followed by 37mg (0.48 1mmol, 5.0equiv) of ammonium acetate and 0.2mL of acetic acid. The mixture was heated to 100 0 C for 15 hours, filtered, washed with dimethylformamide, dichloromethane, methanol and dichloromethane. The crude product was isolated by treatment of the polymer with a solution of trifluoroacetic acid in dichloromethane for 1 hour at 23 0 C. The solvent was removed and the residue was purified by preparative thin layer chromatography WO 98/27065 PCT/US96/20508- 73 methanol-dichloromethane eluent). 'H NMR of 136 (400 MHz, CD 3 0D) 8 5.15 (s, 2H), 6.48 1H), 6.55 1H), 7.25 (br s, 4H), 7.5-7.8 9H), 8.1 1H). MS (ESI negative ion) 493; Method NC R4 R4 N R3
RINH
2
R
2
CO
2 H R 3 RI O NH 4 0Ac H
R
4 COCHO N I N N HN2 R3 137 (A6)-9 By allowing a primary amine (RINH 2 a carboxylic acid (R 2
CO
2 H) and a ketoaldehyde (R 4 COCHO) to react with a polymer bound isocyanide (R 3 NC) and by subsequently cyclizing compound 137 with ammonium acetate wherein RI, R 2
R
3 and R 4 are defined as above in formula (A6).
The first step in this reaction may be carried out on functionalized cross linked polystyrene resins such as Merrifield resin, Wang resin, Rink resin, TentagelTM resin, in a solvent or a combination of solvents such as dichloromethane (CH 2 C12), chloroform (CHC13), methanol (MeOH), tetrahydrofuran (THF) or acetonitrile
(CH
3 CN), in the presence or absence of a catalyst ZnCl 2 MgBr 2 at temperatures ranging from -78 0 C to 80'C, for 1 to 60 hours. The second step in this reaction may be carried out in a solvent such as acetic acid (AcOH) at temperatures ranging from 23 0 C to 120 0 C, for 1 to 60 hours.
W-0 98/27065 WO 9827065PCTUS96/20508 0 Br or 0 Br, Et 2
NHOH)_
Ar MeOH
R
or 0'I
H
Ar R 138 Ar 2-naphthyl, 3,4-dichiorophenyl, R CH 3
CF
3
NO
2
CH
3
O,
and CF 3 O, F, Cl, Br, Ph Prepared according to Gunn et al Org. Chem. 1977, 42, 754).
CO
2
H
HN n 0 1. R5C0CHO, R 2
CO
2 H, RNH 2 R 5 0 N4C 2. NH 4 OAc AcOil 100 0
C
03.20% TFA-CH 2
CI
2 R, -N yN -CF 3
CO
2
H
33
R
2 139 Prepared according to Zhang et al (Tetrahedron Letters 1996, 3 7, 75 1) kil Ph H 2 C s N
M
0 N
S
N'
COH
*TFA
MeO 140 Prepared according to Zhang et al (Tetrahedron Letters 1996, 3 7, 75 1) 'H NMR of mono tert-butyl ester of 140 (400 MHz, CDC1 3 8 1.1 (m,2H), 1.2 1.3 1.5 1.56 2.2 2.9 (m,IH), 3.1 (m,1IH), 3.2 (m,1IH), 3.8 4.6 6.1 IH), 6.9 (tH), 7.1 7.4 2H), 7.6 (d,1IH).
WO 98/27065 PCTIUS96/20508 Method 6 R2 O R1CO 2 H R 2 COCHO R 3 NC O- O R, 0
R
3
NHR
2 N NH 3Y
R,
(A6)-10
NHR
a By allowing a carboxylic acid (RICO 2 H) to react with an isocyanide (R 3
NC)
and a ketoaldehyde (R 2 COCHO) and by allowing compound 141 to cyclize in the presence of ammonium acetate, wherein RI, R 2 and R 3 are defined as above in formula (A6).
The first step in this reaction reaction may be carried out in a solvent or a combination of solvents such as dichloromethane
(CH
2 CI2), chloroform (CHC13), methanol (MeOH), tetrahydrofuran (THF), acetonitrile (CH 3 CN), in the presence or absence of a catalyst ZnC12, MgBr 2 at temperatures ranging from -78 0 C to 0 C, for 1 to 60 hours. The second step in this reaction may be carried out in a solvent such as acetic acid (AcOH) at temperatures ranging from 23 0 C to 120 0 C, for 1 to 60 hours.
Examples
R
2
COCHO
RjCO 2 H 0
R
3
NC
0 R2 NHR 3
NH
4 0Ac AcOH N NH
Y
NHR
3 Prepared according to Bossio et al (Liebigs Ann. Chem. 1991, 1107).
WO 98/27065 PCTIUJS96/20508 76 To an ethyl ether mixture of the carboxylic acid and ketoaldehyde at 0°C was added dropwise an ethyl ether solution of the isocyanide. The mixture was warmed to 0 C and stirred for 2 hours to 3 days. The solution was diluted with ethyl acetate, washed with saturated sodium bicarbonate and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by silica gel chromatography to yield a-Acyloxy-p-ketoamide 142.
A solution of the a-Acyloxy-p-ketoamide 142 (1 equiv) and ammonium acetate (30 equiv) in acetic acid was heated at 100 0 C for 2 to 15 hours. The reaction was cooled to 23 0 C, diluted with ethyl acetate, washed with saturated sodium bicarbonate and dried over sodium sulfate. Solvent was removed in vacuo and the crude mixture was sepaprated by silica gel chromatography to provide imidazole 143.
COtBu OHC 0 0 NCH,
H
0 O 1. n-Butyl-NC S 2. 50%TFA-CH 2
CI
2 144 CO,H F 3 0 OH 'H NMR of 144 (400 MHz, d 6 -acetone) 8 0.85 3H), 1.2-1.6 4H), 3.3 2H), 6.55 1H), 6.62 1H), 7.3 2H), 7.7 1H), 7.82 2H), 8.1 2H), 8.25 (dd, 2H).
W-0 98/27065 WO 9827065PCTIUS96/20508 N C 4
H
9
H
1. NH 4 OAc AcQHi 2. 50%TFA-CH 2 C1 2 N C 4
H,
H
N NH *TFA O
OH
OtBu 'H NMR of 146 (400 MHz, d 6 -acetone) 8 0.9 3H), 1.4 (in, 2H), 1.6 (mn, 2H), 3.35 (mn, 2H), 6.58 IH), 7.12 2H), 7.65 1H), 7.78 2H), 8.1 (s br, I1H), 8.05 (in, l 8.2 2H).
General method for the synthesis of compounds (A7)
R
1
CO
2 H R 2 COCHO R 3 NC -~0 '0 0
R
3 NHR 2 0 N Sl0
NHR
3
R,
WA)
By allowing a carboxylic acid (RCO 2 H) to react with an isocyanide (R 3
NC)
and a ketoaldehyde (R 2 COCHO) wherein RI, R 2 and R 3 are defined as above in formula (A7) and by allowing compound 141 to cyclize in the presence of ammnoniunm acetate.
The first step in this reaction reaction may be carried out in a solvent or a combination of solvents such as dichioromethane
(CH
2 Cl 2 chloroform (CHC1 3 WO 98/27065 PCTfUS96/20509 78 methanol (MeOH), tetrahydrofuran (THF), acetonitrile (CH 3 CN), in the presence or absence of a catalyst ZnCl 2 MgBr 2 at temperatures ranging from -78 0 C to 0 C, for 1 to 60 hours. The second step in this reaction may be carried out in a solvent such as acetic acid (AcOH) at temperatures ranging from 23 0 C to 120 0 C, for 1 to 60 hours.
Examples
R
2 0 1 20 0L,. NHR 3
NH
4 0Ac AcOH 0 R2 NHR 3
NYO
R1 147 Prepared according to Bossio et al (Liebigs Ann. Chem. 1991, 1107).
A solution of the a-Acyloxy-3-ketoamide 141 (1 equiv) and ammonium acetate (2 equiv) in acetic acid was heated at 1000C for 2 to 15 hours. The reaction was cooled to 23 0 C, diluted with ethyl acetate, washed with saturated sodium bicarbonate and dried over sodium sulfate. Solvent was removed in vacuo and the crude oxazole 147 was purified by silica gel chromatography.
WO 98/27065 PCT[US96/20508 79
F
F
CHH
0 N CH H N, 0OTFA O 0 1. NH 4 OAc AcOH 2. 50%TFA-CH 2 C1 2 I 0 OH 0 0tHU 145 148 'H NMR of 148 (400 MHz, d 6 -acetone), 8 0.9 3H), 1.4 (in, 2H), 1.6 (mn, 2H), 3.42 (in, 2H), 6.63 IH), 7.2 2H), 7.7 LH), 7.9 2H), 8.18 (s br, IR), 8.25 2H), 8.6 (in, I H).
General methods for the synthesis of compounds (A8) and (A9) Method 1 R H2
N
H2 R R R, R2 R 2
R
11 I NH >Ri< 2 N N0 R14 R6 RS 1R3 \R 16 R 3 149 R14 R5 R4 R (A8)-1 (A8)-2 By allowing a compound of formula (A5) to react with compound of formula (149) wherein R 1, R2, R3, R 4
R
5 and R 6 are defined as above in formula (A8).
These reactions may be carried out in a solvent or a combination of solvents such as dioxane or acetic acid (AcOH) at temperatures ranging from 23'C to 120'C, for I to 60 hours.
WO 98/27065 WO 9827065PCTJUS96/2050& Examples ButO 2
C
NH, NH
R
150 1. AcOH 100 0
C
2. 50% TFA-CH 2 C1 2 N &ii N* TFA CO~t~u151 A solution of O.lmmol of diamine 150 and O.lmmol of 6 in l.2ml, of 1,4dioxane-acetic acid was heated at 1 00'C. Upon completion of the reaction as judged by thin layer chromatography, ethyl acetate was added and the organic layer was washed with water, 0.5M citric acid, 10% sodium bicarbonate and dried over sodium sulfate. The compounds were purified using silica gel chromatography.
COH
1. AcOH 100 0 C 2. 50% TFA-CH 2 C1 2 N N/ F R, R, C0 2 1BU TABLE 7.
Compound II R 2
R
3 152 H H NO 2
H
153 H Cl Cl H 154 H H CH 3
H
155 H H -CO 2 H H 156 H H CO 2 Me H 157 H Ht
H
98/27065 PCTIUS96/20508 81 152 (400MHz, CD 3 OD) 66.5 2H), 7.3 111), 7.4-7.8(in, I1OH), 7.9 1H), 8.05 I1H). MS ESI (pos ion) for 468 (calculated 467).
153 (400MHz, CD 3 OD) 8 6.48 2H), 7.5 (dd, 8H), 7.6 2H), 8.24 2H). MS ESI (pos ion) for 491, 492 (calculated 490, 49 1).
154 (400MHz, CD 3 OD) 8 3.3 3H), 6.5 2H), 7.59 8H), 7.62 2H), 8.3 11H), 8.55 1H), 8.95 11H). MS ESI (pos ion) for 437 (calculated 436).
155 (400MHz, d 6 -DMSO) 6 6.56 2H), 7.5 (in, 6H), 7.65 4H1), 8.2 IIH), 8.3 I1H), 8.6 I1H). MIS ES! (neg ion) for 465 (calculated 466).
156 (400MHz, CD 3 OD) 6 6.56 2H1), 7.5 (s br, 8H1), 7.65 2H), 8.2 1H), 8.3 I1H), 8.7 IlH). MS ESI (neg ion) for EM-Hi-: 479 (calculated 480).
157 (400MHz, d 6 -DMSO) 6 6.52 2H1), 7.54-8.16 (in, 14H).
Method 2 0
NH
2 R 1 -yR (AS)0 RH,
R
2 N N (A9)-1 A9- Rs (A9)-2 WO 98/27065 PCT/US96/20508 82 By allowing a compound of formula (A5) to react with compound of formula (158) wherein RI, R 2
R
3
R
4 Rs are defined as above in formula (A9).
These reactions may be carried out in a solvent or a combination of solvents such as dioxane or acetic acid (AcOH) at temperatures ranging from 23°C to 120 0
C,
for 1 to 60 hours.
Examples ButO 2
C
NH
2
NNH
2 159 HO,C
CO'H
1. AcOH 100 0
C
2. 50% TFA-CH 2 C1 2 N N TFA
N
160
CO
2 tBu 'H NMR of 160 (400MHz, CD 3 OD) 8 6.5 2H), 7.5-7.7 12H), 7.95 1H), 8.65 1H), 9.15 1H).
MS ESI (pos ion) for 424 (calculated 423).
General method for the synthesis of compounds OH OCOR 2 R 1 R1 R 2
CO
2 H -R R
R
OCOR
2 (A1O)-3 (A10)-1 By allowing a compound of formula (A 10)-1 prepared as above to react with a carboxylic acid (R 2
CO
2 H) wherein R, and R 2 are defined as above in formula WO 98/27065 PCTIUS96/2050.8 83 These reactions may be carried out in a solvent such as tetrahydrofuran (THF), dichloromethane (CH 2 C12), in the presence of diisopropyl carbodiimide (DIC) and a base 4,4-dimethylaminopyridine) at temperatures ranging from 0°C to 23 0 C, for 1 to 60 hours.
Examples
CO
2 tBu H 3 CO
CO
2 tBu o o Ho H,CO CO H O OH DIC DMAP o 22 0 tBuO2C tBuOC
OCH
3 To 50mg of diol 22 in ImL of dichloromethane was added diisopropyl carbodiimide (2.2 equiv) and the reaction was stirred for 1 hour at 23 0 C. To the solution was added 4,4-dimethylaminopyridine (0.2 equiv) followed by paramethoxybenzoic acid (2.2 equiv) in 5mL of tetrahydrofuran and the mixture was stirred for an additional 3 hours at 23 C. The reaction was diluted with ethyl acetate and washed with IN HC1, saturated sodium bicarbonate and the organic layer was dried over sodium sulfate. The crude mixture was purified using radial chromatography (ethyl acetate-hexane eluent). 'H NMR of 161 (400MHz, CDCl 3 18H), 3.8 6H), 6.25 2H), 6.32 2H), 6.85 4H), 7.18 4H), 7.31 (d, 4H), 7.45 2H), 7.95 4H).
WO 98/27065 PCTIUS96/20508 84 HCO CO 2 tBu H 3 CO CO 2
H
o o °0 0 50% TFA-CHzCIl 2 tBuO 2 C 161 OC 3
HO
2 C
OCH
3 'H NMR of 162 (400MHz, CD30D) 8 3.8 6H), 6.4 4H), 6.95 4H), 7.38 4H), 7.5 4H), 7.6 2H), 7.95 4H). MS ESI (neg ion) for 621 (calculated 622).
General method for the synthesis of compounds (All) R, R, OH
OSO
2
R
2 OSORR2 R R, O Rz R- RN OH OH O
R
163 164 (All) By allowing a compound of formula (A10)-1 prepared as above to react with a sulfonyl chloride (R 2
SO
2 CI), and subsequently by oxidizing intermediate 163 and by allowing intermediate 164 to react with a thioamide (R 3
C(S)NH
2 wherein RI, R 2 and R3 are defined as above in formula (All).
