NZ516850A

NZ516850A - 2-pyrazolin-5-ones

Info

Publication number: NZ516850A
Application number: NZ516850A
Authority: NZ
Inventors: Marina M Moset; Isabel F Fernandez; David J Calderwood; Paul Rafferty; Lee Arnold; Jose Maria Castellano Berlanga
Original assignee: Abbott Gmbh & Co
Priority date: 1999-07-30
Filing date: 2000-07-28
Publication date: 2004-09-24
Also published as: AU6388900A; CA2380644A1; HK1049154A1; TR200200928T2; SK1512002A3; CN1193026C; EP1218373A2; HUP0400540A3; CN1377346A; NO20020487D0; KR20020091829A; CZ2002302A3; NO20020487L; MXPA02001088A; ZA200200477B; WO2001009121A2; PL354144A1; BR0012896A; IL147757A0; JP2003506368A

Abstract

A 2-pyrazolin-5-one or physiologically acceptable salts thereof useful as a protein kinase inhibitor has the formula (I) wherein R is optionally substituted indole, imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7-tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrrole, pyrazole, oxazole or thiazole; R1 is hydrogen or -A-Z; A is -(CH2)n-, -(CH2)n-NH-, -(CH2)n-O-, -(CH2)n-S-, -(CH2)n-S(O)- or -(CH2)n-S(O)2-; Z is -H, alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3OC(O)-, -NR4R5, -C(O)NR4R5, R3CO-, R3O-, or an optionally substituted cycloalkane, isoxazole, isothiazole, imidazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole or N-oxides thereof; n is 0 to 3 and R3 to R5 are as defined in the specification limited by the provisos listed in the specification.

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 516850 5168 50 -1- 2-PYRAZOLIN-5-ONES AS TYROSINE KINASE INHIBITORS RELATED APPLICATION(S) This application claims the benefit of U.S. Provisional Application No.: 60/146,563, filed July 30,1999, the entire teachings of which are incorporated 5 herein by reference. This invention relates to certain 2-pyrazolin-5-ones which are inhibitors of protein kinases, particularly tyrosine kinases and seruic/threonine kinases, of which some are novel compounds, to pharmaceutical compositions containing these 10 pyrazolinones and to processes for preparing these pyrazolinones. BACKGROUND OF THE INVENTION There are at least 400 enzymes identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. The phosphorylation is 15 usually a transfer reaction of a phosphate group from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate is transferred is a tyrosine, serine or threonine residue. Since these amino acid residues are the target structures for the phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases. 20 The phosphorylation reactions, and counteracting phosphatase reactions, at the tyrosine, serine and threonine residues are involved in countless cellular processes that underlie responses to diverse intracellular signals (typically mediated through cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. A cascade of protein kinases often participate in 25 intracellular signal transduction and are necessary for the realization of these cellular found as an integral part of the plasma membrane or as cytoplasmic enzymes or localized in the nucleus, often as components of enzyme complexes. In many instances, these protein kinases are an essential element of enzyme and structural 30 protein complexes that determine where and when a cellular process occurs within a cell. ,, intellectual property office of n.z. 1 2 MAR 2004 received WO 01/09121 PCT/US00/20628 Protein Tyrosine Kinases. Protein tyrosine kinases (PTKs) are enzymes which catalyze the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, often enzymes 5 themselves, acts as a molecular switch regulating cell proliferation, activation or differentiation (for review, see Schlessinger and Ulrich, 1992, Neuron 9:383-391). Aberrant or excessive PTK activity has been observed in many disease states including benign and malignant proliferative disorders as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), 10 allograft rejection, and graft vs. host disease. In addition, endothelial-cell specific receptor PTKs such as KDR and Tie-2 mediate the angiogenic process, and are thus involved in supporting the progression of cancers and other diseases involving inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, 15 retinopathy of prematurity, infantile hemangiomas). Tyrosine kinases can be of the receptor-type (having extracellular, transmembrane and intracellular domains) or the non-receptor type (being wholly intracellular). Receptor Tyrosine Kinases (RTKs). The RTKs comprise a large family of 20 transmembrane receptors with diverse biological activities. At present, at least nineteen (19) distinct RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are crucial for the growth and differentiation of a variety of cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57:433-478, 1988; Ullrich and Schlessinger, Cell 61:243-254,1990). The intrinsic 25 function of RTKs is activated upon ligand binding, which results in phosphorylation of the receptor and multiple cellular substrates, and subsequently in a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, receptor tyrosine kinase mediated signal transduction is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, 30 stimulation of the intrinsic protein tyrosine kinase activity and receptor trans-phosphorylation. Binding sites are thereby created for intracellular signal WO 01/09121 PCT/US00/20628 -3- transduction molecules and lead to the formation of complexes with a spectrum of cytoplasmic signaling molecules that facilitate the appropriate cellular response, (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) see Schlessinger and Ullrich, 1992, Neuron 9:1-20. 5 Proteins with SH2 (src homology -2) or phosphotyrosine binding (PTB) domains bind activated tyrosine kinase receptors and their substrates with high affinity to propagate signals into cell. Both of the domains recognize phosphotyrosine. (Fantl et al., 1992, Cell 69:413-423; Songyang et al., 1994, Mol. Cell. Biol. 14:2777-2785; Songyang et al., 1993, Cell 72:767-778; and Koch et al., 10 1991, Science 252:668-678; Shoelson, Curr. Opin. Chem. Biol. (1997), 1(2), 227-234; Cowburn, Curr. Opin. Struct. Biol. (1997), 7(6), 835-838). Several intracellular substrate proteins that associate with receptor tyrosine kinases (RTKs) have been identified. They may be divided into two principal groups: (1) substrates which have a catalytic domain; and (2) substrates which lack such a domain but 15 serve as adapters and associate with catalytically active molecules (Songyang et al., 1993, Cell 72:767-778). The specificity of the interactions between receptors or proteins and SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in the binding affinities between SH2 domains and the amino 20 acid sequences surrounding the phosphotyrosine residues on particular receptors correlate with the observed differences in their substrate phosphorylation profiles (Songyang et al., 1993, Cell 72:767-778). Observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability but also by the array of downstream signal transduction pathways 25 that are activated by a particular receptor as well as the timing and duration of those stimuli. Thus, phosphorylation provides an important regulatory step which determines the selectivity of signaling pathways recruited by specific growth factor receptors, as well as differentiation factor receptors. Several receptor tyrosine kinases such as FGFR-1, PDGFR, and c-Met, and 30 growth factors that bind thereto, have been suggested to play a role in angiogenesis, although some may promote angiogenesis indirectly (Mustonen and Alitalo, J. Cell WO 01/09121 PCT/US00/20628 -4- Biol. 129:895-898, 1995). One such receptor tyrosine kinase, known as "fetal liver kinase 1" (FLK-1), is a member of the type III subclass of RTKs. An alternative designation for human FLK-1 is "kinase insert domain-containing receptor" (KDR) (Terman et al., Oncogene 6:1677-83, 1991). Another alternative designation for 5 FLK-1/KDR is "vascular endothelial cell growth factor receptor 2" (VEGFR-2) since it binds VEGF with high affinity. The murine version of FLK-l/VEGFR-2 has also been called NYK (Oelrichs et al, Oncogene 8(1): 11-15, 1993). DNAs encoding mouse, rat and human FLK-1. have been isolated, and the nucleotide and encoded amino acid sequences reported (Matthews et al., Proc. Natl. Acad. Sci. USA, 10 88:9026-30,1991; Terman