The first step in this sequence of reactions may be carried out in a solvent such as tetrahydrofuran (THF), dichloromethane (CH 2 C12), in the presence of a base (e.g.
i 4 ,4-dimethylaminopyridine, triethylamine, triisopropylamine) and a sulfonyl chloride tosyl chloride, mesyl chloride), at temperatures ranging from -20 0 C to 23 0 C, for 1 to 60 hours. The second step in this sequence of reactions may be carried out in a solvent such as dichloromethane (CH2C1 2 in the presence of an oxidizing reagent WO 98/27065 PCT/US96/20508 tetrapropylammonium perruthenate (VII) (TPAP)) and activated 4A molecular sieves at temperatures ranging from 0°C to 23 C, for 1 to 60 hours. The third step in this sequence of reactions may be carried out in a solvent such as acetic acid, toluene, dioxane at temperatures ranging from 0°C to 120 0 C, for 1 to 60 hours.
Examples COtBu H,C a so'cI Et 3 N DMAP
CH
2
CI
2 bis-tosylated compound tBuO,C To 50mg of diol 22 in ImL of dichloromethane was added Tosyl chloride (42.5 mg), 4,4-dimethylaminopyridine (6mg), triethylamine (95ptl), and the reaction was stirred for 12 hours at 23 0 C. The volatiles were removed in vacuo and the crude mixture (containing 165, the bis-tosylated compound and the corresponding epoxide) was separated by flash chromatography (ethyl acetate-hexane eluent) to give a mixture of 165 and the corresponding bis-tosylated compound (27mg total).
CO
2 tBu
CO
2 tBu bis-tosylated compound TPAP NMO OTs 4A Sieves
CH
2
CI
2 tBuO 2
C
tBuO 2
C
The mixture consisting of 165 and the corresponding bis-tosylated compound was oxidized as described above for compound 24. The crude mixture was purified WO 98/27065 PCTIUS96/20508 86 by flash chromatography (ethyl acetate-hexane eluent) to give3.9mg of 166 and 16mg of the corresponding bis-tosylate. 1H1 NMR of 166 (400MHz, d 6 -acetone) 8 1.5 (d, 18H), 2.4 311), 6.4 111), 6.5 1H), 6.95 1H), 7.35 211), 7.42 2H1), 11H), 7.6 (in, 3 7.7 (dd, 4H), 8 211).
tBU0 2 C C0 2 tBU
CO
2 tBU/ IH 166s tBUO 2
C
OMe 167 To 3.9mg of 166 was added 3mg of para-methoxythiobenzamide and 0.5m1 of toluene and the reaction was heated at 65'C for 12 hours. The solvent was removed in vacuo and the crude mixture was purified by flash chromatography (ethyl acetatehexane eluent) to givel.8mg of 167. 'H NMR of 167 (400MHz, CDCl 3 5 1.5 (d, 18H1), 3.8 3H1), 6.3 (dd, 2H), 6.9 2H1), 7.35 2H), 7.4 (in, 4H1), 7.55 (in, 411), 7.9 211).
WO 98/27065 PCT/US96/20508 87 tBuOC
CO
2 tBu HO 2 C
CO
2
H
20% TFA-CH 2 CIl 2 N S N S *CF 3
CO
2
H
OMe OMe 167 168 'H NMR of 168 (400MHz, CD30D) 5 3.8 3H), 6.45 (dd, 2H), 7.0 2H), 7.4 2H), 7.5-7.7 8H), 7.9 2H).
Biological Protocols PTP-1B Gene Cloning and Protein Purification The following procedure was conducted for recombinant production and purification of protein tyrosine phosphatase PTP-1B, for use as a substrate in PTPase inhibition assays.
A. Production of a PTP-1B cDNA A human placental cDNA library was synthesized in a 50 ul reaction containing 1 ug human placental poly(A)' mRNA (Clontech, Palo Alto, CA), 4 ul random hexamer primers, 8 ul of 10mM dNTPs (Pharmacia, Piscataway NJ), lul (200 U/ul) Moloney murine leukemia virus reverse transcriptase (Gibco-BRL, Canada), ul (26 U/ul) RNAsin (Promega, Madison WI), and 12 ul 5x buffer (Gibco-BRL). The synthesis reaction was incubated at 37'C for one hour and then heat inactivated at C for five minutes.
A PTP-1B cDNA was amplified, using polymerase chain reaction (PCR), from the cDNAs synthesized as described above. More particularly, based on the published sequence of PTB-1B, two PCR primers were synthesized to amplify a WO 98/27065 PCTIUS96/20508 88 portion of the PTP-IB coding sequence known to encode a 321 amino acid fragment containing the PTP-1B catalytic domain and having PTPase activity. See Hoppe et al., Eur. J. Biochem., 223:1069-77 (1994); Barford, et al., J. Molec. Biol., 239:726-730 (1994); Chernoff et al., Proc. Natl. Acad. Sci. USA, 87:2735-2739 (1990); Charbonneau et al. Proc. Natl. Acad. Sci. USA, 86:5252-5256 (1989). The primers had the following respective sequences: (SEQ ID NO: 1) CGCACTGGATCCTCATGGAGATGGAAAAGG 3' PTP-IB-B(3') (SEQ ID NO: 2) CTCCCTGAATTCCTAATTGTGTGGCTCCAGG 3' The first primer, which hybridizes to the non-coding strand, corresponds to the portion of the PTP-1B coding sequence and encodes a BamH I restriction site upstream of the initiation codon, to facilitate cloning. The second primer, which hybridizes to the coding strand, corresponds to the 3' portion of the PTB- B fragment of interest, and encodes a stop codon and an EcoR I restriction site downstream from the stop codon.
A 100 tpl PCR reaction mixture containing approx. 1 ug of the human placental cDNA library, 0.2 mM of each dNTP, 30 uM of each primer, lx Amplitaq DNA polymerase buffer (Perkin-Elmer, Norwalk CT), and 5 units Amplitaq DNA polymerase (Perkin-Elmer) was denatured at 94 C for 5 minutes and then subjected to cycles of amplification as follows: 1) 940C denaturation for 1 minute; 2) 55 0
C
annealing for 1 minute; and 3) 72 0 C primer extension for 1 minute.
The PCR reaction product (992 bp) was digested with BamH I and EcoR I (New England Biolabs, Beverly MA) to yield a 975 bp product encoding the 321 amino acid PTP-1B protein fragment, and having "sticky ends" to facilitate cloning.
WO 98/27065 PCTIUS96/20508 89 B. Production of a PTP-1B expression vector.
The 975 bp PTP-IB partial cDNA was purified by agarose gel electrophoresis and ligated into a BamH I/EcoR I-digested pGEX-3X plasmid vector (Pharmacia, Piscataway, NJ). The pGEX vector is designed to produce a fusion of glutathione-Stransferase (GST) to a protein encoded by another DNA fragment inserted into the vector's cloning site. Complete sequencing of the insert of the resultant plasmid, designated pGEX-3X-PTP-1B, confirmed the identity of the PTP-1B cDNA, and insertion in the proper orientation and reading frame.
C. Expression and Purification of GST/PTP1B fusion protein.
E. coli strain DH5(a (Gibco-BRL) was transformed with plasmid pGEX-3X- PTP- B following the supplier's transformation protocol and grown at 37°C with vigorous shaking in Luria-Bertani broth supplemented with 100 ug/ml ampicillin.
When the cultures reached an O.D.
600 of 0.7-1, production of the GST/PTP-1B fusion protein was induced with 0.1 mM IPTG (Isopropyl b-D-Thiogalactoside). After 3 additional hours of culturing at 37 0 C, the bacteria were pelleted by centrifugation.
The bacterial pellet was resuspended in 10x lysis buffer consisting of -12.5 mM HEPES, 2 mM EDTA, pH 7.0, 15 mM b-mercaptoethanol (bME) and 1 mM PMSF. The lysate was sonicated (on ice) until slight clearing was observed (approx.
three min.) and then centrifuged at 10,000 revolutions per minute (RPM) for 10 min.
The supernatant was diluted 1:4 with buffer A (25 mM HEPES, pH 7.0, and 15 mM bME).
Primary purification was achieved using a 5 ml Hi-Trap pre-packed Q column (Pharmacia). After loading the diluted supernatant onto the column, the column was washed with 10 bed volumes of buffer A. The GST/PTP-1B fusion protein was then eluted using a linear gradient of Buffer A and Buffer B (buffer A 1 M NaCI).
Eluted fractions containing protein were identified by SDS-PAGE and Coomassie Blue staining (Pharmacia PhastSystem), and fractions containing PTP-1B activity were identified using the PTP-1B activity assay described below. Elution of the fusion protein occurred at about 30% Buffer B.
W-0 98/27065 PCT/US96/20508 Fractions containing PTPase activity were pooled, diluted 1:4 with NET buffer mM Tris, pH 8.8, 100 mM NaC1, 1 mM EDTA and 15 mM bME), and loaded onto a 10 ml GST-Sepharose 4B column (Pharmacia). After loading, the column was washed first with 3 bed volumes of NET buffer 1% NP40 (Sigma Chemical Co., St.
Louis, MO), then with NET buffer until O.D. at 280 nm was basal. The GST/PTP-1B fusion protein was eluted from the column using 10 mM glutathione in 33 mM Tris, pH 8.0. Elution of proteins was monitored at O.D.
2 8 0 and fractions were assayed for activity and run on SDS-PAGE as described above. PTP-1B fusion protein eluted after approx. 4-5 minutes (flow rate Iml/min.).
The GST/PTP-lB-containing fractions from the GST-Sepharose 4B purification were pooled, concentrated into a final storage buffer (0.2 M NaCI, mM HEPES, 1 mM EDTA, and 5 mM DTT, pH 7.0) using a 1 ml Hi-Trap Q column (pre-packed, Pharmacia), and stored at -80°C (final concentration of 0.52 mg/ml).
The foregoing procedure yielded approximately 5mg of PTP-1B fusion protein per 500 ml of cultured cells, purified to substantial homogeneity as assessed by SDS-
PAGE.
Assay of PTP-1B Activity.
PTP-1B enzymatic activity of samples was assayed in microtiter plates as follows.
The protein concentration of the PTP-1B enzyme preparation was determined using the Bio-Rad Protein Assay kit (Bio-Rad, Hercules CA). An aliquot from each sample was taken and diluted to 2 mg protein/ml using activity assay buffer (100 mM Sodium Acetate, pH 6.0, 1 mM EDTA, 0.1% TX-100 (International Biotechnologies, Inc.) and 15 mM bME) to form a PTP-I B stock solution.
A 100 ul reaction mixture was prepared containing 10 ul of the PTP-1B stock solution, 10 ul of 9 mM p-nitrophenylphosphate ((pNPP), Sigma Chemical Co., St.
Louis MO), and 80 ul of activity assay buffer (100 mM sodium acetate, pH 6.0, 1 mM EDTA, 0.1% Triton X-100, 15 mM bME). Reactions were mixed gently and incubated at 37 C for 60 minutes. Enzymatic cleavage of phosphate from pNPP (a WAD 98/27065 PCT/US96/20508 91 tyrosine phosphate analog) is marked by a colorimetric change in this substrate. See, Imbert et al., Biochem 297:163-173 (1994); Ghosh and Miller, Biochem.
Biophys. Res. Comm., 194:36-44 (1993); Zanke et al., Eur. J. Immunol., 22:235-39 (1992).
Reactions were stopped by addition of 10 ul of a 0.5 M NaOH/50% EtOH solution. To determine the enzymatic activity, absorbance readings of the reactions were measured at 405 nm using a Molecular Devices Thermomax Plate Reader (Menlo Park CA).
Gene Cloning and Protein Purification The following procedure was conducted for recombinant production and purification of protein tyrosine phosphatase CD45, for use as a substrate in PTPase inhibition assays.
A. Production of aCD45 cDNA, and production of a CD45 expression vector.
A human cDNA library was synthesized from RNA isolated from the human Jurkat cell line, as described above for PTP-1B cDNA was amplified, using polymerase chain reaction (PCR), from the cDNAs synthesized above. Two PCR primers were synthesized to amplify the coding sequence of CD45. The primers had the following respective sequences: (SEQ ID NO: 3) CTACATCCCGGGATGTCCTGCAATTTAGATG 3' (SEQ ID NO: 4) CATTTATGTCCCGGGCTATGAACCTTGAT 3' The first primer corresponds to the 5' portion of the CD45 coding sequence and encodes a Sma I restriction site upstream of the initiation codon, to facilitate cloning.
WO 98/27065 PCT/US96/20508 92 The second primer corresponds to the 3' portion of the CD45 sequence, and encodes a stop codon and a Sma I restriction site downstream from the stop codon.
The PCR reaction product (2127 bp) was digested with Sma I (New England Biolabs, Beverly MA) to yield a 2110 bp product. The pET24C plasmid vector (Novagen, Inc., Madison WI) was digested with the BamH I restriction enzyme, and the "sticky" ends were filled using T4 DNA polymerase according to the manufacturer's instructions (New England Biolabs, Beverly MA); the resulting plasmid DNA was ligated to Sma I-digested CD45 PCR product. The pET24C vector is designed to produce high levels of the protein encoded by cDNA inserted into the vector's cloning site (CD45), in bacterial hosts. Complete sequencing of the insert of the resultant plasmid, designated pET24C-CD45, confirmed the identity of the cDNA, and insertion in the proper orientation and reading frame.
C. Expression and Purification of CD45 protein.
E. coli strain DH5a (Gibco-BRL) was transformed with pET24C-CD45 following the supplier's transformation protocol, plated onto Luria-Bertani agar plates supplemented with 30 ug/ml kanamycin and grown overnight at 37°C. A single bacterial colony was transferred into 50 mis Luria-Bertani broth supplemented with ug/ml kanamycin and grown overnight with vigorous shaking. This overnight culture was split into two equal parts, and added to 2L Luria-Bertani broth supplemented with 50 ug/ml kanamycin. When the cultures reached an O.D.
60 0 of 1, production of the recombinant CD45 protein was induced with 0.1 mM IPTG (Isopropyl b-D-Thiogalactoside). After 5 additional hours of culturing at 37 C, the bacteria were pelleted by centrifugation.
The bacterial pellet (approximately 5 grams) was resuspended in 10x (w/v) lysis buffer consisting of 12.5 mM HEPES, 2 mM EDTA, pH 7.0, 15 mM bME and 1 mM PMSF. The lysate was sonicated (on ice) until slight clearing was observed (approx. three min.) and then centrifuged at 10,000 revolutions per minute (RPM) for min. The supernatant was filtered through 1mm Wattman filter paper, and 9.7 grams 194 grams/L) of ammonium sulfate were added to the solution on ice to WO 98/27065 PCT/US96/20508 93 precipitate soluble proteins. After a 1 hour incubation on ice, the lysate was spun at 10,000 RPM for 30 min. at 4 C; supernatant was removed, and an additional 7.6 grams 151 grams/L) of ammonium sulfate were added. The resulting pellet was resuspended in 3 mis of buffer B (33 mM imidazole-HCl pH 8.0, 2mM EDTA, mM bME, 0.002% PMSF) and stored on ice. After another 1 hour incubation on ice, the spin supernatant with ammonium sulfate was spun again at 10,000 RPM for mins at 4 C. The resulting pellet from the second centrifugation was resuspended in 2 mis of buffer B. The two pellet solutions were pooled and dialyzed overnight against buffer B.
Secondary purification was achieved using a Mono-Q column. (Pharmacia).
After loading the diluted supernatant onto the column, the column was washed with bed volumes of buffer B. The recombinant CD45 protein was then eluted using a linear gradient of Buffer B and Buffer C (buffer B 1 M NaCI). Eluted fractions containing protein were identified by SDS-PAGE and Coomassie Blue staining (Pharmacia PhastSystem), and fractions containing CD45 activity were identified using the CD45 activity assay described below.
The CD45-containing fractions from the MonoQ column purification were pooled and stored at 4 C.
Assay of CD45 Activity.
enzymatic activity of samples was assayed in microtiter plates as follows.
A 100 ul reaction mixture was prepared containing 10 ul of the CD45 stock solution, 10 ul of 9.3 mM p-nitrophenylphosphate ((pNPP), Sigma Chemical Co., St.
Louis MO), and 80 ul of activity assay buffer (100 mM sodium acetate, pH 6.0, 1 mM EDTA, 0.1% Triton X-100, 15 mM bME). Reactions were mixed gently and incubated at 37 0 C for 60 minutes. Reactions were stopped by addition of 10 ul of a M NaOH/50% EtOH solution. To determine the enzymatic activity, absorbance readings of the reactions were measured at 405 nm using a Molecular Devices Thermomax Plate Reader (Menlo Park CA).
WO 98/27065 PCTIUS96/20508 94 In vitro PTPase Inhibition Assay The ability of the compounds of the present invention, such as the cinnamic acid derivative compounds of Example 2, to inhibit the PTPase activity of PTP-1B, PTP-1C, and PTPa was determined using modifications of the PTP-IB and activity assays described in Examples 3 and 4.
First, 0.001 mmol of the cinnamic acid derivative (or other PTPase inhibitor compound) was dissolved in 100 ul of DMSO to create a 10 mM stock solution. The mM stock solution was used to add varying concentrations (100 uM, 33 uM, uM, 3 uM, 1 uM, 0.3 uM, 0.1 uM, 0.03 uM, 0.01 uM or 0.003 uM) of the inhibitor compound to a series of otherwise identical PTPase activity assay reactions (100 ul final volume in microtiter wells). Thus, each 100 ul reaction contained 10 ul PTPase enzyme stock solution (final phosphatase concentration of approximately 20 ng/well), ul activity assay buffer, 10 ul pNPP stock solution (final pNPP concentration of .9 mM for PTP-1B assay, 0.93 mM for CD45 assay, 0.5 mM for PTPa assay, and 8 mM for PTP-1C assay), and 10 ul of the diluted inhibitor compound in DMSO. Assay buffers contained: for CD45 and PTP-1B assays, 100 mM sodium acetate at pH 1 mM EDTA, 0.1% Triton X-100, and 15 mM bME; for PTP-1C assays, 100 mM sodium acetate at pH 5.5, 0.1% BSA, and 15 mM bME; for PTPa assays, 100 mM sodium acetate at pH 5.25, 0.1% BSA, and 15 mM bME. Purified phosphatase was added to the reaction mixtures to begin the reactions; the reactions were incubated at 37C for 60 min. (for PTP-IB and CD45 assays) or at 27 C for 60 min. (for PTP-1C and PTPa assays), stopped, and colorimetrically analyzed as described above. As positive and negative controls, reactions were performed containing 10 ul DMSO with no inhibitor compound or containing the known PTPase inhibitors vanadate (final concentration .5 mM; for PTP-1B and CD45 assays) or ammonium molybdate (final concentration 1 mM; for PTP- C and PTPa assays) substituted for the inhibitor compound of the invention.
The concentration of inhibitor compound required to inhibit 50% of the PTPase activity (IC50) was determined as follows. First, absorbance readings from WO 98/27065 PCTIUS96/20508 the negative control reactions were treated as a baseline and subtracted from the absorbance readings of the experimental reactions. Then, for each reaction, a percent inhibition was calculated using the following formula: 100 X 1 O.D.
405 reaction O.D.
405
DMSO)]
For each inhibitor compound tested, an IC50 concentration was calculated from a best-fit computer analysis of the calculated percent inhibition for the various dilutions of the compound.
Inhibitor compounds having an IC50 less than 10 uM (and optimally less than for a particular PTPase were scored as highly effective inhibitors of that PTPase enzyme, and are preferred inhibitors of the present invention.
WO 98/27065 PCTIUS96/20508 96 As it will be apparent to those persons skilled in the art, the foregoing biological data is not absolute and will vary according to many factors such as assay conditions and the like.
TABLE 8.
%inhibition %inhibition %inhibition Compound of PTP1B of PTPca ofPTPIC at lpM at 100M at 100M 36 52 0 42 37 85 63 59 38 93 71 63 39 82 47 53 88 82 62 41 39 20 17 42 84 92 88 43 76 82 79 44 79 87 86 85 85 84 46 75 73 61 47 68 48 63 48 69 3 33 49 37 0 50 37 WAO 98/27065 PCTIUS96/20508 97 TABLE 9. IC50 values (in liM) against PTP1B and CD45 for given compounds IPTP1B CD451 iPTP1BrCD 4 5 r PTN 9 0.37 3.9 70 0.42 1.9 95 2 6 13 31 71 0.43 0.53 96 0.4 2.4 23 0.27 72 0.52 5.5 97 6 0.89 73 0.62 2.8 9 8 6 27 0.5 74 0.64 4.2 99 1.5 7.4 29 0.8 75 0.68 3.4 100 26 >100 32 1.8 76 0.68 0.93 133 54 0.072 0.73 77 0.78 7.5 134 3.4 0.1 0.56 78 0.79 1.15. 136 0.7 8 56 0.135 0.9d4 79 4.8 8.2 140 1.2 57 0.25 1.0 80 10 20 144 3 58 0.25 0.97 81 26 19 146 5.9 59 0.25 0.35 82 11.9 12.8 148 9 0.29 1.0 83 1.3 1.5 152 0.85 1.2 61 0.97 0.955 84 1.2 2.7 153 2.65 1.91 62 1.5 0.985 85 1.5 1.8 154 3.83 2.45 63 1.7 2.4 86 1.8 7.1- 155 1 1.3 64 3.0 6.4 87 1.0 1.1 156 1.7 1.3 1.3 1.4 88 2.65 7.8 157 5.5 66 1.7 2.5 89 13.7 >100 160 0.98 1.52 67 1.0 1.25 90 0.86 1.12 162 1.8 68 0.3 0.865 91 25.9 >100 168 3 69 0.41 1.9 F94 0.7 7 *:data not available WO 98/27065 WO 9827065PCIUJS962509 TABLE 10. %inhibition %inhibition Compound of PTP1B of at 14iM atlp.M 103 44% 14% 104 24% 14% 105 61% 18% 106 45% 21% 107 25% 51% 108 30% 62% 109 _*14% 110 _*22% 11ll_ 18% 112 _*16% 113 1% TABLE 11.
data not available %inhibition %inhibition Compound of PTP1B Compound of PTP1B atlp.M atlp.M 116 41% 123 117 67% 124 83% 118 56% 125 93% 119 71% 126 59% 120 67% 127 79% 121 73% 128 122 87% 1 WO 98/27065 PCT/US96/205088 99 The compounds of the present invention have asymmetric centers and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereoisomers, with all isomeric forms being included in the present invention as well as mixtures thereof.
Pharmaceutically acceptable salts of the compounds of Formula (Al) thru (All) where a basic or acidic group is present in the structure, are also included within the scope of this invention. When an acidic substituent is present, such as COOH, there can be formed the ammonium, sodium, potassium, calcium salt, and the like, for use as the dosage form. When a basic group is present, such as amino or a basic heteroaryl radical, such as pyridyl, an acidic salt, such as hydrochloride, hydrobromide, acetate, maleate, pamoate, methanesulfonate, p-toluenesulfonate, and the like, can be used as the dosage form.
Also, in the case of the -COOH being present, pharmaceutically acceptable esters can be employed, methyl, tert-butyl, pivaloyloxymethyl, and the like, and those esters known in the art for modifying solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.
In addition, some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of the invention.
The term "therapeutically effective amount" shall mean that amount of drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. Generally, a daily dose of about 0.5mg/Kg to 100mg/Kg body weight in divided doses is suggested to treat PTPase related diseases. Such dosage has to be individualized by the clinician.
The present invention also has the objective 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, WO 98/27065 PCTIUS96/20508 100 powders, granules, emulsions, capsules, syrups or elixirs. The composition for oral use may contain one or more agents selected from the group of sweetening agents, flavouring agents, colouring agents and preserving agents in order to produce pharmaceutically elegant and palatable preparations. The tablets contain the acting ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be, for example, (1) inert diluents such as calcium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Coating may also be performed using techniques described in the U.S. Patent Nos. 4,256,108; 4,160,452; and 4,265,874 to form osmotic therapeutic tablets for control release.
Formulations for oral use may be in the form of hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin. They may also be in the form of soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.
Aqueous suspensions normally contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspension. Such expicients may be: suspending agent such as sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents which may be naturally occurring phosphatide such as lecithin; a condensation product of an alkylene oxide with a fatty acid, for example, polyoxyethylene stearate; a condensation product of WO 98/27065 PCTIUS96/2008 101 ethylene oxide with a long chain aliphatic alcohol, for example, heptadecaethylenoxycetanol; a condensation product of ethylene oxide with a partial ester derived from a fatty acid and hexitol such as polyoxyethylene sorbitol monooleate, or a condensation product of ethylene oxide with a partial ester derived from fatty acids and hexitol anhydrides, for example polyoxyethylene sorbitan monooleate.
The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to known methods using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also 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.
Compounds of Formula (Al) thru (Al 1) may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
The compounds of the present invention may also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of Formula (Al) thru (A 11) are employed.
WO 98/27065 PCTIUS96/20508 102
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Claims (202)

1. A protein tyrosine phosphatase activity-modulating compound with the structure depicted in Formula X-C(R)=C(R")COOR" (B) wherein R' and RC are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted arylC 1 11 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 1 1 alkyl, arylC I 11 alkyl, Co-lialkyloxyC. 11 alkyl, arylCo-l 1 alkyloxyC.. 11 alkyl, C 0 1 alkylthioC.. 1 jalkyl, arylC 0 11 alkylthioC.. 11 alkyl, C 0 1 alkylaminoC. 11 alkyl, arylCo.. 1 1 alkylaminoC 0 11 alkyl, di(arylC 1- jalkyl)aminoCO. 11 alkyl, C 1 .lialkylcarbonylC.. 1 alkyl, arylC 1 I jalkylcarbonylC..I jalkyl, C 1 11 alkylcarboxyC.. 11 akl, ary IC 1 1 alkylcarboxyC.. 11 alkyl, C 1 1 alkylcarbonylaminoC. 11 alkyl, arylC 1-1 lalkylcarbonylaminoC. 1 jalkyl, C 0 1 1 alkylCOOR 1 -CO~ 1 alkyICONR 2 R 3 wherein RI, R 2 and R 3 are independently selected from hydrogen, C 1 jalkyl, arylC 0 1 alkyl, or R 2 and R. 3 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 jalkyl, arylCO-C, jalkyl substituent. (ii) is selected from the group consisting of hydrogen, CI 1 1 alkyl, substituted C 1 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 1 ,alkyloxy, arylCO.. 11 alkyloxy, CO..,,alkylthio, arylC 0 ,,alkylthio, CO 11 alkylamino, arylC 0 alkylainino, di(arylC. 1 1 alkyl)amino, C 1 _1 alkylcarbonyl, aryIC 1 11 alkylcarbonyl, alkylcarboxy, arylC 1- 1 ,alkylcarboxy, C 1 1 jalkylcarbonylaruino, aryl C 1 1 ,alkylcarbonylaxnino, ,alkylCOOR4, jalkylCONR 5 R 6 wherein R 4 R. 5 and R. 6 are independently selected from hydrogen, C 1 jalkyl, arylCO-C, 1 alkyl, or WO 98127065 PCT/US96/20508 106 R 5 and R 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 1 alkyl, arylCo- C 1 1 alkyl substituent, mono-, di- and tri-substituted arylC 0 -Ci 1 alkyl wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and R, and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxaliny 1, 1 ,8-naphthyridinyl, pteridinyl, carbazo lyl, acridinyl, phenaziny 1, phenothiazinyl, phenoxaziny 1, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
2. A compound as defined in claim 1 wherein aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
3. A compound as defined in claim 1 wherein aryl is selected from thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrobenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pynidyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, WO 98/27065 PCT/US96/20509 107 quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
4. A compound as defined in claim 1 wherein aryl is selected from thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, phenothiazinyl, thiazolyl, isothiazolyl, benzthiazolyl, thiadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 1 wherein aryl is selected from furyl, pyrany 1, benzofuranyl, isobenzofuranyl, 2,3 -dihydrobenzofuranyl, phenoxazinyl, chromanyl, benzodioxolyl, hydroxypyronyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
6. A compound as defined in claim 1 wherein aryl is selected from pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, I ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, purinyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, *benzoxazolyl, oxadiazolyl, thiadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
7. A compound as defined in claim 1 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, benzothienyl, isobenzothienyl, furyl, benzofuranyl, isobenzofliranyl, pyrrolyl, indolyl, isoindolyl, imidazolyl, benzimidazolyl, pyridyl, WO 98/27065 PCTIUS9620508 108 pyrazinyl, pyradazinyl, pyrimidinyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, thiadiazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
8. A compound as defined in claim 1 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, benzothienyl, furyl, benzofuranyl, pyrrolyl, indolyl, imidazolyl, benzimidazolyl, pyridyl, quinolyl, thiazolyl, benzthiazolyl, oxazolyl, benzoxazolyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
9. A compound as defined in claim 1 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 1 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
11. A compound as defined in claim 1 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
12. A compound as defined in claim 1 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
13. A compound as defined in claim 1 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
14. A compound as defined in claim 1 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. WAO 98/27065 PTU9fOO PCTIUS96/20508 109 A compound as defined in claim 1 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
16. A compound with the structure depicted in Formula (A2): 0 0 (A2) wherein at least one of R I, R 2 and R 3 substituents has the general structure depicted in Formula (B) (B) wherein R' and are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C I 11 alkyl, optionally substituted arylC 1 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 -IIalkyl, arylCI- 11 alkyl, C 0 1 1 alkyloxyC.. 11 alkyl, arylC 0 1 1 alkyloxyCO- 11 alkyl, C 0 1 1 alkylthioC 0 1 jalkyl, arylCo- 1 jalkylthioC 0 1 1 alkyl, CO-, lalkylaminoC., jalkyl, arylC.. 1 lalkylaminoC 0 11 alkyl, di(arylC 1- jalkyl)aminoC 1 1 alkyl, C 1 .lialkylcarbonylC 0 1 1 alkyl, arylC 1 lialkylcarbonylC 01 1 alkyl, C 1 11 alkylcarboxyC- 1 I alkyl, ary 1Cl-l alkylcarboxyC 0 11 alkyl, C 1 ialkylcarbonylaminoCo 11 alkyl, arylC 1 alkylcarbonylaminoC. 1 1 alkyl, CO-, I alkylCOOR4, alkylCONR 5 R 6 wherein R 4 R 5 and R 6 are independently selected from hydrogen, C I-C1 1 alkyl, arylCO-C 1 alkyl, or R 5 and R 6 are taken together WO 98/27065 WO 9827065PCTIUS96/20508 110 with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-C, jalkyl, arylC 0 1 alkyl substituent. (ii) is selected from the group consisting of hydrogen, CI 1 1 alkyl, substituted C 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO-. 11 alkyloxy, arylCO. 1 1 alkyloxy, C 0 11 alkylthio, arylC- 1 1 alkylthio, C 0 1 alkylamnino, arylCO. 1 1 alkylamino, di(aryl1C- 1 1 alkyl)amino, C, I alkylcarbonyl, arylCj_ 11 alkylcarbonyl, C 1 1 alkylcarboxy, arylC 1 11 alkylcarboxy, Cl-. 1 alkylcarbonylamino, aryl C 1 1 alkylcarbonylamino, 1 alkylCOOR 7 1 ,alkyICONR 8 R 9 wherein R 7 R 8 and R(9 are independently selected from hydrogen, C I-C 1 alkyl, arylC 0 -C 1 alkyl, or R 8 and R(9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C I Ialkyl, arylCo- C1 1 alkyl substituent, mono-, di- and tni-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for R and R (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrcbenzofiiranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenaziny 1, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, WO 98/27065 PCT/US96/20508 111 and wherein the remaining of RI, R2 and R 3 are independently selected from the group consisting of: hydrogen; (ii) C l-ialkyl, substituted CI. lalkyl wherein the alkyl substituents are defined as above, (iii) arylCo.1 1 alkyl, (iv) mono-, di- and tri-substituted arylCo-Cl alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
17. A compound as defined in claim 16 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
18. A compound as defined in claim 16 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
19. A compound as defined in claim 16 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 16 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
21. A compound as defined in claim 16 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
22. A compound as defined in claim 16 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. WAD 98/27065 PCTIUS96/20508 112