et al., 1991, supra; Terman et al., Biochem. Biophys. Res. Comm. 187:1579-86,1992; Sarzani et al., supra-, and Millauer et al, Cell 72:835-846, 1993). Numerous studies such as those reported in Millauer et al., supra, suggest that VEGF and FLK-1 /KDR/VEGFR-2 are a ligand-receptor pair that play an important role in the proliferation of vascular endothelial cells, and 15 formation and sprouting of blood vessels, termed vasculogenesis and angiogenesis, respectively. Another type EI subclass RTK designated "fins-like tyrosine kinase-1" (Flt-1) is related to FLK-1/KDR (DeVries et al. Science 255;989-991, 1992; Shibuya et al., Oncogene 5:519-524, 1990). An alternative designation for Flt-1 is "vascular 20 endothelial cell growth factor receptor 1" (VEGFR-1). To date, members of the FLK-1/ KDR/VEGFR-2 and Flt-1/ VEGFR-1 subfamilies have been found expressed primarily on endothelial cells. These subclass members are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) family of ligands (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7: 259-25 270,1996). Vascular endothelial cell growth factor (VEGF) binds to Flt-1 with higher affinity than to FLK-1/KDR and is mitogenic toward vascular endothelial cells (Terman et al., 1992, supra; Mustonen et al. supra; DeVries et al., supra). Flt-1 is believed to be essential for endothelial organization during vascular development. Flt-1 expression is associated with early vascular development in 30 mouse embryos, and with neovascularization during wound healing (Mustonen and Alitalo, supra). Expression of Flt-1 in adult organs such as kidney glomeruli WO 01/09121 PCT/US00/20628 -5- suggests an additional function for this receptor that is not related to cell growth (Mustonen and Alitalo, supra). As previously stated, recent evidence suggests that VEGF plays a role in the stimulation of both normal and pathological angiogenesis (Jakeman et al., 5 Endocrinology 133: 848-859, 1993; Kolch et al., Breast Cancer Research and Treatment 36: 139-155, 1995; Ferrara et al., Endocrine Reviews 18(1); 4-25, 1997; Ferrara et al., Regulation of Angiogenesis (ed. L. D. Goldberg and E.M. Rosen), 209-232,1997). In addition, VEGF has been implicated in the control and enhancement of vascular permeability (Connolly, etal., J. Biol. Chem. 264: 20017-10 20024, 1989; Brown et al., Regulation of Angiogenesis (ed. L.D. Goldberg and E.M. Rosen), 233-269, 1997). Different forms of VEGF arising from alternative splicing of mRNA have been reported, including the four species described by Ferrara et al. {J. Cell. Biochem. 47:211-218,1991). Both secreted and predominantly cell-associated 15 species of VEGF have been identified by Ferrara et al. supra, and the protein is known to exist in the form of disulfide linked dimers. Several related homologues of VEGF have recently been identified. However, their roles in normal physiological and disease processes have not yet been elucidated. In addition, the members of the VEGF family are often 20 coexpressed with VEGF in a number of tissues and are, in general, capable of forming heterodimers with VEGF. This property likely alters the receptor specificity and biological effects of the heterodimers and further complicates the elucidation of their specific functions as illustrated below (Korpelainen and Alitalo, Curr. Opin. Cell Biol., 159-164, 1998 and references cited therein). 25 Placenta growth factor (P1GF) has an amino acid sequence that exhibits significant homology to the VEGF sequence (Park et al., J. Biol. Chem. 269:25646-54, 1994; Maglione et al. Oncogene 8:925-31, 1993). As with VEGF, different species of P1GF arise from alternative splicing of mRNA, and the protein exists in dimeric form (Park et al., supra). P1GF-1 and P1GF-2 bind to Flt-1 with high 30 affinity, and P1GF-2 also avidly binds to neuropilin-1 (Migdal et al, J. Biol. Chem. 273 (35): 22272-22278), but neither binds to FLK-1/KDR (Park et al, supra). P1GF WO 01/09121 PCT/US00/20628 -6- has been reported to potentiate both the vascular permeability and mitogenic effect of VEGF on endothelial cells when VEGF is present at low concentrations (purportedly due to heterodimer formation) (Park et al., supra). VEGF-B is produced as two isoforms (167 and 185 residues) that also appear 5 to bind Flt-1/VEGFR-1. It may play a role in the regulation of extracellular matrix degradation, cell adhesion, and migration through modulation of the expression and activity of urokinase type plasminogen activator and plasminogen activator inhibitor 1 (Pepper et al, Proc. Natl. Acad. Sci. U. S. A. (1998), 95(20): 11709-11714). VEGF-C was originally cloned as a ligand for VEGFR-3/Flt-4 which is 10 primarily expressed by lymphatic endothelial cells. In its fully processed form, VEGF-C can also bind KDR/VEGFR-2 and stimulate proliferation and migration of endothelial cells in vitro and angiogenesis in in vivo models (Lymboussaki et al, Am. J. Pathol. (1998), 153(2): 395-403; Witzenbichler et al, Am. J. Pathol. (1998), 153(2), 381-394). The transgenic overexpression of VEGF-C causes proliferation 15 and enlargement of only lymphatic vessels, while blood vessels are unaffected. Unlike VEGF, the expression of VEGF-C is not induced by hypoxia (Ristimaki et al,J. Biol. Chem. (1998), 273(14),8413-8418). The most recently discovered VEGF-D is structurally very similar to VEGF-C. VEGF-D is reported to bind and activate at least two VEGFRs, VEGFR-3/Flt-4 20 and KDR/VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is most prominently expressed in the mesenchymal cells of the lung and skin (Achen et al, Proc. Natl. Acad. Sci. U. S. A. (1998), 95(2), 548-553 and references therein). As for VEGF, VEGF-C and VEGF-D have been claimed to induce increases 25 in vascular permeability in vivo in a Miles assay when injected into cutaneous tissue (PCT/US97/14696; W098/07832, Witzenbichler et al., supra). The physiological role and significance of these ligands in modulating vascular hyperpermeability and endothelial responses in tissues where they are expressed remains uncertain. There has been recently reported a virally encoded, novel type of vascular 30 endothelial growth factor, VEGF-E (NZ-7 VEGF), which preferentially utilizes KDR/Flk-1 receptor and carries a potent mitotic activity without heparin-binding WO 01/09121 PCT/US00/20628 -7- domain (Meyer etal, EMBO J. (1999), 18(2), 363-374; Ogawa et al, J. Biol. Chem. (1998), 273(47), 31273-31282.). VEGF-E sequences possess about 25% homology to mammalian VEGF and are encoded by the parapoxvirus Orf virus (OV). This parapoxvirus that affects sheep and goats and occasionally, humans, to generate 5 lesions with angiogenesis. VEGF-E is a dimer of about 20 kDa with no basic domain nor affinity for heparin, but has the characteristic cysteine knot motif present in all mammalian VEGFs, and was surprisingly found to possess potency and bioactivities similar to the heparin-binding VEGF 165 isoform of VEGF-A, i.e. both factors stimulate the release of tissue factor (TF), the proliferation, chemotaxis and 10 sprouting of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF 165, VEGF-E was found to bind with high affinity to VEGF receptor-2 (KDR) resulting in receptor autophosphorylation and a biphasic rise in free intracellular Ca2+ concentrations, while in contrast to VEGF 165, VEGF-E did not bind to VEGF receptor-1 (Flt-1). 15 Based upon emerging discoveries of other homologues of VEGF and VEGFRs and the precedents for ligand and receptor heterodimerization, the actions of such VEGF homologues may involve formation of VEGF ligand heterodimers, and/or heterodimerization of receptors, or binding to a yet undiscovered VEGFR (Witzenbichler et al., supra). Also, recent reports suggest neuropilin-1 (Migdal et 20 al, supra) or VEGFR-3/FU-4 (Witzenbichler et al., supra), or receptors other than KDR/VEGFR-2 may be involved in the induction of vascular permeability (Stacker, S.A., Vitali, A., Domagala, T., Nice, E., and Wilks, A.F., "Angiogenesis and Cancer" Conference, Amer. Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetelogia 40: SI 18-120 (1997)). Until now, no direct evidence for the essential 25 role of KDR in VEGF-mediated vascular hyperpermeability has been disclosed. The Non-Receptor Tyrosine Kinases. The non-receptor tyrosine kinases represent a collection of cellular enzymes which lack extracellular and transmembrane sequences. At present, over twenty-four individual non-receptor tyrosine kinases, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, 30 Zap70, Fes/Fps, Fak, Jak, Ack and LIMK) have been identified. At present, the Src subfamily of non-receptor tyrosine kinases is comprised of the largest number of WO 01/09121 PCT/US00/20628 -8- PTKs and include Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes has been linked to oncogenesis and immune responses. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogene 8:2025-2031, which is incorporated herein by reference. 5 Many of the tyrosine kinases, whether an RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in . numerous pathogenic conditions, including cancer, psoriasis, and other hyperproliferative disorders or hyper-immune responses. Development of Compounds to Modulate the PTKs. In view of the surmised 10 importance of PTKs to the control, regulation, and modulation of cell proliferation, the diseases and disorders associated with abnormal cell proliferation, many attempts have been made to identify receptor and non-receptor tyrosine kinase "inhibitors" using a variety of approaches, including the use of mutant ligands (U.S. Application No. 4,966,849), soluble receptors and antibodies (Application No. WO 15 94/10202; Kendall & Thomas, 1994, Proc. Natl. Acad. Sci 90:10705-09; Kim et al., 1993, Nature 362:841-844), RNA ligands (Jellinek, et al., Biochemistry 33:10450-56; Takano, et al., 1993, Mol. Bio. Cell 4:358A; Kinsella, et al. 1992, Exp. Cell Res. 199:56-62; Wright, et al., 1992, J. Cellular Phys. 152:448-57) and tyrosine kinase inhibitors (WO 94/03427; WO 92/21660; WO 91/15495; WO 94/14808; U.S. Patent 20 No. 5,330,992; Mariani, et ah, 1994, Proc. Am. Assoc. Cancer Res. 35:2268). More recently, attempts have been made to identify small molecules which act as tyrosine kinase inhibitors. For example, bis monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808) have been described generally as tyrosine kinase 25 inhibitors. Styryl compounds (U.S. Patent No. 5,217,999), styryl-substituted pyridyl compounds (U.S. Patent No. 5,302,606), certain quinazoline derivatives (EP Application No. 0 566 266 Al; Expert Opin. Ther. Pat. (1998), 8(4): 475-478), selenoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxylic compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 30 91/15495) have been described as compounds for use as tyrosine kinase inhibitors for use in the treatment of cancer. Anilinocinnolines (PCT W097/34876) and WO 01/09121 PCT/US00/20628 quinazoline derivative compounds (PCT W097/22596; PCT W097/42187) have been described as inhibitors of angiogenesis and vascular permeability. In addition, attempts have been made to identify small molecules which act as serine/threonine kinase inhibitors. For example, bis(indolylmaleimide) 5 compounds have been described as inhibiting particular PKC serine/threonine kinase isoforms whose signal transducing function is associated with altered vascular permeability in VEGF-related diseases (PCT W097/40830; PCT W097/40831). Plk-1 Kinase Inhibitors Plk-1 is a serine/threonine kinase which is an important regulator of cell 10 cycle progression. It plays critical roles in the assembly and the dynamic function of the mitotic spindle apparatus. Plk-1 and related kinases have also been shown to be closely involved in the activation and inactivation of other cell cycle regulators, such as cyclin-dependent kinases. High levels of Plk-1 expression are associated with cell proliferation activities. It is often found in malignant tumors of various origins. 15 Inhibitors of Plk-1 are expected to block cancer cell proliferation by disrupting processes involving mitotic spindles and inappropriately activated cyclin-dependent kinases. Cdc2/Cvclin B Kinase Inhibitors (Cdc2 is also known as cdkl) Cdc2/cyclin B is another serine/threonine kinase enzyme which belongs to 20 the cyclin-dependent kinase (cdks) family. These enzymes are involved in the critical transition between various phases of cell cycle progression. It is believed that uncontrolled cell proliferation, which is the hallmark of cancer is dependent upon elevated cdk activities in these cells. The inhibition of elevated cdk activities in cancer cells by cdc2/cyclin B kinase inhibitors could suppress proliferation and 25 may restore the normal control of cell cycle progression. The identification of effective small compounds which specifically inhibit signal transduction and cellular proliferation by modulating the activity of receptor and non-receptor tyrosine and serine/threonine kinases to regulate and modulate abnormal or inappropriate cell proliferation, differentiation, or metabolism is 30 therefore desirable. In particular, the identification of methods and compounds that specifically inhibit the function of a tyrosine kinase which is essential for angiogenic -10- processes or the formation of vascular hypeipermeability leading to edema, ascites, effusions, exudates, and macromolecular extravasation and matrix deposition as well as associated disorders or which at least provide the public with a useful choice would be beneficial. 5 SUMMARY OF THE INVENTION I Generally described herein are compounds of the formula Rwvx R1 15 and physiologically acceptable salts thereof, wherein, R is a substituted or unsubstituted aliphatic, aromatic, heterocyclic or aralkyl group, and R2 is a hydrogen, lower alkyl group or aryl group. R1 is hydrogen or -A-Z, wherein A is -(CH^-, -CCH2)nNH-, -(CH2)nO-, -(CH^S-, -(CH2)nS(0)- or -(CH2)nS(0)2-; and Z 20 is -H, a lower alkyl, aralkyl, trihalomethyl, R3CO-, trihalomethylcarbonyl, R30C(0)-, -NR4R5, -C(0)NR4R5, R30-, or a ring system selected from the group consisting of a C3-C6 cycloalkane, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, thiophene, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole, benzothiazole, tetrahydrofuran, triazine and 25 the applicable N-oxides thereof which can be optionally substituted with one or more halogens, a lower alkyl, R30-, HO-, HOC(O)-, R3OC(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4Rs or -NR4R5. R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl 30 group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group. R4 and Rs for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic ✓ intellectual property office of n.z. 1 2 MAR 2004 a P fi F i \t e h WO 01/09121 PCT/USOO/20628 -11- group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R" and Rs together with the nitrogen to which they are attached represent morpholino, pyrrolidine, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally 5 substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; Numerical index n is an integer from 0 to 3. Suitable substitutents for R include halogens, lower alkyl groups, R30-, 10 hydroxy, HOC(O)-, R30C(0)-, R30C(0)R6-, R3OR6-, trihalomethyl, trihalomethylcarbonyl, nitro, -C(0)NR4R5, -NR4R5, R3CO-, -(CH2)n-R7, -C(0)(CH2)n-R7, -C(0)-(CH2)I1-C(0)-R7, -0(CH2)„R7, -C(0)NR4(CH2)nR7, -C(0)0(CH2)nR7, -0C(0)(CH2)nR7, -NR4C(0)(CH2)nR7, -R6NR4R5, -R6N(R4)-R6-R7, -R6N[R6-R7]2, -R6C(0)NR4(CH2)nR7, -R6C(0)0(CH,)nR7, -R60C(0)(CH2)nR7, -15 R6NR4C(0)(CH2)nR7, -R6CH[C(0)0R4][NR5C(0)R4] or a substituted aryl or aralkyl group, wherein the substituent is selected from the group consisting of halogen, trihalomethyl, hydroxy, -NR4R5, nitro, -CONR4Rs, lower alkyl group, R30-, -C(0)0R4 or -0C(0)R3. R6 is a lower alkyl group or an aryl group. R7 is alkoxy, haloalkyl, lower alkyl piperazine, hydroxy, R30-, R3C(0)- or -NR4R5. 20 Suitable substituents for R3, R4 and R5 include one or more moieties selected from the group consisting of halogens, lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkyl ester, trihalomethyl preferrably trifluoromethyl, nitro, phenyl, phenyl-lower alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl-alkyl, CN, amino, alkylamino, dialkylamino, -C(0)NH2, -C(0)NH(alkyl) and -C(0)N(alkyl)2. 