23. A compound as defined in claim 16 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or-solvates thereof.
24. A compound with the structure depicted in Formula (A3): 0 R 3 0 R NHR 2 0 WA) wherein at least one of RI, R(2 and R(3 substituents has the general structure depicted in Formula (B) X-C(R)=C(R")COOR" (B) wherein R' and are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 1 alkyl, optionally substituted arylC 1 1 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano. trihalomethyl, hydroxypyronyl, C, -Ialkyl, arylC 11 alkyl, C 0 11 alkyloxyC.. 11 alkyl, arylC 0 1 1 alkyloxyC.. 11 alkyl, C 0 11 alkylthioC 0 1 1 alkyl, arylCo., lalkylthioC. 1 1 jalkyl, Co-, jalkylaminoC. 1 jalkyl, arylC 0 1 I jalkylaminoC 0 11 alkyl, di(arylC 1 1 jalkyl)aminoC. 1 jalkyl, C 1 .l alkylcarbonylC.- 1 alkyl, arylC 1 11 alkylcarbonylC. 11 alkyl, C 1 11 alkylcarboxyC. 1 1 alkyl, ary 1C 1 1 alkylcarboxyC 0 11 alkyl, C 1 1 1 alkylcarbonylaminoC. 11 alkyl, arylCl-.l alkylcarbonylaminoC 011 alkyl, Co- 1 ialkylCOOR 4 -Co 1 1 jalkylCONR 5 R 6 wherein R(4, R(5 and R6 are independently selected from hydrogen, C 1 -C 1 jalkyl, arylCO-C, jalkyl, or R5 and R(6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 jalkyl, arylC 0 -C 1 jalkyl substituent. (ii) is selected from the group consisting of hydrogen, WO 9=7065 WO 9827065PCr[US9620508 113 C,..,,alkyl, substituted 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 ,alkyloxy, arylC- 1 1 alkyloxy, C 0 11 alkylthio, arylC 0 alkylthio, C 0 1 alkylaxnino, arylCo-., alkylamino, di(arylC 0 ,alkyl)amino, C, -lialkylcarbonyl, arylC,.. lialkylcarbonyl, C 1 1 1 alkylcarboxy, aryiCl ,alkylcarboxy, C, ,alkylcarbonylamino, aryl C 1 1 alkylcarbonylamino, -C 0 ,alkylCOOR 7 -C 0 .,,alkylCONR 8 R 9 wherein R 7 R 8 and R 9 are independently selected from hydrogen, ,alkyl, arylC 0 ,alkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, IIalkyl, arylC 0 C, IIalkylI substituent, mono-, di- and tni-substituted arylC 0 ,alkyl wherein the aryl substituents are defined as above for R and R, (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluoreny 1, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxaliriyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of RI, R 2 and R 3 are independently selected from the group consisting of: hydrogen; WO 98/27065 PCT/US96/20508 114 (ii) Cl. 1 alkyl, substituted C 1 11 alkyl, Cl-i.alkylcarbonyl, substituted C 1 Slalkylcarbonyl wherein the alkyl substituents are defined as above, (iii) arylCo-. alkyl, arylCo-l alkylcarbonyl, (iv) mono-, di- and tri-substituted arylCo-Cllalkyl, mono-, di- and tri- substituted arylCo-Cnlalkylcarbonyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 24 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
26. A compound as defined in claim 24 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
27. A compound as defined in claim 24 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
28. A compound as defined in claim 24 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
29. A compound as defined in claim 24 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 24 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
31. A compound with the structure depicted in Formula (A4): WO 98/27065 PTU9100 PCTIUS96/20508 115 0 OH (A4) wherein at least one of RI, R 2 substituents has the general structure depicted in Formula (B) (B) wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 1 alkyl, optionally substituted arylI 1 jalkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, -Ialkyl, arylC i-I 1 alkyl, C 0 1 1 alkyloxyC- 1 1 alkyl, aryICO- 1 1 alkyloxyC 0 11 alkyl, C 0 alkylthioC 0 I jalkyl, arylC. 1 jalkylthioC 0 jalkyl, CO-, lalkylaminoC 0 1 alkyl, arylC 0 alkylaminoC 0 1 1 alkyl, di(arylC 1 1 jalkyl)aminoC 0 1 ,alkyl, C 1 1 alkylcarbonylC 0 ,alkyl, arylCl- I IalkylcarbonylC 0 jalkyl, C 1 1 alkylcarboxyC 0 1 1alkyl, ary IC,. 1 alkylcarboxyC 0 1,alkyl, C 1 ,alkylcarbonylaminoC. 11 alkyl, arylC, llalkylcarbonylaminoC 0 ,,alkyl, lalkylCOOR 3 jalkylCONR 4 R 5 wherein R 3 R 4 and R 5 are independently selected from hydrogen, C I-C, 1 alkyl, arylCO-C 1 ,alkyl, or R 4 and R 5 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, IIalkyl, aryl C 0 IIalkyl substituent. (ii) is selected from the group consisting of hydrogen, C,,,1alkyl, substituted C,.,,alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 alkyloxy, arylC 0 alkyloxy, C 0 ,,alkylthio, arylC 0 ,alkylthio, C 0 1 alkylamino, arylC 0 ,alkylamino, di(arylC.., alkyl)amino, C, -I alkylcarbonyl, arylC,. WAO 98/27065 PCTIUS96/20508 116 lialkylcarbonyl, C 1 1 alkylcarboxy, arylCl l alkylcarboxy, C 11 1 alkylcarbonylamino, aryl C 1 1 alkylcarbonylamino, -C 0 1 1 alkyICOOR 6 1 alkyICONR 7 R 8 wherein R 6 R 7 and R 8 are independently selected from hydrogen, C I-C 11 alkyl, arylC 0 -C 11 alkyl, or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-C 1 1 alkyl, arylCo- C 1 alkyl substituent, mono-, di- and tn-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for R and R (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyreny 1, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrctenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiaziny I, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of RI, R 2 is selected from the group consisting of: hydrogen; (ii) C 1 1 1 alkyl, substituted CI- 1 1 alkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 1 alkyl, (iv) mono-, di- and tri-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof WO 98/27065 PCT[US96/20508 117
32. A compound as defined in claim 31 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
33. A compound as defined in claim 31 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
34. A compound as defined in claim 31 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 31 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
36. A compound as defined in claim 31 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
37. A compound as defined in claim 31 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
38. A compound as defined in claim 31 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
39. A compound with the structure depicted in Formula 0 Rz R2 0 wherein at least one of R2 substituents has the general structure depicted in Formula (B) WO 98/27065 WO 9827065PCT/US9620508 118 X-C(R')=C(R")COOR"' (B) wherein R and R are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted arylC 1 I 1 Ialkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C, 1 1 1 alkyl, arylC I.. 11 alkyl, C 0 1 1 alkyloxyCo-li 1 alkyl, arylCO. 1 1 alkyloxyC. 11 alkyl, C 0 11 alkylthioC.. 11 alkyl, arylCo. 11 alkylthioCo- 11 alkyl, C 0 11 alkylaminoC.. 11 alkyl, arylCo- 11 alkylaminoC 0 11 alkyl, di(arylC 1 1 alkyI)aminoC 0 1 alkyl, Cl.. 1 alkylcarbonylC.. 11 alkyl, arylC 1 I lalkylcarbonylC.. I lalkyl, C 1 1 alkylcarboxyC.. 11 alkyl, ary ICl-. 11 alkylcarboxyC.. 11 alkyl, C 1 1 alkylcarbonylaminoC. 11 alkyl, arylC 1 l alkylcarbonylaminoC.. 11 alkyl, C 0 1 alkylCOOR 3 -C. 1 1 alkylCONR 4 R 5 wherein R 3 R 4 and R 5 are independently selected from hydrogen, C I-C I Ialkyl, arylCO-C 1 alkyl, or R 4 and R 5 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 1 1 alkyl, aryIC 0 -C 11 alkyl substituent. (ii) is selected from the group consisting of hydrogen, C 1 11 alkyl, substituted C 1 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO.. 1 alkyloxy, aryICO. 1 1 alkyloxy, CO-., 1 alkylthio, aryIC 0 1 ,aikylthio, C 0 1 alkylamino, arylC.. 1 jalkylamino, di (aryIC. 1 jalkyl)amino, C 1 1 alkylcarbonyl, arylC 1 1 1 alkylcarbonyl, C,. 1 1 alkylcarboxy, arylC.. 1 alkylcarboxy, C, 1 alkylcarbonylamino, aryl C 1 I alkylcarbonylamino, -CO-.1 1 1 alkyICOOR 6 -Co- 11 akylCONR 7 R 8 wherein R 6 R 7 and R 8 are independently selected from hydrogen, C 1 ,alkyl, arylCO-Cl, alkyl, or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a WO 98/27065 PCT/US96/20508 119 cyclic system containing 3 to 8 carbon atoms with at least one C 1 -Cl 1 alkyl, arylCo- C IIalkyl substituent, mono-, di- and tri-substituted arylC 0 -C 11 alkyl wherein the aryl substituents are defined as above for R and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R and R, and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pynimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyI, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, puriny1, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of RI, R 2 is selected from the group consisting of: hydrogen; (ii) C 1 alkyl, substituted C 1 jalkyl wherein the alkyl substituents are defined as above, (iii) arylC. 1 alkyl, (iv) mono-, di- and tri-substituted arylC 0 -C 1 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 39 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 10 120
41. A compound as defined in claim 39 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
42. A compound as defined in claim 39 wherein aryl is 1ahty, or its pharmaceutically acceptable salts, prodrugs, esters. or solvates thereof.
43. A compound as defined in claim 39 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs', esters, or solvates thereof.
44. A compound as defined in claim 39 wherein aryl is thienyl, or its pharmaceutically acceptable salts. prodrugs, esters. or solvates thereof.
45. A compound as defined in claim 39 wherein aryl is furylI. or its pharmaceutically acceptable salts. prodrugs. esters, or solvates thereof.
46. A compound as defined in claim 39 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs. esters. or solvates thereof.