25 Aliphatic groups include straight chained or branched Cj-C18 hydrocarbons, or cyclic C3-C18 hydrocarbons which are completely saturated or which contain one or more units of unsaturation. Lower alkyl groups are straight chained or branched C,-C6 hydrocarbons or C3-C6 cyclic hydrocarbons which are completely saturated. Aromatic groups, as used herein, include carbocyclic ring systems (e.g. 30 benzyl and cinnamylidene) and fused polycyclic aromatic ring systems (e.g. naphthyl). In addition, aromatic groups includes heteroaryl ring systems (e.g. -12- pyridine, thiophene, furan, pyrrole, imidazole, oxazole, thiazole, pyrazole, triazole, pyrimidine and pyrazine) and heteroaryl ring systems in which a carbocyclic aromatic ring, carbocyclic non-aromatic ring or heteroaryl ring is fused to one or more other heteroaryl rings (e.g. benzimidazole, benzothiazole, indole, tetrahydroindole, azaindole, indazole, isoxazole, isothiazole. imidazole and quinoline). An aryl group, as used herein, refer to an aromatic group having five or six atoms. An aralkyl group is an aromatic substituent that is linked to a compound by an aliphatic group having from one to six carbon atoms. A heterocyclic group, as used herein, refers to a mono-, bi- or tri-cyclic heterocyclic group that is not aromatic or has a degree of unsaturation wherein the utisaturation does not make the group an aromatic group. Tautomers, stereoisomers, enantiomers and mixtures of these compounds are included in this invention. Pharmaceutically acceptable addition salts of these compqunds are also included in this invention. Useful compounds include but are not limited to those where R2 is hydrogen, and R is, preferably, a substituted indole, or a substituted or unsubstituted imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, pyrrole, pyrazole, 4,5,6,7-tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene or pyrazine. In a preferred embodiment, R2 is hydrogen, n is zero, and Z is a cyclopropyl, 3-pyridyl or pyrazinyl group. In another preferred embodiment, R2 is hydrogen, A is -CK n is 0 and Z is ethyl, propyl or isopropyl. In yet another preferred embodiment, R2 is hydrogen, A is CHj, n is 2 and Z is benzene which is optionally substituted with halogen, trihalomethyl, hydroxy, -NR4R5, nitro, -C(0)NR4Rs, lower alkyl group, R30-, -C(0)0R4 or -0C(0)R\ - In a first aspect, the present invention provides a compound represented by the following structural formula: 140979 1.DOC intellectual property OFFICE OF N.Z. 12 MAR 2004 -13- followedbypage 13a and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of substituted or unsubstituted: indole, imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7-tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrrole, pyrazole, Oxazole and thiazole; R1 is hydrogen or -A-Z; A is -(CH2)n"i -(CH2)nNH-, -(CH2)nO-, -(CH2)nS-, -(CH2)nS(0)- or - (CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, r30c(0)-, -nr^5, -c(0)nr4r5, r3co-, r3o-, or a ring system selected from the group consisting of a c3-Q5 cycloalkane, isoxazole, isothiazole, imidazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-t HO-, H0C(0)-, R30C(0)-, trihalomethyl, nitro, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic _-groups Jiniiralkylgroupra(C3-C6)cycloalkyl-alkyi groups heterocyclyUalkyl groupv-CN,- C(0)NR4R5 or -NR^R5; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; 140979 1.DOC intellectual property office of n.z. 12 MAR 2004 d p r. fi v f n -13a- followed by page 13b R4 and R5 for each occurrence are each, independently, hydrogen, or are selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (Cy C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen atom to which they are attached represent morpholjno, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-l-yl groups each optionally substituted by one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, ail aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3; provided that when R is an unsubstituted indol-3-yl then R1 is not -NH2; and provided that the compound is not 3H-pyrazol-3-one, 2,4-dihydro-4-[[4-hydroxy-3,5-bis(i-methylethyl)phenylJmethylene]-5-methyl., OC2HS og 0c3h6 OCH(CH3)2 f-if H 140979 1.DOC intellectual property OFFICE OF N.Z. 12 MAR 2004 -13b- followed by page 13c h3c- n CH ^ /~lC2H4N ch. n o > -f=ch- / C4H, if \ C,Hs(n) C4H9(n) 1—OH ] ^ Js,N*^o ANi h 0 m h H 0 H0 H chaso, y—wh-,—f, V-r^H-i—it NvNArt /LJl , Nn A 1 jj, °HO ' OW> COOC9H7(n) OW) ocA,n) f 1 r==Crtn—if "1 « 8 "O HO' Y C4H9(l> ( CaH9(t) COOCH, C V-p-rY VrT^ ^ o HcA[f" > 0 COOCH, H 0 HO {J CONHC,H4(n) CONHC,H,(n) ^ $ T3 n ° ho h N(CHj)J. < NyiA /Li >| ° HO N >| OH? Jf -p., nhcoch, ; ,nhcoch, chsco ,ch5co tox Xxrizi trxi H ■»"« H H ® «'Y "»U'' \V />..f !! OHO N c4tv»v - AH,C© =m-tY A^N ho (j NHCONHCW .NHCONHC.H. CN^ ; ... ,CN CONHC„H1J(n)^ .OONHC.H„(n) Xx°xic XC^ N 0 HO fl 3 0 HO M K 0 HO N 740979 1.DOC intellectual property office of n.z. 25 mm received -13c- followed by page 14 nhcoojh„(i) nhcocsh„(i) /*\_C0NM C/ rT^Tf '.VttY N-A ,._^N „>u-n tv0 ho {{' 8 0 ►» B' ch, int^np^ral property OFBCF OF N.Z. 2 ® JUt 2fi RECEIVED 140979_1.DOC -14- ^ In a preferred embodiment, the present invention is a compound represented by the following structural formula: ^R1 T* oA/» H and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of substituted or unsubstituted: 15 indole, imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7- tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrrole, pyrazole, oxazole and thiazole; R1 is hydrogen or -A-Z; A is -(CH2)n-, -(CH2)nNH-, -(CH^O-, -(CH2)dS-, -(CHa)nS(Q)- or -20 (CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R30C(0)-, -NR4R5, -C(0)NR4Rs, R3CO-, R30-, or a ring system selected from the group consisting of a C3-C6 cycloalkane, isoxazole, isothiazole, imidazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, 25 thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting ofKaTogensJoweialkyL R^-.Tro-.H^OCCD}7, R'OCCO)-" trThalomethyl, nitro,an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a 30 (C3-C6)cycloalkyl-alkyl group, a heterocyclyl-alkyl group, -CN, -C(0)NR4R5 or -NR4RS; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, intellectual property office of n.z. 1 2 MAR 2004 WO 01/09121 PCT/US00/20628 -15- an aromatic group, a (C3-C6)cycloaIkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or is selected from the group consisting of substituted or unsubstituted: a lower alkyl 5 group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted with one or 10 more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and when R is unsubstituted indol-3-yl then R1 is not -NH2; and when R is a substituted or unsubstituted benzene or an unsubstituted imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, oxazole or thiazole; then R' is not a lower alkyl, a (C3-C6)cycloalkyl, 20 benzene, or -C(0)NR4R5, wherein R4 and R5 are each independently H, a lower alkyl or a carbocyclic aryl. In another preferred embodiment, the present invention is directed to a compound represented by the following structural formula: H 30 and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of substituted or unsubstituted: indole, imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7- 15 n is an integer from 0 to 3; provided that: 25 WO 01/09121 PCT/US00/2G628 -16- tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrrole, pyrazole, oxazole and thiazole; R1 is hydrogen or -A-Z; A is -<CH2)„-, -(CH2)nNH-, -(CH2)nO-, -(CH2)nS-, -(CH2)nS(0)- or -5 (CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R30C(0)-, -NR4R5, -C(0)NR4R5, R3CO-, R30-, or a ring system selected from the group consisting of a C3-C6 cycloalkane, isoxazole, isothiazole, imidazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, 10 thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a 15 (C3-C6)cycloalkyl-alkyl group, a heterocyclyl-alkyl group, -CN, -C(0)NR4R5 or -NR4R5; R3 for each occurrence is, independently, selected from the group consisting of a substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, a (C3-20 C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; 25 optionally, R4 and R5 together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamoipholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted by one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloaIkyl 30 group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and WO 01/09121 PCT/USOO/20628 -17- n is an integer from 0 to 3; provided that: a) R is not pyrrol-3-yl or pyrrol-3-yl substituted with an alkyl or a carbocyclic aryl group; 5 b) R is not indol-3-yl or indol-3-yl substituted with an alkyl or a carbocyclic aryl group; and c) R is not azaindole or azaindole substituted at the 2-position with an alkyl or a carbocyclic aryl group. 10 In another preferred embodiment, the present invention is directed to a compound represented by the following structural formula: and physiologically acceptable salts thereof, wherein: R is substituted pyrrole or is selected from the group consisting of substituted 20 or unsubstituted: indole, imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7-tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrazole, oxazole and thiazole; R1 is hydrogen or -A-Z; A is -iCH2),r, -(CH2)nNH-, -(CH2)nO-, -(CH2)nS-, -(CH2)„S(0)- or -25 (CH^OV; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R30C(0)-, -NR4R5, -C(0)NR4R5, R3CO-, R30-, or a ring system selected from the group consisting of a C3-C6 cycloalkane, isoxazole, isothiazole, imidazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, 30 thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, an WO 01/09121 PCT/US00/20628 -18- aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, a heterocyclyl-alkyl group, -CN, -C(0)NR4R5 or -NR4RS; R3 for each occurrence is, independently, selected from the group consisting 5 of: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl 10 group, aromatic group, (C3-C6)cycloalky) group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally 15 substituted by one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3; 20 provided that: a) when R is substituted pyrrole, the pyrrole is substituted with R30C(0)R6, R3OR6-, trihalomethyl, trihalomethylcarbonyl, -(CH2)p-R7, -0(CH2)pR7, -C(0)N(R4)(CH2)pR7, -C(0)0(CH2)pR7, -0C(0)(CH2)pR7, -N(R4)C(0)(CH2)pR7, -R*NR4R5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, -25 R6C(0)N(R4)(CH2)pR7, -R6C(0)0(CH2)pR7, -R60C(0)(CH2)pR7, - R6N(R4)C(0)(CH2)pR7, -R6CH(C(0)0R4)(N(R4)C(0)R4), a substituted aryl or aralkyl group, wherein: R6 for each occurrence is independently a lower alkyl group or an aryl group; R7 for each occurrence is independently an alkoxy, haloalkyl, lower 30 alkylpiperazine, hydroxy, R30-, R3C(0)- or NR4RS; and p is an integer from 1-3; WO 01/09121 PCT/US00/20628 -19- b) when R is indol-3-yl, the indol-3-yl is substituted with R30C(0)R6, R3OR6-, trihalomethyl, trihalomethylcarbonyl, -(CH2)p-R7, -0(CH2)pR7, -C(0)N(R4)(CH2)PR7, -C(0)0(CH2)pR7, -OCCOXCH,)^7, -N(R4)C(0)(CH2)pR7, -RWR5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, - 5 R6C(0)N(R4)(CH2)pR7, -R6C(0)0(CH2)pR7, -R60C(0)(CH2)pR7, - RsN(R4)C(0)(CH2)pR7, -RsCH(C(0)0R4)(N(R4)C(0)R4) or a substituted aryl or aralkyl group; and c) when R is pyrazol-3-yl, the pyrazol-3-yl is substituted with R30C(0)R6, R3OR6-, trihalomethyl, trihalomethylcarbonyl, -(CH2)p-R7, -0(CH2)pR7, 10 -C(0)N(R4)(CH2)pR7, -C(0)0(CH2)pR7, -0C(0)(CH2)pR7, - N(R4)C(0)(CH2)pR7, -R6NR4R5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, -R6C(0)N(R4)(CH2)pR7, -R'CCOJOCCH^pR7, -R50C(0)(CH2)pR7, -R6N(R4)C(0)(CH2)pR7, -R6CH(C(0)0R4)(N(R4)C(0)R4) or a substituted aryl or aralkyl group. 15 In another preferred embodiment, the present invention is directed to a compound represented by the following structural formula: /R1 H and physiologically acceptable salts thereof, wherein: R is substituted pyrrole or is selected from the group consisting of substituted 25 or unsubstituted: indole, imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7-tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrazole, oxazole and thiazole; R1 is hydrogen or -A-Z; A is -(CH2)n-, -(CH2)nNH-, -(CH2)nO-, -(CH2)nS-, -(CH2)nS(0)- or -30 (CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R30C(0)-, -NR4R5, -C(0)NR4R5, R3CO-, R30-, or a ring system selected from the group consisting of a C3-C6 cycloalkane, isoxazole, isothiazole, imidazole, benzene, WO 01/09121 PCT/US00/2O628 -20- pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting 5 of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, a heterocyclyl-alkyl group, -CN, -C(0)NR4R5 or -NR4R5; R3 for each occurrence is, independently, selected from the group consisting 10 of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl 15 group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C6)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino orperhydro-l,4-diazepin-l-yl groups each optionally 20 substituted by one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3; 25 provided that: a) when R is an unsubstituted indol-3-yl then R1 is not -NH2; b) when R is a substituted or unsubstituted benzene or an unsubstituted imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, oxazole or thiazole; then R1 is not a lower alkyl, a (C3- 30 C6)cycloalkyl, benzene, or -C(0)NR4R5, wherein R4 and R5 are each independently H, a lower alkyl or a carbocyclic aryl; WO 01/09121 PCT/USOO/20628 -21- c) R is not pyrrol-3-yl or pyrrol-3-yl substituted with an alkyl or a carbocyclic aryl group; d) R is not indol-3-yl or indol-3-yl substituted with an alkyl or a carbocyclic aryl group; 5 e) R is not azaindole or azaindole substituted at the 2-position with an alkyl or a carbocyclic aryl group f) when R is substituted pyrrole, the pyrrole is substituted with R30C(0)R6, R3OR6-, trihalomethyl, trihalomethylcarbonyl, -(CH2)p-R7, -0(CH2)pR7, -C(0)N(R4)(CH2)pR7, -C(0)0(CH2)pR7, -0C(0)(CH2)pR7, - 10 N(R4)C(0)(CH2)pR7, -RWR5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, - R6C(0)N(R4)(CH2)pR7, -R6C(0)0(CH2)pR7, -R60C(0)(CH2)pR7, -R6N(R4)C(0)(CH2)pR7, -RsCH(C(O)0R4)(N(R4)C(0)R4), a substituted aryl or aralkyl group, wherein: R6 for each occurrence is independently a lower alkyl group or an aryl group; 15 R7 for each occurrence is independently an alkoxy, haloalkyl, lower alkylpiperazine, hydroxy, R30-, R3C(0)- or NR4R5; and p is an integer from 1-3; g) when R is indol-3-yl, the indol-3-yl is substituted with R30C(0)R6, R3OR6-, trihalomethyl, trihalomethylcarbonyl, -(CH2)P-R7, -0(CH2)pR7, 20 -C(0)N(R4)(CH2)pR7, -C(0)0(CH2)pR7, -0C(0)(CH2)pR7, - N(R4)C(0)(CH2)pR7, -R6NR4R5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, -R6C(0)N(R4)(CH2)pR7, -R6C(0)0(CH2)pR7, -R60C(0)(CH2)pR7, -R6N(R4)C(0)(CH2)pR7, -R6CH(C(0)0R4)(N(R4)C(0)R4) or a substituted aryl or aralkyl group; and 25 h) ' when R is pyrazol-3-yl, the pyrazol-3-yl is substituted with R30C(0)R6, R3OR6-, trihalomethyl, trihalomethylcarbonyl, -(CH2)p-R7, -0(CH2)pR7, -C(0)N(R4)(CH2)pR7, -C(0)0(CH2)pR7, -0C(0)(CH2)pR7, -N(R4)C(0)(CH2)pR7, -R5NR4R5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, -R6C(0)N(R4)(CH2)pR7, -R6C(0)0(CH2)pR7, -R60C(0)(CH2)pR7, - 30 R6N(R4)C(0)(CH2)pR7, -R6CH(C(0)0R4)(N(R4)C(O)R4) or a substituted aryl or aralkyl group. WO 01/09121 PCT/US00/20628 -22- In a more preferred embodiment, the present invention is directed to any of the foregoing compounds wherein A is -NH-, -0-, -S-, -S(O)- or -S(0)2-; and Z is cyclopropyl, 3-pyridyl or pyrazinyl. In yet another more preferred embodiment, the present invention is directed 5 to any of the foregoing compounds wherein A is -0-; and Z is ethyl, n-propyl or isopropyl. In still another more preferred embodiment, the present invention is directed to any of the foregoing compounds wherein A is -CH2-; and Z is phenyl, wherein said phenyl is optionally substituted with one or more moieties selected from the 10 group consisting of halogens, trihalomethyl, hydroxy, -NR4R5, nitro, -CONR4R5, lower alkyl group, R30-, -C(0)0R4 and -0C(0)R4. In still another preferred embodiment, the present invention is directed to any of the foregoing compounds wherein R is substituted with one or more substituents, each independently selected from the group consisting of halogens, lower alkyl 15 groups, R30-, hydroxy, HOC(O)-, R30C(0)-, R30C(0)R6-, R3OR6-, trihalomethyl, trihalomethylcarbonyl, nitro, -C(0)NR4R5, -NR4R5, R3CO-, -(CH2)n-R7, -' C(0)(CH2)n-R7, -C(0)-(CH2)n-C(0)-R7, -0(CH2)nR7, -C(0)NR4(CH2)nR7, -C(0)0(CH2)aR7, -0C(0)(CH2)nR7, -NR4C(0)(CH2)„R7, -R6NR4R5, -R6N(R4)-R6-R7, -R6N(R6-R7)2, -R6C(0)NR4(CH2)nR7, -R6C(0)0(CH2)i1R7, -R60C(0)(CH2)nR7, -20 R6NR4C(0)(CH2)nR7, -R6CH(C(0)0R4)(NR5C(0)R4), an optionally substituted aryl and an optionally substituted aralkyl group. The optionally substituted aryl and optionally substituted aralkyl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, -NR4R5, nitro, -CONR4R5, lower alkyl group, R30-, -C(0)0R4 and -0C(0)R3. Rs is a 25 lower alkyl group or an aryl group. R7 is alkoxy, haloalkyl, lower alkyl piperazine, hydroxy, R30-, R3C(0)- or -NR4R5. In one aspect of this