47. A compound with the structure depicted in Forrnuh (A6): R 3 HR R 2 (A6) wherein at least one of R, and R, substituents is a l,4-benzodioxanyl or has the general structd~re depicted in Formula (B) RA4,, 1 wherein E is -O or -NH 7 _1J (B3) WO 98/27065 WO 9827065PCTIUS96/20508 121 wherein R' and are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, CI- 11 alkyl, optionally substituted arylC 1 11 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, 1 alkyl, aryiC, ,alkyl, C 0 alkyloxyC 0 1 alkyl, arylCO-I alkyloxyC 0 alkyl, C 0 ,,alkylthioCo- 11alkyl, arylC 0 alkylthioCO-, alkyl, CO. 1 ,alkylaminoC 0 alkyl, arylC 0 alkylaminoC.. ,,alkyl, di(arylC 1-1 jalkyl)aminoC 0 jalkyl, C 1 ,alkylcarbonylC 0 ,alkyl, aryiCI- I 1 alkylcarbonylC 0 alkyl, C 1 1 ,alkylcarboxyC 0 alkyl, ary iCI. ,alkylcarboxyC 0 lialkyl, C, ,alkylcarbonylaminoC 0 alkyl, arylCl-.i alkylcarbonylaminoC 0 1alkyl, CO-,,alkylCOOR 5 alkylCONR 6 wherein R 5 R 6 and R 7 are independently selected from hydrogen, C,-CI jalkyl, aryICO-CI jalkyl, or R 6 and R 7 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C I Ialkyl, aryl CO-C, IIalkyl substituent. (ii) is selected from the group consisting of hydrogen, CI-1,alkyl, substituted C,,,1alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 ,,jalkyloxy, arylC 0 alkyloxy, C 0 alkylthio, arylCo-il alkylthio, C 0 ,alkylamino, arylC 0 ,alkylamino, di(ary IC 0 1 alkyl)amino, C, alkylcarbonyl, arylC,. alkylcarbonyl, ,,alkylcarboxy, aryiC, 1-1 alkylcarboxy, ,,alkylcarbonylamino, aryl alkylcarbonylamino, -C ,IalkylCOOR 8 -C 0 alkylCONR 9 Rj 0 wherein R 8 R(9 and Ri are independently selected from hydrogen, C,-CI 1 alkyl, arylC 0 -C 1 1 jalkyl, or R(9 and RIO are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-Clalkyl, arylCo- CI, alkyl substituent, mono-, di- and tri-substituted aryvIC 0 -C 1 ,alkyl wherein the aryl substituents are defined as above for R and R,. (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and ary! is selected from phenyl, biphenyl. naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryt, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2.3-dihydrobenzothienyl. fury!, pyranyl, benzofuranyi. isobenzofuranyl, 2.3-dihydrcbenzofiiranyl. pyi-rolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl. benzimidazolyl, pyridyl, -pyrazinyl. pyradazinyl, pyrimidinyl. triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl. *C 10 cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, I ,8-naphthyridinyl, pteridinyl. carbazoly I. acridinyl, phenaziny I, phenothiazinyl, phenoxazinvi. chromany I. :benzodioxnyi, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyi, tetrazolvi, thiazolvi. isothiazolyl, benzthiazolyl, ocxazolyl. isoxazolyl. benzoxazolyl. oxadiazolvj, thiadiazolyl or hydroxyl 15 and wherein the remaining of R 1 R 2 R 3 and R 4 are independently selected from the group consisting of: hydrogen; (ii) C jalkyl, substituted C 1 1 jalkyI wherein the alkyl substituents are defined as above, (iii) arylC 0 11 Ialky!, (iv) mono-, di- and tri-substituted arylC 0 1 alkyl wherein the aryl substituents are defined as above, with the proviso that when R 3 and R4 are selected from substituted phenyl or substituted fury! then the phenyl and fury! substituents exclude hydroxy. halo. trifluoromethyli, C 1 6 alkyl; C 14 alkyloxv. C 14 6alkvlthio. amino. C 1 aklmndi(C,4alkyl)amino. phenyiC .,Alkyiamiino and di(pheny!C,. or its pharmaceutically acceptable salts., prodrugs. esters, or solvates thereof. WO 98/27065 PCr[US96/20508 123
48. A compound as defined in claim 47 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
49. A compound as defined in claim 47 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 47 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
51. A compound as defined in claim 47 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
52. A compound as defined in claim 47 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
53. A compound as defined in claim 47 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
54. A compound as defined in claim 47 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound with the structure depicted in Formula (A6): R 3 R 4 N N. R1 R 2 (A6) WO 98/27065 WO 9827065PCTIUS96/20508 124 wherein R 4 is selected from -C0R 5 -COOR 6 -CONR 7 R 8 wherein R(5 thru R 8 are independently selected from hydrogen, C 1 -C 1 1 alkyl, substituted C 1 1 jalkyl where the alkyl substituents are as defined below, optionalIly substituted arylC 0 -C 1 alkyl where the aryl substituents are as defined below, or R(7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -Cl 1 alkyl, arylC 0 1 alkyl substituent, and wherein at least one of RI, R 2 and R(3 substituents has the general structure depicted in Formula (B) X-C(R)=C(R )COOR" (B) wherein R' and R 'are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted arylC 1 1 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 I 11 alkyl, aryiC -1 alkyl, C 01 1 alkyloxyC. 11 alkyl, arylC.. 11 alkyloxyC.. 11 alkyl, C 0 11 alkylthioCo. lialkyl, arylC 0 1 1 alkylthiioC. 1 1 alkyl, C 0 1 1 alkylaminoC- 1 1 alkyl, arylC 0 1 1 alkylaminoC 0 11 alkyl, di(arylC 1 1 1 alkyl)aminoC.. 1 1 alkyl, C 1 .lialkylcarbonylC. 1 1 alkyl, arylCl- I IalkylcarbonylC.. 11 alkyl, C 111 alkylcarboxy C 0 1 1alkyl, ary lC, .l alkylcarboxy C 0 11 alkyl, C ialkylcarbonylaminoC 01 1 alkyl, arylC 1 1 alkylcarbonylaminoC 0 11 alkyl, C 0 1 1 alkylCOOR 9 1 alkyICONR 0 R 1 wherein Rio and R 11 are independently selected from hydrogen, C 1 -Cl~alkyl, arylC 0 -Clialkyl, or Ri and R 1 1 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-Cl 1 alkyl, arylCO-C 1 1 alkyl substituent. (ii) is selected from the group consisting of hydrogen, C 1 11 alkyl, substituted CI 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, WO 98/27065 WO 9827065PCTIUS96/20508 125 tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 alkyloxy, arylCO.., alkyloxy, C 0 1 alkylthio, arylC 0 alkylthio, C 0 1 alkylamino, arylCo., alkylamino, di(arylCo-lalkyl)amino, C 1 lialkylcarbonyl, arylC 1 1 1 alkylcarbonyl, 1 ,alkylcarboxy, aryiC alkylcarboxy, C ialkylcarbonylaxnino, aryl lalkylcarbonylamino, -CO-, 1 alkylCOOR1 2 -Co, alkylCONR, 3 R, 4 wherein R1 2 R1 3 and R1 4 are independently selected from hydrogen, CI-C, ,alkyl, arylC 0 C, ,alkyl, or R1 3 and R1 4 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one Cj- C 1 jalkyl, arylC 0 jalkyl substituent, mono-, di- and tn-substituted arylC 0 -C,,alkyl wherein the aryl substituents are defined as above for R and R (iii) X is a mono-, di- or tnisubstituted aryl wherein the aryl substituents are defined as above for R and R and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, fury 1, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrdbenzofuranyl, pyrrolyl, indolyl, isoindolyl, inidolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of R I, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (ii) C 1-1 jalkyl, substituted jalkyl wherein the alkyl substituents are defined as above, (iii) arylCo- 1 ,alkyl, WO 98/27065 PCT/US96/20508 126 (iv) mono-, di- and tri-substituted arylCo-C 11 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
56. A compound as defined in claim 55 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
57. A compound as defined in claim 55 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
58. A compound as defined in claim 55 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
59. A compound as defined in claim 55 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 55 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
61. A compound as defined in claim 55 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
62. A compound as defined in claim 55 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
63. A compound with the structure depicted in Formula (A6): 127 R 3 R N N-, yR (A6) wherein either R 3 or R, are independently selected from -COR. 5 -COOR 6 -CONR 7 R 8 wherein PR 5 tbru R, are independently selected from hydrogen, CI-Cl 1 alkyl, substituted C,-C,,alkyl where the alkyl substituents are as defined below, optionally substituted aryl. C 0 ,-Cl 1 allcyl where the aryl substittuents are as defined below, or R 7 and R. are taken :::together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 11 alkyl, arylC 0 -Cj 1 allcyl substituent, and wherein at least one of R 1 R 2 and R, substituents has the general structure depicted in Formula (B) X-C(R )=C(R-)CQOR-' *4*s (B) wherein R' and Rare independently selected from the group consisting of 10 hydrogen, halo, cyano, nitro, trihalomethyl, C 1 1 alkyl, optionally substituted arylC 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano. trihalornethyl, hydroxypyronyl, C 1 1 ,alkyl,. arylC,. 1 1 alkyl, Co 1 1 alkyloxyCo., 1 alkyl, aryICo 1 alkyloxyC. 11 alkyl, C 0 11 alkylthioCo- I 1 alkyl, arylCo..I alkylthioC 0 1 ,alkyl, Ce., alkylaniinoCo. 1 1 al, arylCo. 1 1 alkylaminoCo. lialkylcarbonylCo 1 ,alkyl, C 1 ,alkylcarboxyCo., alkyl, ary IC 1- lalkcarboxyCo. 1 1 alkyl, C 1 ,alkylcarbonylaminoCo- ,alkyi, aryiC 1.1 lalkylcarbonylamindo., jalkyi, C..,alkyICOOR.-C.,,alyCQNR, 0 wherein R 9 R, 0 and RI, are independently selected from hydrogen, Ci-C,,alcyl, arylCo-C,,alkyl, or Rio and R11 are taken 2- together with the nitrogen to which they are attached forming a cyclic system WO 98/27065 WO 9827065PCTIUS96/20508 128 containing 3 to 8 carbon atoms with at least one CI-Cl 1 alkyl, arylC 0 -C 1 1 alkyl substituent. (ii) is selected from the group consisting of hydrogen, C 1 11 alkyl, substituted C 1 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 11 alkyloxy, arylCO- 1 1 alkyloxy, CO- 11 alkylthio, arylC- 1 1 alkylthio, CO.. 11 alkylamnino, arylC. 1 1 alkylamino, di(arylIC 0 1 1 alkyl)amino, C, Il alkylcarbonyl, aryIC 1 lialkylcarbonyl, C 1 1 alkylcarboxy, arylC i-n alkylcarboxy, C ilalkylcarbonylamino, aryl C 1 1 1 alkylcarbonylamino, -C. 1 1 alkylCOOR 12 -C 011 alkylCONR 1 3 R 14 wherein R 12 R 13 and R 14 are independently selected from hydrogen, C 1 -C 1 1 alkyl, arylC 0 Cl 1 alkyl, or R 13 and R 14 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C- C 1 1 alkyl, arylCO-Cl 1 alkyl substituent, mono-, di- and tni-substituted arylC 0 -ClialkyI wherein the aryl substituents are defined as above for R' and R", (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, furyl, pyranyl, benzofurany 1, isobenzofuranyl, 2,3 -dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl,
129. and wherein the remaining of RI,R 2 andeith~er R 3 or R4are independently selected from the group consisting of: hydrogen; (ii) C 1 1 1 alkyl, substituted C 11 alkyl wherein !he alkyl substituents are defined as above, (iii)aryl~., I lkyl (iv) mono-, di- and tri-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically accept able salts, prodnigs, esters, or solvates thereof. ~64. A compound as defined in claim 63 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, ftzryl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 63 wherein aryl -is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 66. A compound as defined in claim 63 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 67. A compound as defined in claim 63 wherein aryl is biphenyl. or. its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof 68. A compound as defined in claim 63 wherein aryl is -thienyl, or its pamctilly acceptable salts, prodrugs, esters, or solvates thereof. 69. A compound as defined in claim 63 wherein aryl is furyl, or its- pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof WO 98/27065 PCTIUS96/20508 130 A compound as defined in claim '63 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 7 1. A compound with the structure depicted in Formula (A7): R 3 R 2 WA) wherein R 2 is selected from -COR 5 -COOR 6 -CONR 7 R 8 wherein R 5 thru. R 8 are independently selected from hydrogen, CI-C 1 1 alkyl, substituted C 1 1 alkyl where the alkyl substituents are as defined below, optionally substituted arylC 0 -C 1 alkyl where the aryl substituents are as defined below, or R 7 and R 8 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 11 alkyl, arylC 0 -C 1 1 alkyl substituent, and wherein at least one of R, and R 3 substituents has the general structure depicted in Formula (B) X-C(R I)=C(R')COOR:" (B) wherein R' and R are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted arylC 1 1 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C, 1 jalkyl, arylC~I- 1 alkyl, Co. 1 1 alkyloxyCo 11 alkyl, arylC.. 1 ylxyO- 1 alkyl, C 0 1 alkylthioC 0 11 alkyl, aryl 1 lalkylthioCo. 1 alkyl, Co: 11 lalkylaminoC. 11 alkyl, arylC.. 11 alkylaminoC 0 11 alkyl, di(arylC 1. 1 alkyl)aminoC.- 1 alkyl, C 1 .lialkylcarbonylC 0 1 1 alkyl, arylC 1 1 1 alkyfcarbonylC 0 11 alkyl, C 1 1 lalkylcarboxyC 11 alkyl, ary IC 1 1 alkylcarboxyC 0 WO 98/27065 PTU9100 PCTIUS96/20508 131 lialkyl, C 1 1 alkylcarbonylaminoCo- 11 alkyl, arylC 1 l alkylcarbonylaminoCO 11 alkyl,- Co-, 1 lalkylCOOR 9 1 alkylCONRI 0 R 1 I wherein R 9 RIO and R, 1 are independently selected from hydrogen, CI-C 11 alkyl, arylCo-C 11 alkyl, or Rio and R 11 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -C 1 1 alkyl, arylC 0 -C 1 1 alkyl substituent. (ii) is selected from the group consisting of hydrogen, C 1 11 alkyl, substituted C 1 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C- 1 1 alkyloxy, arylC 0 1 1 alkyloxy, C 0 11 alkylthio, arylCo. 1 1 alkylthio, C 0 11 alkylamnino, arylC 0 1 1 alkylamino, di(arylC 1G 1 1 alkyl)amino, C, -lialkylcarbonyl, arylC 1 11 alkylcarbonyl, C 1 11 alkylcarboxy, arylC 1 1 alkylcarboxy, C 1 1 1 alkylcarbonylamino, aryl C 1 11 alkylcarbonylamino, -C 0 11 alkylCOOR 12 -C 0 1 1 alkylCONR 1 3 RI 4 wherein R 12 R 13 and R 14 are independently selected from hydrogen, C 1 -C 1 1 alkyl, arylCo- C 1 1 alkyl, or R 13 and R 1 4 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 I C 1 1 alkyl, arylC 0 -CI 1 alkyl substituent, mono-, di- and tri-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for R' and R (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and R and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofurany 1, isobenzofuranyl, 2,3 -dihydrdbenzofuiranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, I ,8-naphthyridinyl, pteridinyl, WO 98/27065 PCT/US96/20508 132 carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of R, and R 3 are independently selected from the group consisting of: hydrogen; (ii) C i 1 alkyl, substituted CI._,alkyl wherein the alkyl substituents are defined as above, (iii) arylCo. 1 alkyl, (iv) mono-, di- and tri-substituted arylCo-Cl alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 72. A compound as defined in claim 71 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 73. A compound as defined in claim 71 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 74. A compound as defined in claim 71 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 71 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 76. A compound as defined in claim 71 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. WO 98/n7065 PCTIUS96/20508 133 77. A compound as defined in claim 71 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 78. A compound as defined in claim 71 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 79. A compound with the structure depicted in Formula (A8): R 1 R 2 N N (A8) wherein at least one of R, and R 2 substituents has the general structure depicted in Formula (B) X-C(R)=C(R")COOR" (B) wherein R and R are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C I-,,alkyl, optionally substituted arylCI 1 1 alkyi wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, CI 11 alkyl, arylC 1 1 alkyl, Co- 1 alkyloxyC 01 1 alkyl, arylC 0 1 jakyloxy 1 alkyl, C 011 alkylthioCo- 1 alkyl, arylCo-. 1 alkylthioC. 11 alkyl, C 0 1 alkylamninoC 01 1 alkyl, arylC.. 1 alkylaminoCo. lialkyl, di(arylC 1- 1 alkyl)aniinoC 011 jalkyl, CI 1 1 alkylearbonylC 0 11 alkyl, arylCl- IIalky ,bnlC1Ialkyl, C 1 1 lalkylcarboxyC. 1 I alkyl, arylI- 1 1 alkylcarboxyCo- WO 98/27065 WO 9827065PCTIUS96/20508 134 11 alkyl, C 1 1 alkylcarbonylaminoC.. 11 alkyl, arylCl-l alkylcarbonylaninoC.. 11 alkyl,- CO 01 lalkylCOOR 4 jalkylCONR 5 R 6 wherein R. 4 R. 5 and R. 6 are independently selected from hydrogen, C 1 -Cl 1 alkyl, arylC 0 -C 1 1 alkyl, or R 5 and R. 6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 jalkyl, arylC 0 1 alkyl substituent. (ii) is selected from the group consisting of hydrogen, C 1 11 alkyl, substituted CI- 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 11 alkyloxy, arylC 0 1 1 alkyloxy, C 0 11 alkylthio, arylC 0 1 1 alkylthio, C 0 11 alkylamnino, aryIC- 1 1 alkylamino, di(arylC 1G 0 1 alkyl)amino, C, -Ialkylcarbonyl, arylC 1 lialkylcarbonyl, C 1 1 1 alkylcarboxy, arylCl-. 1 alkylcarboxy, Cl 1 alkylcarbonylamino, aryl C alkylcarbonylamino, -Co.. 11 alkylCOOP. 7 -Co- 11 alkylCONR 8 R 9 wherein R. 7 R. 8 and P. 9 are independently selected from hydrogen, C I-C 1 ,alkyl, arylC 0 -C 1 alkyl, or R. 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -Cl 1 alkyl, arylCo- C 1 jalkyl substituent, mono-, di- and tri-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for P. and R (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, antluyl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3 -dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, WO 98/27065 WO 9827065PCTIUS96/20508 135 benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of R, and R 2 is independently selected from the group consisting of: hydrogen; (ii) C 1 1 ,alkyl, substituted jalkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 1 alkyl, (iv) mono-, di- and tri-substituted arylC 0 -C 1 ,alkyl wherein the aryl substituents are defined as above, and wherein m is an integer between 0 and 4 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 1 alkyl, C 0 1 alkyloxyC 0 ,alkyl, arylCo- ,alkyloxyC 0 alkyl, C 0 lialkylthioC.., alkyl, arylCo-., alkylthioC 0 ,alkyl, C 0 1 alkylaminoC 0 alkyl, arylC 0 1 alkylaminoC 0 ,alkyl, di(aryl C 1 1 alkyl)aminoC 0 alky I, ,alkylcarbonylC.. 