embodiment, R is pyrrolyl, indolyl, azaindolyl, phenyl, pyrazolyl, imidazolyl, thienyl, 4,5,6,7-tetrahydroindolyl, or quinolinyl. In another aspect of this embodiment, R is pyrrol-2-yl, pyrrol-3-yl, indol-2-yl, indol-3-yl, azaindol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, 30 thien-2-yl or quinolin-5-yl. WO 01/09121 PCT/US00/20628 -23- In still another preferred embodiment, the present invention is directed to any of the foregoing compounds wherein R1 is trifhioromethyl, amino, cyclopropylamino, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylcyclopropyl, 2,2,3,3-tetramethylcyclopropyl, 2-phenylcyclopropyl, 5 cyclobutyl, cyclopentyl, cyclohexyl, -(CH2)p-0-phenyl, -(CH2)p-0-(4- methoxyphenyl), -(CH2)p-0-(4-chlorophenyl), -(CH2)p-0-(4-methylphenyl), -(CH2)p-0-(3-methylphenyl), -(CH2)p-0-(4-phenylphenyl), -(CH2)p-0-(4-hydroxyphenyl), -(CH2)p-0-(4-nitrophenyl), -(CH2)p-0-(4-aminophenyl), -(CH2)p-0-(4-carbamoylphenyl), -(CH2)p-0-(4-methoxycarbonylphenyl), -NH-phenyl, -NH-(4-10 methoxyphenyl), -NH-(4-chlorophenyl), -NH-(4-fluorophenyl), -NH-(4- isopropylphenyl), isopropoxy, ethoxy, cyclopentyloxy, -(CH2)p-indolyl, -(CH2)p-pyridyl, -(CH2)p-benzothiazolyl, -(CH2)p-pyrrolyl, -(CH2)p-tetrahydrofiiryl, -(CH2)p-pyrazinyl, -(CH2)p-furyl, -(CH2)p-thienyl, -(CH2)p-phenyl, -(CH2)p-isoxazolyl, -(CH2)p-(5-methyhsoxazolyl), -(CH2)p-pyrimidinyl, -(CH2)p-pyridazinyl, -(CH2)n-15 C(0)-0Me, -(CH2)n-C(0)-0Et or benzyl optionally substituted with one or more of CI, F, OMe, methyl or amino, p is an integer from 1 to 3. In one aspect of this embodiment, R is optionally substituted with one or more moieties selected from the group consisting of Br, CI, F, aminomethyl, N,N-dimethylaminomethyl, carboxy, carboxymethyl, carboxyethyl, carbonylmethyl, carbonylethyl, methoxycarbonyl, 20 ethoxycarbonyl, phenyl, 4-morpholinomethyl, -C(0)-0-(CH2)2-N(Me)2, -C(0)-0-(CH2)2-N(Et)2, -C(0)-0-CH2-N(Me)2, -C(0)-0-(CH2)2-N(Me)2, -C(0)-NH-(CH2)2-N(Me)2, -CH2-NH-C(0)-CF3 and an optionally substituted moiety selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and phenyl, where the optionally substituted moiety is optionally substituted with one or more of Br, CI, F, 25 hydroxy, nitro, amino or lower alkyl. In another aspect, the present invention provides a pharmaceutical composition comprising any one or more of the compounds of the present invention, as defined herein, and a pharmaceutically acceptable carrier or diluent. -24- followed by page 24a In a further aspect, the present invention provides a use, in the manufacture of a medicament for inhibiting one or more protein kinase activities, of a compound represented by the formula: and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C$)cycloalkyI group, a heterqcyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C<s)cycloalkyl-alkyl group, and a heteTOcyclyl-alkyl group; A is -CCH2)fl-, -(CH2)nNH-, —(CHAO-, -(CH2)ftS-, ~(CH2)nS(0)- or— (CH2)nS(0)2-; of a (C3-C<0cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected > from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CNj -C(0)NR4R5 and -NR^5; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -iSfR4Rs, -C(0)NR4R5, R3Q-, or a ring system selected from the group consisting intellectual PROPERTY office of n.z. 140979 1.DOC 25 JUN 2004 DECEIVED -24a- followed by page 24b R3 for each occurrence is independently selected from the group consisting of • > substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an somatic group, a (C3-Cfi)cycIoaIkyl group, a heterocyclic group, an aralkyl group, a (C3-Cjs)cycIoalkyl-alkyl group and a heterocyplyl-alkyl group; ~ R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (Q-QOcycloalkyl group, a heterocyclic group, an araJky! group, a (C3-Co)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and Rs together with the nitrogen to which they are attached represent morpholino, pyrroljdino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-l -yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower, alkoxy lower alkyl, an aromatic group, a (C3-C(s)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3, provided that the compound is not 3H-pyrazol-3-one, 2,4-dihydro-4-[[4-hydroxy-3,5-bis(l-methylethyl)phenyl]methylene]-5-methyl. Described but not claimed herein is a method of inhibiting one or more protein kinase activity comprising the administration of a compound represented by the formula: R and physiologically acceptable salts and biologically active metabolites thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (Cj-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a ((VC^cycloalkyl-alkyl group and a heterociyclyl-alkyl group; 140979 1.DOC intellectual property office. of n.z. 2 5 JUN 200*1 received -24b- followed by page 25 R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3- CJcycloalkyl-alkyl group, a heterocyclyl-alkyl group; A is -(CHA-, -(CH2)BNH-, -(CH^O-, -(CH^S-, -(CH^SCO)- or -(CH^SCOV; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR4R5, -C(0)NR4R5, R30-, or a ring system selected from the group consisting of a (Cj-C^cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, /40979 i nnr. intellectual property office of n.z. 12 MAR 2004 RECEIVED WO 01/09121 PCT/US00/20628 -25- HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and -NR"R5; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy 5 lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and Rs for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a 10 lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-15 1-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and 20 n is an integer from 0 to 3. A preferred method of the foregoing method is where the inhibition of the protein kinase is in a recipient in need thereof. A preferred method of any of the foregoing methods is where the compound is a mixture of stereoisomers. 25 A preferred method of any of the foregoing methods is where the stereoisomers are enantiomers. A preferred method of any of the foregoing methods is where the stereoisomers are E and Z isomers. A preferred method of any of the foregoing methods is where the compound 30 is a mixture of structural isomers. -26- followed by page 26a A preferred method of any of the foregoing methods is where the structural isomers are tautomers. A preferred method of any of the foregoing methods is where said protein kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase. kinase is selected from the group consisting of KDR, Flt-1, TIE-2, FGFR, PDGFR, IGF-l-Rj c-Met, Lcki Src, fyn, L-yn, Blk, and yes. In a still further aspect, the present invention provides use for manufacturing a medicament for treating or essentially inhibiting inflammatory diseases in a recipient in need thereof of a compound represented by the formula: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (Ca-C^cycloalkyl group, a heterocyclic group, an aralkyl group, a ..... .. ^ . (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycl6alkyl-alkyl group, and. a heterocyclyl-alkyl group; A is-(CH2)n-, -(CH2)nO-, -<CH2)nS-, -(CH2)nS(0)- or- (CH2)aS(0)2-; is where said tyrosine R N and physiologically acceptable salts thereof, wherein: INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 MAR 2004 140979 1.DOC n C> A f! I l( C H -26a- followed by page 26b Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR^5, -C(0)NR4R5, R30-, or a ring system selected from the group consisting of a (C3-C6)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and -NR*R5; R3 is selected from the group consisting of substituted or unsubstituted: lower alkyl group* lower alkoxy lower alkyl group, an aromatic group, a (C3-C,s)cycl6alkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-aIkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (Ca-Cfi/cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Cs)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and Rs together with the nitrogen to which they are attached represent morpholino, pyrrolidine, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1 -yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C<s)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Q)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3. ^ In. another aspect, the present invention provides use for manufacturing a medicament for treating or essentially inhibiting hyperproliferative disorders in a recipient in need