11 alkyl, C,1-1, alkylcarboxyC.., 1 alkyl, C 1 alkylcarbonylaxninoC 0 ,,alkyl, arylIC 1 IalkylcarbonylC 0 alkyl, arylC ,alkylcarboxyC 0 1 alkyl, arylC, 1- lalkylcarbonyl- aminoC 0 1 ,alkyl, -CH=CHCOORI, -CH=CHCONR, ,R1 2 -C 0 alkylCOOR1 3 alkylCONRI 4 R, 5 wherein RIO thru R1 5 are independently selected from hydrogen, C,-C, 1 alkyI, arylC 0 -C, 1 alkyl, or R 1 1 and R 12 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, 11alkyl, arylCO- C 1 ,alkyl substituent, or R, 4 and R1 5 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C, IIalkyl, arylCO-C, IIalkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. WO 98127065 PCT/US96/20508 136 A compound as defined in claim 79 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 81. A compound as defined in claim 79 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 82. A compound as defined in claim 79 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 83. A compound as defined in claim 79 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 84. A compound as defined in claim 79 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 79 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 86. A compound as defined in claim 79 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 87. A compound with the structure depicted in Formula (A8): Ri R 2 N N (AR) (A) WO 98/27065 PCT/US96/20508 137 wherein R, is selected from -C0R 16 -C00R 17 -C0NR 18 R 19 wherein R 1 6 thru Rig are independently selected from hydrogen, C 1 -C 1 1 alkyl, substituted C 1 1 alkyl where the alkyl substituents are as defined below, optionally substituted arylC 0 I alkyl where the aryl substituents are as. defined below, or R 18 and R, 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C I Ialkyl, arylC 0 -C 11 alkyl substituent, and wherein R 2 has the general structure depicted in Formula (B) X-C(R)=C(R")COOR" (B) wherein R' and R' are independently selected from the group consisting of hydrogen, halo, cyano, itro, trihalomethyl, C I 1 alkyl, optionally substituted arylC 1 11 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 11 alkyl, arylCI- 1 alkyl, C 0 alkyloxyCO-. 1 1alkyl, arylCO.., 1 alkyloxyCO. 11 alkyl, CO. 1 ,alkylthioC.. 1,alkyl, arylC. 1 1 alkylthioC.. 1 ,alkyl, Co.. 1 alkylaminoC 0 1 alkyl, arylC 0 1 1 alkylaminoC.. 1,alkyl, di (aryC 1 1 jalkyl)aminoC 0 jalkyl, C 1 1 jalkylcarbonylC 0 1 ,alkyl, arylC 1 11 alkylcarbonylC 0 ,I alkyl, C 1 ,alkylcarboxyC. 1 1 alkyl, ary 1C 1 1 1 alkylcarboxyC.. 11 alkyl, Cl-. 1 alkylcarbonylaminoC. 1 1 alkyl, arylC 1 .llalkylcarbonylaminoC 0 11 ialkyl, C 0 ]alkylCOOR 4 I alkyICONR 5 R 6 wherein R 4 R 5 and R(6 are independently selected from hydrogen, C,-Cl 1 alkyl, arylC 0 -C 11 alkyl, or R 5 and R6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1-C, jalkyl, arylC 0 ,alkyl substituent. (ii) is selected from the group consisting of hydrogen, CI 1 .,alkyl, substituted C 1 .,alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 1 alkyloxy, arylC.. 1 alkyloxy, C 0 alkylthio, arylCo., 1 alkylthio, C 0 1 alkylamino, 138 arylCo-tialkylamino.. di(ary lC~j 0 alky!)Amino, C, alkylcarbonyl, aryiCl. 11alkylcMarbl UC 1 C 1 alkylcarboxy, arylC.- 1 alkylcarboxy. C 1 .1aalkylcarbonylaznino, aryl C 1 1 ialkylcarbonylarnino Co., alkylCOOR 7 -CO 41 aIkylCONRaR 4 -wherein R 7 Rs and R, are independently select#-' from hlYdrogen. Ca-CialkyL, arylCo-Cjjalkyl. or R8 and R9 are taken together with the n itrogen to which they are 'attached. formning a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -c 1 1 alkvl, aiylC 0 C, alkyl substituent, mono-. di- and tri-substituted arYlCo-Cualkyl wherein the aryl .substituents are defined as above for R* and R,. (iii) X. is a mono-, di- or trisubstituted aryl wherein the aryl substituents are aa -defined as above for R* and and aryl is selected from Phenyl. biphenyl. naphthyl. dihydronaphthyl, tetrahydronaph thyl, indenyl. indanyl, a zulenyl. anthryl.I phenanthryl. fluorenyl. pyrenyl, thienyl, benzothjenvl, isobenzothienyl. 2.3-dihydrobenzothienyj. furYl. PYranYl, benzofuranYl, isobenzofuranyl, 2.3-dihydrdbenofuranyl, pyrrolyl. :indolyl, isoindolyl, indolizinyl, indazolyl. imidazolyl. benzimidazolvl.' pyridyl. pyrazinYl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl. isoquinolyl. 4H-quinolizinyl. cinnolinyl. phthalazinyl, quinazolinyl, quinoxaliny 1. 1 .8-naphthyridinyl, pteridinyl, :carbazoly 1, acridinyl. phenazinyl, phenothiazinv I. phenox azinyl. chronianyl. benz~ioxolyl, piperonyl, purinyl, hydroxypyronyl. pyrazolyl. tinazolyl. tetraolyl.* thiazolyl, isotiazolyl, benzthiazolyl. oxazolyl. isoxazlyl. benzoxaZOlyl. oxadiazolyl. or thiadiazlyl, and wherein R 3 is selected from the group consisting o'f: hydrogen; (ii) CW i alkyl. substituted C,. 1 alkYl wherein the alkyl substituents are defined as above, (iii) arylCO.,1alkyl, (iv) -mono-. di- and tri-substituted arvlCD-C, I alkyl wherein the aryl substitumns are defined as above, W.0 98/27065 WO 9827065PCTIUS96/20508 139 and wherein m is an integer between 0 and 4 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, CI 1 1 alkyl, C 0 11 alkyloxyC.. 11 alkyl, arylC 0 1 1 alkyloxyC 01 1 alkyl, Co- 11 alkylthioC 01 1 alkyl, arylCo- 1 alkylthioC 0 1 1 alkyl, Co. 1 1 alkylanuinoCo-li alkyl, arylCO.. lialkylaminoC. 1 1 alkyl, di(aryCl- 1 alkyl)aminoC. 11 alky 1, C 1 1 1 alkylcarbonylC.. 11 alkyl, C 1 1 lalkylcarboxyC.. 1 jalkyl, C 1 i alkylcarbonylaminoC 0 11 alkyl, arylC.. lialkylcarbonylC.. 11 alkyl, arylC 1 1 alkylcarboxyC.. 11 alkyl, arylCl-. 1 alkylcarbonyl- aminoC.. 1 jalkyl, -CH=CHCOOR 0 -CH=CHCONR 1 1 R 1 2 1 alkylCOOR 13 -CO-, 1 jalkylCONR 14 RI 5 wherein Rio thru R 15 are independently selected from hydrogen, C 1 -C 1 1 alkyl, arylC 0 -C 1 1 alkyl, or RI, and R 12 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 1 alkyl, arylCO- C 1 1 alkyI substituent, or R 1 4 and R 15 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-Cl 1 alkyl, aryl C 0 -C 1 alkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 88. A compound as defined in claim 87 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 89. A compound as defined in claim 87 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound as defined in claim 87 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 91. A compound as defined in claim 87 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. WO 98/27065 PCT/US96/20508 140 92. A compound as defined in claim 87 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 93. A compound as defined in claim 87 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 94. A compound as defined in claim 87 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. A compound with the structure depicted in Formula (A9): R R 2 N N N Y N 1(R3) m (A9) wherein at least one of R, and R 2 substituents has the general structure depicted in Formula (B) X-C(R)=C(R")COOR" (B) wherein R and R are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C. 11 nalkyl, optionally substituted arylCll 1 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, Ci.-alkyl, arylC l-alkyl, Co.- 1 alkyloxyCo 0 alkyl, arylCo-n alkyloxyCo- 11 alkyl, Co-n.alkylthioCo. WO 98/27065 PCTIUS96/20509 141 11 alkyl, arylC 0 11 alkylthioC.. 11 alkyl, C 0 1 allcylaminoC.. 11 alkyl, arylC.. 11 alkylaminoCo- 11 alkyl, di(arylC 1. jalkyl)aminoCO- 1 jalkyl, C 1 1 alkylcarbonylCo.. 1 alkyl, arylC.. lialkylcarbonylCo.. 11 alkyl, C 11 lalkylcarboxyC. 1 I alkyl, ary iC 1 1 alkylcarboxyC 0 1 1 allcyl, C 1 1 alkylcarbonylaminoCo-l alkyl, arylCI., 1 lalkylcarbonylanino C 0 1 I alkyl, CO.. 11 alkylCOOR 4 -Co.. 1 alkylCONR 5 R 6 wherein R 4 R(5 and R 6 are independently selected from hydrogen, C 1 -Cl 1 alkyl, arylCO-Cilalkyl, or R5 and R6 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C I Ialkyl, arylC 0 -C 1 alkyl substituent. (ii) is selected from the group consisting of hydrogen, C 3 1 1 alkyl, substituted C 1 1 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydroftiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 1 1 alkyloxy, arylC 0 11 alkyloxy, C 0 11 alkylthio, arylC. 1 1 alkylthio, 1 alkylamino, arylC 0 1 1 alkylamino, di(arylC. 1 1 alkyl)amino, C 1 _Ijalkylcarbonyl, arylC 1 lialkylcarbonyl, C 1 1 1 alkylcarboxy, arylC 1 1 alkylcarboxy, C 1 1 alkylcarbonylamino, aryl C 1 1 alkylcarbonylamino, -C 0 31 alkylCOOR 7 -C 011 alkyICONR 8 R 9 wherein R 7 R8 and R(9 are independently selected from hydrogen, C 1 jalkyl, arylC 0 -C 1 1 alkyl, or R 8 and R(9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I-C 11 alkyl, arylC 0 C 1 alkyl substituent, mono-, di- and tni-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for R' and R, (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrdbenzofuiranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, WO 98/27065 WO 9827065PCT1US96/20508- 142 pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of R, and R 2 is independently selected from the group consisting of: hydrogen; (ii) C 1- ,,alkyl, substituted C 1 1 jalkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 ,1 Ialkyl, (iv) mono-, di- and tni-substituted arylC 0 ,alkyl- wherein the aryl substituents are defined as above, and wherein m is an integer between 0 and 3 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, ,alkyl, C 0 1 alkyloxyC. 11 alkyl, arylCo 1 ,alkyloxyC 0 1 alkyl, Co. ,,alkylthioC.., 1 alkyl, arylC o-I 1 alkylthioC 0 alkyl, C 0 11 alkylaminoC.., 1 alkyl, arylCO_ lialkylaminoC. 1 1 alkyl, di(ary IC 1 1 alkyl)aminoC 0 1 ,alky 1, C 1 1 1 alkylcarbonylC 0 11 alkyl, C 1 1 ,alkylcarboxyCO- 1 jalkyl, C1 alkylcarbonylaminoC 0 alkyl, aryl lialkylcarbonylC 0 alkyl, arylC 1 1 alkylcarboxyC 0 1 alkyl, aryiC 1 1 lalkylcarbonyl- aminoC 0 I alkyl, -CH=CHCOORI 0 -CH=CHCONR 1 ,R 12 1 alkylCOOR, 3 -C 0 alkylCONR, 4 R, 5 wherein Rio thru R1 5 are independently selected from hydrogen, ,alkyl, arylC 0 ,alkyl, or RI, and R1 2 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 1 alkyl, arylC 0 C, jalkyl substituent, or R1 4 and R1 5 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 ,alkyl, arylC 0 1 alkyl substituent, WO 98/27065 PCT/US96/20508 143 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 96. A compound as defined in claim 95 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 97. A compound as defined in claim 95 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 98. A compound as defined in claim 95 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 99. A compound as defined in claim 95 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 100. A compound as defined in claim 95 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 101. A compound as defined in claim 95 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 102. A compound as defined in claim 95 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 103. A compound having the structure depicted in Formula (A9): WO 98/27065 PCTIUS96/20508 144 R, R N N V~'(R 3 WA) wherein R, or R 2 is selected from -C0R 16 -C00R 17 -C0NR 18 R 19 wherein R 16 thru Rgare independently selected from hydrogen, C 1 -C 1 1 alkyl, substituted CI 1 1 alkyl where the alkyl substituents are as defined below, optionally substituted arylC 0 Cl 1 alkyl where the aryl substituents are as defined below, or R 18 and Rig are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one CI-Clialkyl, arylC 0 -Cilalkyl substituent, and wherein the remainder of R, or R 2 has the general structure depicted in Formula (B) X-C(R')=C(R")COOR" (B) wherein R' and are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 11 alkyl, optionally substituted arylC .I I alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 1 jalkyl, arylC ~I- 1 alkyl, C 0 1 1 alkyloxyC.. 11 alkyl, arylCo. 11 alkyloxyC 011 alkyl, C 011 alkylthioCo- 1 allcyl, arylC 0 11 jkylt ii1 alkyl, CO-, jalkylaminoC 0 1 1 jalkyl,.arylC 01 1 lalkylaminoC 0 11 alkyl, di(arylC 1 1 alkyl)amninoC 0 1 alkyl, C 1 l alkylcarbonylC. 1 1 alkyl, arylC 1 11 alkylcarbonylC.. 1 1 alkyl, C 1 1 alkylcarboxyC 0 11 alkyl, ary IC 1 1 alkylcarboxyC 0 11 alkyl, Cl-. 11 alkylcarbonylaminoC. 11 alkyl, arylC 1 l alkylcarbonylaminoC.. 11 alkyl, CO.. 1 alkylCOOR 4 -C 0 11 jalky1CONR 5 R 6 wherein R 4 R 5 and R 6 are independently selected from hydrogen, CI-C 1 1 alkyl, arylC 0 -C 1 1 alkyl, or R 5 and R 6 are taken together WO 98/27065 WO 9827065PCT/US96/20508 145 with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 jalkyl, arylC 0 -C 1 jalkyl substituent. (ii) is selected from the group consisting of hydrogen, CI- 11 alkyl, substituted C 1 11 alkyI wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 1 1 alkyloxy, arylC 0 1 1 alkyloxy, C 0 1 1 alkylthio, arylC 0 1 1 alkylthio, C.. 1 1 alkylamino, aryl CO- I]alkylamino, di(aryl C- 1 1 alkyl)amino, C, 1 alkylcarbonyl, arylC 1 lialkylcarbonyl, C 1 1 1 alkylcarboxy, arylC 1 1 1 alkylcarboxy, C 1 1 1 alkylcarbonylamino, aryl Cl. 1 1 alkylcarbonylamino, -C 04 1 alkylCOOR 7 -CO.. 11 alkyICONR 8 R 9 wherein R 7 R 8 and R 9 are independently selected from hydrogen, C I-C I Ialkyl, arylC 0 -C 1 ,alkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -Cl 1 alkyl, arylC 0 C 11 alkyl substituent, mono-, di- and tni-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for R and R, (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and R and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyrany 1, benzofuranyl, isobenzofuranyl, 2,3 -dihydrdbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidaz olyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenaziny 1, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, 146 and wherein R 3 is selected from the group consisting of: hydrogen; (ii) C j., 1 alkyl, substituted C 1 1 jalkyl wherein the alkyl substituents are defined as above, (iii) arylCO. 11 Ialkyl. (iv) mono-, di- and tri-substituted arYiC 0 -C 1 1 alkyl wherein the aryl subsituntsare defined a's above, and wherein mn is an integer between. 0 and 3 and each R 3 is independently selected from the group consisting of hydrogen, halo, nitro, cyino, trihalomethyl, hydroxypyronyl, C 1 1 alkyI, C 0 1 1 alkyloxyCo-. 11 alk, arylC 1 1 alkyloxyCo. 1 ,alkyl, Co. 11 alkylthioC. 11 alkyl, arylCo. 1 alkylthioCo. 1 alkl, Co-. 1 alkylaminoC 1 alkyI, arylC 0 I IalkyLammoC,., I alkyl, di(arylC ,alkyl)aminoC. 1 jalkyl, C 1 1 lalkylcarbonylC 0 1 alky 1, C 1 1 alkylcarboxyC. 11 alkyl, C 1 .lialkylcarbonylazninoC 0 11 alkyl, arylCl. 11 alkylcarbonylC 1 ,alkyl. arylC,. 1 ,alkylcarboxyCo. 11 akl, arylC,. 1 ,alkylcarbonyl- aininoCo. jalkyl, -CHCHCOOR 0 -CH-CHCONR 1 IR 12 -Co-, 1 ,alkylCOOR 13 -Co., 1 lalkylCONR 14 R 15 wherein Rio thru R 15 are independently selected from. hydrogen, C I-C I Ialkyl, arylCo-C 11alkcyl, or R I and R 12 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -C ,alkyl. aryIC 0 C 1 alkyl substituent, or R1 4 and Ris are taken together with the'nitrogen-to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C,-C 1 Alkyl arylCo-Ci 1 alkyl substituent, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 104. A compound as- defined in claim 103 wherein aryl is selcted'fromn phenyL, naphthyL, biphenyl, thienyl, fwryl, pynidyl, or its pharaceutically acceptable salts, prodnigs, esters, or solvates thereof. 105. A compound as defined in claim 103 wherein aryl is phenyl.- 147 or its pharmaceutically acceptable salts, prodrugs, esters or solvates thereof. 106. A compound as defined in claim 103 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters or solvates thereof. 107. A compound as defined in claim 103 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters. or solvates thereof. 108. A compound as defined in 6laim 103 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 109. A compound as defined in claim 103 wherein aryl is furyl, or its pharmaceutically acceptable salts. prodrugs, esters, or solvates thereof. 10 110. A compound as defined in claim 103 wherein aryl is pyridyl, or its pharmaceutically acceptable salts,. prodrugs, esters, or solvates thereof. I111. A compound with the structure depicted inFormula (A Z, R 2 Z 2 wherein Z, and Z 2 are independently selected from the group consisting of 0, OR 3 SR 4 NRSR&, wherein R 3 R 4 R!6 R. 6 are independently selected from: hydrogen; (ii) 1 alkyl, substituted C 1 11 alkyl, Ci-, 1 alkylcarbonyl, substituted C 1 I, afqcroy wherein the alkyl substituents are defined as below, (iii) arylCO.ii1alkyl, arylCO.. I alkylcarbonyl; WO 98/27065 PCTIUS96/20508 148 (iv) mono-, di- and tn-substituted arylCO-C 1 ,alkl; mono-, di- and tri- substituted arylCO-Clialkylcarbonyl wherein the aryl substituents are defined as in below, and wherein at least one of R, and R 2 substituents has the general structure depicted in Formula (B) X-C(R)=C(R")COOR" (B) wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C 1 .I 1 alkyl, optionally substituted arylC 1 11 alkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, CI 1 1 alkyl, arylC 11 alkyl, C 0 1 ,alkyloxyC 0 11 alkyl, arylCo- 1 alkyloxyCo-lialkyl, CO. 11 alkylthioC.. lialkyl, arylCo-. 1 alkylthioCo-li 1 alkyl, C 0 1 alkylaminoC.. 11 alkyl, arylCo 1 1 alkylaminoC.. 1 alkyl, di(arylC 1 1 jalkyl)aminoC. 1 jalkyl, C 1 .i alkylcarbonylC.. 1 alkyl, arylCj_ i 1 alkylcarbonylC. 11 alkyl, C 1 11 alkylcarboxyC., 1 alkyl, ary 1C 1 1 alkylcarboxyC.. 11 alkyl, C 1 1 alkylcarbonylaminoC. 1 alkyl, arylC 1 11 alkylcarbonylaminoC. 11 alkyl, CO-, 1 1 alkylCOOR 7 1 1 alkylCONR 8 R 9 wherein R 7 R 8 and R 9 are independently selected from hydrogen, C 1 jalkyl, arylCO-C, jalkyl, or R 8 and R 9 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C 1 -C 1 I alkyl. arylCO-C 1 jalkyl substituent. (ii) is selected from the group consisting of hydrogen, CI- 11 alkyl, substituted C 1 11 alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, CO.. 11 alkyloxy, arylC 0 11 alkyloxy, Co. 11 alkylthio, arylC.. 11 alkylthio, C 11 alkylamino, arylC. 