thereof of a compound represented by the formula: 140979 1DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 MAR 2004 received -26b- followed by page 26c and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CKbV, -(CH2)nNH-, -(CH2)nO-, -(CH2)nS-, -<CH2)n$(0)- or -(CH^O),-; Z is-H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR^5, -C(0)NR4R5, R30~, or a ring system selected from the group consisting of a (C3-C6)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, H0C(0)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR'lR5 and -NR^R5; «5 R is seleaed from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6>cycloalkyl group, a 140979 1.DOC INTELLECTUAL PROPERTY ' OFFICE OF N.Z. 1 2 MAR 2004 RECEIVED -26c- followed by page 26d heterocyclic group, an aralkyl group, a (Cj-CeJcycIoalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and Rs for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (Cs-C^cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C<5)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidine, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, . / hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C<j)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3. Also described but not claimed is a method of treating or essentially inhibiting hyperproliferative disorders or inflammatory diseases in a recipient in need thereof comprising the administration to said recipient of any of the compounds of the present invention as defined herein. In a yet further aspect, the present invention provides a use, in the manufacture of a medicament for treating or inhibiting angiogenesis in a recipient in need thereof, of a compound represented by the formula: R 0 N and physiologically acceptable salts thereof, wherein: INTELLECTUAL property OFFICE OF N.Z. 140979 1.DOC 2 5 JUN 2004 RECEIVED -26d- followed by page 26e R is selected from the group consisting Of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-Q)cycloalkyl group, a heterocyclic group, an aralkyl group, a (G3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (Ca-C^cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C<;)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is KCHaV. -(CH2)nNH-, -<CH2)nO-, -(CH2)„S-, -(CH2)nS(0)- or -(CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R3OC(OK -NR4R5, -C(0)NRilR5, R30 -, or a ring system selected from the group consisting of a (C3-C<j)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, — benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-,.HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and -NR4R5; A R for each occurrence is each, independently is selected from the group consisting of substituted or unsubstituted: lpwer alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-Q)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and Rs for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C$)cyclQalkyl group, a heterocyclic group, an aralkyl group, a (Cs-CeJcyclQalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and Rs together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-l-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl. 140979 1.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 MAR 2004 -26e- followed by page 26f hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycIoaIkyl-alkyI group and a heterocyclyl-alkyl group; arid n is an integer from 0 to 3. Also described but not claimed is a method of treating or inhibiting angiogenesis in a recipient in need thereof comprising the administration to said recipient of any of the compounds of the present invention as defined herein. In another aspect, the present invention provides a use, in the manufacture of a medicament for inducing an anti-angiogenic effect in a recipient in need thereof, of a compound represented by the formula: and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C6>cycloalkyl group, a heterocyclic group, an aralkyl group, (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; ' R1 is hydrogen or-A-Z^ R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C<j)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CH2V, -(CH2)nNH-,-(CH2)„0-, -(CH^S-, -(CH2)nS(0)- or -(CH2)„S(0)2- 140979 1.DOC intellectual property office of n.z. 2 5 JUN 20M -26f- followed by page 26g Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR*R5, -CCONR^R5, R30-, or a ring system selected from the group consisting of a (Ca-QsXycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be option all/substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitrO, aryl, -CN, -C(0)NR4R5 and -NR^5; % R for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl ©roup, a (C3-C6>eycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from / ■ the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (Cj-C^cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and Rs together with the nitrogen to which they are attached represent moipholino, pyrrolidine, piperidino, imidazol-l-yl, .piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted with ode or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3; provided that the compound is not di-phenyl-1,3 N-piperidino methylene-4-pyrazolone-5, phenyl-1 methyl-3 N-piperidino methylene-4 pyrazolone-5, phenyl-1 propyl-3-N-piperidino methylene-4 pyrazolone-5 or phenyl-1 methyl-3 N-morpholino methylene-4 pyrazolone-5. Described but not claimed is a method of inducing an anti-angiogenic effect in a recipient in need thereof comprising the administration to said recipient of any of the compounds of the present invention as defined herein. In another aspect, the present invention provides a use in the manufacture of a medicament for treating or inhibiting the progression of a disease or condition in a recipient in need thereof, of a compound represented by the formula: INTELLECTUAL PROPERTY OFFICE OF N.Z. 2 5 JUN 20M -26g- followed by page 26h R .R O and physiologically acceptable salts and biologically active metabolites thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C5)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; Ais -<CH2)aNH-, -(CHJ.O-, -(CH2)nS-, -(CH2)nS(0> or- (CH^SCO),-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR4R5, -C(0)NR4R5, R30-, or a ring system selected from the group consisting of a (CVC^cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, H0C(0)-, R30G(0>, trihalomethyl, nitro, aiyl, -CN, -C(0)NR4R5 and - NR4RS: 140979_1.DOC -26h- followed by page 26i R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (Cj-C^cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cj-QJcycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cy-C^cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin- i i 1-yl groups each optionally substituted with one or more moieties selected I from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (Cj-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cj-CJcycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3 where said disease or condition is selected from the group consisting of cancer, arthritis, atherosclerosis, restenosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, wound healing, peptic ulcer, Helicobacter related diseases, virally induced angiogenic disorders, fractures, diabetic retinopathy, Crohn's disease, inflammatory bowel disorder, cat scratch fever, retinopathy or prematurity, ulcers, thyroid hyperplasia, burns, trauma, acute lung injury, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, sepsis, adult respiratory distress syndrome, multiple-organ dysfunction syndrome, ascites and tumor-associated effusions and edema. INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 MAR 20W 140979JJ>OC -26i- followed by page 27 Described but not claimed is a method of treating or inhibiting the progression of a disease or condition in a recipient in need thereof comprising the administration to said recipient of any of the compounds of the present invention, as defined herein, where said disease or condition is selected from hemangioma, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, wound healing, peptic ulcer, Helicobacter related diseases, virally induced angiogenic disorders, fractures, diabetic retinopathy, Crohn's disease, inflammatory bowel disorder, cat scratch fever, retinopathy or prematurity, ulcers, thyroid hyperplasia, burns, trauma, acute lung