1 1 alkylamino, di(arylC 0 1 alkyl)amino, C 1 -i alkylcarbonyl, arylC 1 I 1 alkylcarbonyl, C 14 1 alkylcarboxy, arylCl-ll alkylcarboxy, C 1 1 alkylcarbonylamnino, WO 98/27065 WO 9827065PCTUS96/20508. 149 aryl C 1 1 1alkylcarbonylamino, -CO. 11 alkylCOOR 1 0 -Co-l alkylCONR 1 R 12 wherein Rio, R, I and R 12 are independently selected from hydrogen, C 1 -Cl 1 alkyl, arylC 0 C 1 1 alkyl, or RI, and R 12 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I- C, jalkyl, arylC 0 -C 1 jalkyl substituent, mono-, di- and tri-substituted arylC 0 -C 11 alkyl wherein the aryl substituents are defined as above for R and R, (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and R and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3 -dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobeazofuranyl, 2 ,3-dihydrcbenzofuranyl, pyrrolyl, indolyl, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pyridyl, pyrazinyl, pyradazinyl, pyrimidinyl, triazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of RI, and R 2 is independently selected from the group consisting of: hydrogen; (ii) C 11 aky1, substituted C 11 I jalkyl wherein the alkyl substituents are defined as above, (iii) arylC 0 1 alkyl, (iv) mono-, di- and tri-substituted arylC 0 -Clialkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. WO 98/27065 PCT/US96/20508 150 112. A compound as defined in claim 111 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, furyl, pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 113. A compound as defined in claim 111 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 114. A compound as defined in claim 111 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 115. A compound as defined in claim 111 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 116. A compound as defined in claim 111 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 117. A compound as defined in claim 111 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 118. A compound as defined in claim 111 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 119. A compound with the structure depicted in Formula (All): R 3 R 2 NpS R, (All) W-0 98/27065 PCTIUS96/20508 151 wherein at least one of R 1 R(2 and R(3 substituents has the general structure depicted in Formula (B) X-C(R')=C(R")COOR" (B) wherein R' and R" are independently selected from the group consisting of hydrogen, halo, cyano, nitro, trihalomethyl, C,.,,alkyl, optionally substituted aryl C, I ,Ialkyl wherein the aryl substituents are independently selected from the group consisting of hydrogen, halo, nitro, cyano, trihalomethyl, hydroxypyronyl, C 1 -IIalkyl, arylCI-.11alkyl, CO-, 1 alkyloxyC.., alkyl, arylCo-lalkyloxyC 0 1 alkyl, C 0 alkylthioCo. lalkyl, arylCo.,, alkylthioCo-.,,alkyl, C 0 alkylaminoC 0 ,,alkyl, arylC 0 alkylaminoC 0 11 alkylcarbonylC 0 Ialkyl, C, ,alkylcarboxyC 0 alkyl, ary lC ,..,,alkylcarboxyC 0 1,alkyl, C,1-1 ,alkylcarbonylaminoC.., 1 alkyl, arylC,., ,alkylcarbonylaminoC 0 ,alkyl, lalkylCOOR 5 jalkyICONR 6 R 7 wherein R 5 R(6 and R 7 are independently selected from hydrogen, C I-C, IIalkyl, arylCO-C, I alkyl, or R 6 and R(7 are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C I IIalkyl, arylC 0 11alkyl substituent. (ii) is selected from the group consisting of hydrogen, CI., 1 alkyl, substituted C,..,,alkyl wherein the substituents are independently selected from halo, cyano, nitro, trihalomethyl, carbamoyl, tetrahydrofuiryl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, hydroxypyronyl, C 0 ,alkyloxy, arylC 0 ,alkyloxy, C 0 1 alkylthio, arylC 0 ,alkylthio, C 0 jalkylamino, arylCO., ,alkylamino, di(arylCo., ,alkyl)amino, C, alkylcarbonyl, arylC,.. lialkylcarbonyl, ,alkylcarboxy, arylC,.., alkylcarboxy, 1 alkylcarbonylamino, aryl ,alkylcarbonylamino, 1 alkylCOOR 8 -C 0 ,alkylCONR 9 R, 0 wherein R 8 R(9 and RIO are independently selected from hydrogen, ,alkyl, arylCO-CI ,alkyl, or WO 98/27065 PCTIUS96/20508 152 R 9 and Rio are taken together with the nitrogen to which they are attached forming a cyclic system containing 3 to 8 carbon atoms with at least one C]-Cl 1 alkyl, arylC 0 C I Ialkyl substituent, mono-, di- and tni-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above for R' and (iii) X is a mono-, di- or trisubstituted aryl wherein the aryl substituents are defined as above for R' and and aryl is selected from phenyl, biphenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl, indanyl, azulenyl, anthryl, phenanthryl, fluorenyl, pyrenyl, thienyl, benzothienyl, isobenzothienyl, 2,3-dihydrobenzothienyl, furyl, pyranyl, benzofuranyl, isobenzofuranyl, 2,3-dihydrcbenzofuiranyl, pyrrolyl, indoly 1, isoindolyl, indolizinyl, indazolyl, imidazolyl, benzimidazolyl, pynidyl, pyrazinyl, pyradazinyl, pyrimidinyl, tniazinyl, quinolyl, isoquinolyl, 4H-quinolizinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1 ,8-naphthynidinyl, pteridinyl, carbazolyl, acridiny 1, phenazinyl, phenothiazinyl, phenoxazinyl, chromanyl, benzodioxolyl, piperonyl, purinyl, hydroxypyronyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, isothiazolyl, benzthiazolyl, oxazolyl, isoxazolyl, benzoxazolyl, oxadiazolyl, or thiadiazolyl, and wherein the remaining of R I, R 2 and R 3 are independently selected from the group consisting of: hydrogen; (ii) C 1- jalkyl, substituted C 1 1 jalkyl wherein the alkyl substituents are defined as above, (iii) arylC 01 I Ialkyl, (iv) mono-, di- and tni-substituted arylC 0 -C 1 1 alkyl wherein the aryl substituents are defined as above, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 120. A compound as defined in claim 119 wherein aryl is selected from phenyl, naphthyl, biphenyl, thienyl, fliryl, pyridyl, WO 98/27065 PCT/US96/205 153 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 121. A compound as defined in claim 119 wherein aryl is phenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 122. A compound as defined in claim 119 wherein aryl is naphthyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 123. A compound as defined in claim 119 wherein aryl is biphenyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 124. A compound as defined in claim 119 wherein aryl is thienyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 125. A compound as defined in claim 119 wherein aryl is furyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 126. A compound as defined in claim 119 wherein aryl is pyridyl, or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 127. A compound as defined in claim 1 with the structure as depicted below CHO3 COH 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 128. A compound as defined in claim 1 with the structure as depicted below WO 98/27065 PCT1US96/20508 154 OCOH 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 129. A compound as defined in claim 63 with the structure as depicted below Ph COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
130. A compound as defined in claim 63 with the structure as depicted below Ph 0 O N H H COzH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
131. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508- 155 MeO H HO or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
132. A compound as defined in claim 47 with the structure as depicted below N' H COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
133. A compound as defined in claim 47 with the structure as depicted below CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
134. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/2050 156 SCOzH I NO NO, 2 CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
135. A compound as defined in claim 47 with the structure as depicted below COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
136. A compound as defined in claim 47 with the structure as depicted below CO H N MeO_/ I CO 2 H S 15 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
137. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCTIUS96/20509 157 N MeO NO, CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
138. A compound as defined in claim 47 with the structure as depicted below SCO 2 H N 0 N' H CO 2 H or-its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
139. A compound as defined in claim 47 with the structure as depicted below CO 2 H EtN0 4'I COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
140. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/2050& 158 CO 2 H C0 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
141. A compound as defined in claim 47 with the structure as depicted below N s N H CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
142. A compound as defined in claim 47 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
143. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 159 CO 2 H MeO S N MeO OMe COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
144. A compound as defined in claim 47 with the structure as depicted below CO 2 H N NC H COH COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
145. A compound as defined in claim 47 with the structure as depicted below CO 0 2 H HC N N\ H CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
146. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 ~CHN CHN *CO,H COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
147. A compound as defined in claim 47 with the structure as depicted below CO 2 H F N H F COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
148. A compound as defined in claim 47 with the structure as depicted below N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
149. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCTIUS96/20509 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
150. A compound as defined in claim 47 with the structure as depicted below CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
151. A compound as defined in claim 47 with the structure as depicted below ,CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
152. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 162 CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
153. A compound as defined in claim 47 with the structure as depicted below COH CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
154. A compound as defined in claim 47 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
155. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 CO'H F N NH H CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
156. A compound as defined in claim 47 with the structure as depicted below CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
157. A compound as defined in claim 47 with the structure as depicted below CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
158. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 ,COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
159. A compound as defined in claim 47 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
160. A compound as defined in claim 47 with the structure as depicted below CO,H N H CO'H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
161. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 165 COH Cl N HI Ci Cl I COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
162. A compound as defined in claim 47 with the structure as depicted below COH F CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
163. A compound with the structure as depicted below SCO 2 H F F I N F F F I CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
164. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 ,CO,H CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
165. A compound as defined in claim 47 with the structure as depicted below H CH 3 O HC CH, ,CO 2 H COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
166. A compound as defined in claim 47 with the structure as depicted below CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
167. A compound as defined in claim 47 with the structure as depicted below W-O 98/27065 PCT/US96/20508 167 SCO 2 H N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
168. A compound as defined in claim 47 with the structure as depicted below N ICNH CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
169. A compound as defined in claim 47 with the structure as depicted below CO 2 H N N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
170. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 N s N' .CO,H CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
171. A compound as defined in claim 47 with the structure as depicted below CO H CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
172. A compound as defined in claim 47 with the structure as depicted below CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
173. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 Q or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
174. A compound as defined in claim 47 with the structure as depicted below ,COH CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
175. A compound as defined in claim 47 with the structure as depicted below CO,H N COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
176. A compound as defined in claim 47 with the structure as depicted below WO 98/27065 PCT/US96/20508 170 HOC H H N H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
177. A compound with the structure as depicted below o o CO COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
178. A compound as defined in claim 39 with the structure as depicted below Br 0 0 CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
179. A compound as defined in claim 39 with the structure as depicted below HO,C CO 2 H WO 98/27065 PCT/US96/2050& 171 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
180. A compound as defined in claim 39 with the structure as depicted below COH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
181. A compound as defined in claim 39 with the structure as depicted below CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
182. A compound as defined in claim 39 with the structure as depicted below N 1 0 H O 0 CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
183. A compound as defined in claim 39 with the structure as depicted below WO 98/27065 PCT/US96/20508 N H CO,H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
184. A compound as defined in claim 47 with the structure as depicted below .CH, CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
185. A compound as defined in claim 47 with the structure as depicted below 0 o H N NH CHO NO 2 CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
186. A compound as defined in claim 47 with the structure as depicted below 173 *5 S S. 0 SO *5 H OCH 3 N NO 2 CO2H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
187. A compound as defined in claim 47 with the structure as depicted below O H I CH 3 N NO 2 CO2H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
188. A compound as defined in claim 47 with the structure as depicted below O F H O N F CH 3 0 NO 2 CO 2 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
189. A compound as defined in claim 47 with the structure as depicted below -174- *r S *r S S or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
190. A compound as defined in claim 47 with the structure as depicted below O CH3 CH 3 H N F CO2H 5 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
191. A compound as defined in claim 47 with the structure as depicted below O C H3 CH 3 H N NO2 C N0 2 O2H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. S192. A compound as defined in claim 47 with the structure as depicted below 175 S S. S S* S S S S *SSS *5 S S S S S S 5 S. S S S S S *5 *5 C S *S S CH 3 CH 3 CH 3 H CH 3 002 its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
194. A compound as defined in claim 47 with the structure as depicted below CH 3 1 -176- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
195. A compound as defined in claim 47 with the structure as depicted below CH 3 00 0 0 0 0000 0 0 *0 0 *0 00 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
196. A compound as defined in claim 47 with the structure as depicted below 11- O CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
197. A compound as defined in claim 47 with the structure as depicted below 0 N ^ND H N -177- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
198. A compound as defined in claim 47 with the structure as depicted below H 'CO 2 H CC C C C. C C C. CCC. C C Ce.. CC C CC C or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 5 199. A compound as defined in claim 47 with the structure as depicted below H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
200. A compound as defined in claim 47 with the structure as depicted below 'N H CH 3 'CO 2 H -178- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
201. A compound as defined in claim 47 with the structure as depicted below 0S St 9 be S 0* 9 9 9 .999. 09 .9 C 9 9 9 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
202. A compound as defined in claim 47 with the structure as depicted below H CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
203. A compound as defined in claim 47 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. -179-
204. A compound as defined in claim 47 with the structure as depicted below 0 N H H N F C02H Sor its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. S* 205. A compound as defined in claim 47 with the structure as depicted below 00@0 *H H .N SC02H S or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
206. A compound as defined in claim 47 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. -180-
207. A compound as defined in claim 47 with the structure as depicted below 0 0 0 N SCO or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 000
208. A compound as defined in claim 63 with the structure as depicted below HO 2 H 3 C 0 0 O or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
209. A compound as defined in claim 24 with the structure as depicted below HOCH OCH 5S: 5 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 209. A compound as defined in claim 24 with the structure as depicted below HO 2 CQ or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 181-
210. A compound as defined in claim 24 with the structure as depicted below Br or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
211. A compound as defined in claim 24 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
212. A compound as defined in claim 24 with the structure as depicted below -182- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
213. A compound as defined in claim 24 with the structure as depicted below :0 .0 0 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 5 214. A compound as defined in claim 24 with the structure as depicted below HO 2 C HOO O 0C JC 0 C 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
215. A compound as defined in claim 24 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. 183-
216. A compound as defined in claim 24 with the structure as depicted below HO 2 C HO N CO 2 H H O O OMe or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
217. A compound as defined in claim 24 with the structure as depicted below S S S S S. S or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
218. A compound as defined in claim 24 with the structure as depicted below HO 0 2 C N CO 2 H H -184- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
219. A compound as defined in claim 24 with the structure as depicted below HO 2 C 0 N CO 2 H H O 0 F or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
220. A compound as defined in claim 24 with the structure as depicted below a a. a a or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
221. A compound as defined in claim 24 with the structure as depicted below -185- HO 2 C 0 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
222. A compound as defined in claim 24 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
223. A compound as defined in claim 24 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
224. A compound as defined in claim 24 with the structure as depicted below 186- HOH or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
225. A compound as defined in claim 24 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
226. A compound as defined in claim 24 with the structure as depicted below CO2 H H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
227. A compound as defined in claim 24 with the structure as depicted below -187- N H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
228. A compound as defined in claim 55 with the structure as depicted below *r 9 9 9 *9 9 99 .9 9 9* 9 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
229. A compound as defined in claim 71 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
230. A compound as defined in claim 79 with the structure as depicted below 188- C0 2 H N N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
231. A compound as defined in claim 79 with the structure as depicted below C 0 2 H C0 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
232. A compound as defined in claim 79 with the structure as depicted below C1oa C02H CO2H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof. SC02H N H3CCO 2 CO 2 H 9. 9 9 9 9 99 9 .9 9* 9 9 -189- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
234. A compound as defined in claim 79 with the structure as depicted below CO 2 H N HO 2 C N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
235. A compound as defined in claim 79 with the structure as depicted below CO 2 H N CH 3 0 2 C N"N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
236. A compound as defined in claim 87 with the structure as depicted below N 02N 0 0 2 N N 1! C 2 H CO 2 H 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
237. A compound as defined in claim 87 with the structure as depicted below 190- 0 2 N CO 2 H S 0 fl 9 S* 00** 0 00 0 0 9* *900 0 0* 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
238. A compound as defined in claim 95 with the structure as depicted below CO 2 H N N N CO 2 H or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
239. A compound as defined in claim 103 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
240. A compound as defined in claim 103 with the structure as depicted below 0 0 0 0 S. S 0 S 0004 S p 0S a 0 0060 0@ 191- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
241. A compound as defined in claim 111 with the structure as depicted below OH HO, 2 C\ CO 2 H HO or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
242. A compound as defined in claim 111 with the structure as depicted below CH 3 0 2 C 0 0 HO2C CO 2 H HO or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
243. A compound as defined in claim 111 with the structure as depicted below OCH 3 0o 0 HO 2 C\ CO 2 H HO 0 or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
244. A compound as defined in claim 111 with the structure as depicted below 192- OCH 3 CO 2 H 0 0 0. 0 0 o or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
245. A compound as defined in claim 111 with the structure as depicted below or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
246. A compound as defined in claim 119 with the structure as depicted below 193- or its pharmaceutically acceptable salts, prodrugs, esters, or solvates thereof.
247. A pharmaceutical composition comprising as active component a compound according to any one of the preceding compound claims together with a o• 5 pharmaceutically acceptable carrier or diluent.
248. A pharmaceutical composition suitable for modulating the activity of PTPases or other molecules with tyrosine phosphate recognition unit(s) comprising an effective amount of a compound according to any one of the preceding compound claims together ooo oi oo: with a pharmaceutically acceptable carrier or diluent. 10 249. The pharmaceutical composition according to claim 247 or claim 248 suitable for treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic disease, osteoporosis, proliferative disorders including cancer and psoriasis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.
250. The pharmaceutical composition according to any one of claims 247, 248 or 249 comprising between 0.5mg and 1000mg of a compound according to any one of the Sceding compound claims per unit dose. 194-
251. A method of modulating the activity of PTPases or other molecules with phosphotyrosine recognition unit(s) in a subject in need of such treatment comprising administering to said subject an effective amount of a compound or composition according to any one of the preceding compound or composition claims.
252. The use of a compound according to any one of the preceding compound claims for preparing a medicament.
253. The use of a compound according to any one of the preceding compound claims for preparing a medicament for modulating the activity of PTPases or other molecules with phophotyrosine recognition unit(s). 10 254. The use of a compound according to any one of the preceding compound claims for preparing a medicament for treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including .ooo autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic disease, osteoporosis, proliferative disorders including cancer and psoriosis, diseases 15 with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases.
255. The use of a compound according to any one of the preceding compound claims for preparing a medicament for treating a subject in need of such treatment.
256. The use of a compound according to any one of the preceding compound claims for preparing a medicament for use as an immunosuppressant.
257. An immobilized compound comprising a suitable solid-phase coupled with a compound according to any one of the preceding compound claims. -195-
258. A method for coupling a compound according to any one of the preceding compound claims to a suitable solid-phase matrix, said method comprising contacting said compound with said matrix under conditions sufficient for said coupling to occur.
259. A method for isolating a protein or a glycoprotein with affinity for a compound according to any one of the preceding compound claims from a biological sample, comprising contacting an immobilized compound according to claim 257 with said biological sample in order for said immobilized compound to form a complex by binding said protein or glycoprotein 10 removing unbound material from said biological sample and isolating said complex extracting said protein or glycoprotein from said complex.
260. A method for isolating a protein-tyrosine phosphatase with affinity for a compound according to any one of the preceding compound claims from a biological sample, comprising contacting an immobilized compound according to claim 257 with said biological sample in order for said immobilized compound to form a complex by binding said protein-tyrosine phosphatase removing unbound material from said biological sample and isolating said complex extracting said protein-tyrosine phosphatase from said complex.
261. A method for isolating a Src-homology 2 domain containing protein or a phosphotyrosine binding domain containing protein with affinity for a compound according to any one of the preceding compound claims from a biological sample, Scomprising -196- contacting an immobilized compound according to claim 257 with said biological sample in order for said immobilized compound to form a complex by binding said Src-homology 2 domain containing protein or a phosphotyrosine binding domain containing protein removing unbound material from said biological sample and isolating said complex extracting said Src-homology 2 domain containing protein or a phosphotyrosine binding domain containing protein from said complex.
262. A compound according to any one of the preceding compound claims coupled to a 10 fluorescent or radioactive molecule.
263. A method for detecting a protein-tyrosine phosphatase or other molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound according to claim 262 comprising: contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a complex with said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s) detecting said complex, thereby detecting the presence of said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s).
264. A method for quantifying the amount of protein-tyrosine phosphatase or other molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound according to claim 262 comprising: contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a -197- complex with said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s) measuring the amount of said complex, thereby detecting the presence of said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s).
265. A method for determining the function of a given protein-tyrosine phosphatase or group of protein-tyrosine phosphatases or said molecules with phosphotyrosine recognition unit(s) in a cell or in a subject using a compound according to claim 262 c S comprising: 10 contacting said cell or an extract thereof or a biological sample from said subject or by injecting said compound into said subject in order for said compound to produce a complex with said protein-tyrosine phosphatase or said other molecules with phosphotyrosine recognition unit(s) measuring the biological effects induced by said complex. 15 266. A method of treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic disease, osteoporosis, proliferative disorders including cancer and psoriosis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and schizophrenia, and infectious diseases comprising administering a therapeutically effective amount of a compound according to any one of the preceding compound claims to a subject in need thereof. -198-
267. A method of treatment comprising administering a therapeutically effective amount of a compound according to any one of the preceding compound claims to a subject in need thereof.
268. A protein tyrosine phosphatase activity modulating compound, substantially as herein described with reference to any one of the examples but excluding comparative examples.
269. A compound with the structure depicted in Formula A2, substantially as herein described with reference to any one of the examples but excluding comparative examples. 10 270. A compound with the structure depicted in Formula A3, substantially as herein described with reference to any one of the examples but excluding comparative examples. 9*9*99
271. A compound with the structure depicted in Formula A4, substantially as herein described with reference to any one of the examples but excluding comparative 9*99 examples.
272. A compound with the structure depicted in Formula A5, substantially as herein described with reference to any one of the examples but excluding comparative examples.
273. A compound with the structure depicted in Formula A6, substantially as herein described with reference to any one of the examples but excluding comparative examples.
274. A compound with the structure depicted in Formula A7, substantially as herein described with reference to any one of the examples but excluding comparative examples. -199-
275. A compound with the structure depicted in Formula A8, substantially as herein described with reference to any one of the examples but excluding comparative examples.
276. A compound with the structure depicted in Formula A9, substantially as herein described with reference to any one of the examples but excluding comparative examples.
277. A compound with the structure depicted in Formula A10, substantially as herein described with reference to any one of the examples but excluding comparative examples. S 10 278. A compound with the structure depicted in Formula All, substantially as herein described with reference to any one of the examples but excluding comparative examples. 999499
279. A pharmaceutical composition comprising a compound with the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, A10 or Al substantially as 15 herein described with reference to any one of the examples but excluding comparative examples. 4 .4 4 o°
280. A method of modulating the activity of PTPases or other molecules with phosphotyrosine recognition units, substantially as herein described with reference to any one of the examples but excluding comparative examples.
281. The use of a compound with the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, A10 or All, substantially as herein described with reference to any one of the examples but excluding comparative examples.
282. A method for coupling a compound with the structure depicted in any one of Formulas A2, A3, A4, A5, A5, A7, A8, A9, A10 or All, substantially as herein -200- described with reference to any one of the examples but excluding comparative examples.
283. An immobilized compound comprising a suitable solid-phase coupled with a compound with the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, A10 or Al 1, substantially as herein described with reference to any one of the examples but excluding comparative examples.
284. A method for isolating a protein or a glycoprotein with affinity for compound with the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, A10 or Al l, substantially as herein described with reference to any one of the examples but 0** t. 10 excluding comparative examples. 9*
285. A method for isolating a protein tyrosine phosphatase with affinity for compound a with the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, or Al 1, substantially as herein described with reference to any one of the examples but excluding comparative examples. 15 286. A method for isolating a Src-homology 2 domain containing protein or a o: phosphotyrosine binding domain containing protein with affinity for a compound with ft the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, A10 or All, substantially as herein described with reference to any one of the examples but excluding comparative examples.
287. A method for detecting a protein-tyrosine phosphatase or other molecules with phophotyrosine recognition unit(s), substantially as herein described with reference to any one of the examples but excluding comparative examples.
288. A method for quantifying the amount of protein-tyrosine phosphatase or other molecules with phosphotyrosine recognition unit(s), substantially as herein described SRA% 25 with reference to any one of the examples but excluding comparative examples. -201-
289. A method for determining the function of a given protein-tyrosine phosphatase or group of protein-tyrosine phosphatases or said molecules with phosphotyrosine recognition unit(s), substantially as herein described with reference to any one of the examples but excluding comparative examples.
290. A method of treating or preventing type I diabetes, type II diabetes, impaired glucose tolerance, insulin resistance, obesity, immune dysfunctions including autoimmunity and AIDS, diseases with dysfunctions of the coagulation system, allergic disease, osteoporosis, proliferative disorders including cancer and psoriosis, diseases with decreased or increased synthesis or effects of growth hormone, diseases with 10 decreased or increased synthesis of hormones or cytokines that regulate the release of/or response to growth hormone, diseases of the brain including Alzheimer's disease and O schizophrenia, and infectious diseases comprising administering a compound with the structure depicted in any one of Formulas A2, A3, A4, A5, A6, A7, A8, A9, A10 or Al 1, substantially as herein described with reference to any one of the examples but excluding 0 15 comparative examples. DATED 28 t day of August 2001 0• ONTOGEN CORPORATION Attorney: CHARLES TANSEY Registered Patent and Trade Mark Attorney of Australia of BALDWIN SHELSTON WATERS
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