injury, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel 140979 1.DOC -27- followed by page 27a syndrome, sepsis, adult respiratory distress syndrome, multiple-organ dysfunction syndrom?, ascites and tumor-associated efliisions and edema. In another aspect, the present invention provides a use, in the manufacture of a medicament for affecting vascular hyperpermeability or the production of edema in a recipient in need thereof, of a compound represented by the formula: and physiologically acceptable salts thereof, Wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C(s)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C$)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; Rl is hydrogen or-A-Z; R is hydrogen or is selected from the group consisting of a substitute^ or unsubstituted: lower alkyl group, an aromatic group, a (Ca-Qicycjoalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is ^CH^-, -(CH2)„NH-, -(CH2)nO-, -(CH2)dS-, -(CH^SCO)- or-(CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcaibonyl, R3CO-, R30C(0)-, -NR^5, •C(0)NR¥, R30-, or a ring system selected from the group consisting of a (C3-C6)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, ..." ( *- ' benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more rooieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, H0C(0)-, R30c(0)-, trihalomethyl, nitro, aryl, -CN, -C(G)NR4R5 and -NR4RS; " INTELLECTUAL PROPERTY OFFICE OF N.Z. 140979 1.DOC 2 5 JUN 2004 received -27a- followed by page 27b R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Cj)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and Rs for each occurrence axe each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-Q)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-a]kyl group and a heterocyclyl-alkyl group; optionally, R4 andRs together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C$)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cs-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3. Also described but not claimed is a method of affecting vascular hyperpermeability or the production of edema in a recipient in need thereof comprising the administration to said recipient of any of the compounds of the present invention, as defined herein. A preferred method of the immediately foregoing method is where the effect on the production of edema is antiedematous. In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament for inhibiting one or more protein kinase activities. In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament for treating a recipient in need of having one or more protein kinases inhibited. In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament for affecting hyperproliferative disorders in a recipient. In another aspect, the present invention provides a use of a compound of the invention in the manufacture of a medicament for affecting angiogenesis. 180185 1.DOC intellectual property OFFICE OF N.Z. 2 5 JUN 2004 -27b- followed by page 28 A preferred method of any of the foregoing methods is where the protein kinase is a serine kinase. A preferred method of any of the foregoing methods is where the protein kinase is a threonine kinase. 3-Cyclopropyl-4-{[(3J5-dimethyl-4-(4-methy-l-piperazinylmethyl)pyrrol-2- yl]methyIene}-2-pyrazolin-5-one, 3-Cyciopropyi-4-[(3,5-dimethyi-4-(l-pyrroHdinylmethyip3aroi-2-yi)methylene]-2- pyrazoiin-5-one, £- 3-Cyclopropyl-4-[(4-diethylaminometh.yl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -Cyclopropyl-4-[(3,5 -dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-2-pyrazoiin-5-one, 3-Cyclopropyl-4-[(4-diethanolaminomethyi-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-dimethylaminomethyl-4,5-tetramethylenepyrrol-2- yI)methylene]-2-pyrazolin-5-one, 3- Cyclopropyl-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3- Cyclopropyl-4-[(3-diethyIaminomethyl-4,5-tetramethylenepyrrol-2- yl)methylene]-2-pyrazolin-5-one, 3- Cyclopropyl-4-{[3-(4-methyl-l-piperazinylmethyl)-4,5-tetramethylenepyrrol-2- yl]methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2- yl]methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyctopropyl-4-[(4-diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3- Cyclopropyl-4-(3,5-dibromo-4-hydroxybenzylidene)-2-pyrazolin-5-one, 140979 1.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 MAR 2004 n C #» c I M ft n WO 01/09121 PCT/U S00/20628 -28- 3- Cyclopropyl -4-[(4-oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5-one, 3- Cyclopropyl -4-[(4-dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 5 4-[(5-Chloropyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-trifluoromethylpyrroI-2-yl)methyleiie]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[4-(2-dimethyiaminoethylaminocarbonylpyrrol-2-yl)methylene]-2-10 pyrazolin-5-one, 3-Cyclopropyl-4-[(3-ethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[3-(2-dimethylaminoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[3-(2-dimethylaminoethylaminocarbonylindol-2-yl)methylene]-2-15 pyrazolin-5-one, 3-Cyclopropyl-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[4-(4-morpholinoethylaimnocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-Cyclopropyl-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 25 4- {[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene} -3-cyclopropyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazoIin-5-one, 30 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4- {[(3,5 -Dimethyl-4- [(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene } -3 -(3 - pyridyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3-pyridyl) -2-35 pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)m.ethylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 40 4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2-45 pyrazolin-5-one, WO 01/09121 PCT/US0O/2O628 -29- 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(3-pyridyl)-2-pyrazolin-5-one, 5 3-(3-Pyridyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2-pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, a vsa a c c n ^ , ,i\ i -*> /o o -f-uncuiy j / ~ icu anj ui umuuj.-^-.y iyj ncuiy ICIICJ -J ~ J'11U^1 10 pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yI)methylene]-3-(3-pyridyl)-2-pyrazoIin-5-one, 4-(3,5-Dibromo-4-hydroxybenzy Iidene)-3 -(3 -pyridyl)-2-pyrazolin-5 -one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(3-pyiidyl)-2-pyrazolin-5-one, 15 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(3-pyridyI)-2-pyrazoIin-5-one, 4- [(4-Chloropyrrol-2-yl)methylenej -3 -(3 -pyridyl)-2-pyrazolin-5 -one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(3-pyridyl-2-pyrazolin-5-one, 20 3-(3-Pyridyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4- [(4-Ethoxycarbonylpyrrol-2-yl)methylene] -3 -(3 -pyridyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylammocarbonylpyrrol-2-yl)methylene]-3-(3.-pyridyl)-2-25 pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-30 pyrazolin-5-one, 4- [4-(4-Morpholmoethoxycarbonylpyrrol-2-yl)methylene]-3 -(3 -pyridyl)-2-pyrazolin-5 -one, 4-[4-(4-Morpholmoethylaminocarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 35 4-[3-(4-Morpholinoethoxycarbonylmdol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]- 3-(3-pyridyl)- 2-pyrazolin-5-one, 40 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-(3-pyridyl)-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)inethylene]-3-(3 -pyridyl)-2-pyrazolin-5 -one, 45 4-[(5-Chloro~4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]- 3-(3-pyridyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -30- 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazoIm-5-one, 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-isopropoxy-2-pyrazo]in-5-one, 5 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-diraethyl-pyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-f(355-Dimethyl-4-(piperidinornethylpyrrol-2-yl)rnethylene]-3-isopropoxy-2-pyrazolin-10 5-one, 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yI)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3-Dimethylanrinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 15 3-Isopropoxy-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3 -Isopropoxy-4- {[3 -(4-methyl-1 -piperazinyl)methyl-4,5 -tetramethylenepyrrol-2-20 yl]methylene}-2-pyrazolin-5-one, 3-Isopropoxy-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethyIenepyrrol-2-yI]methylene}-2-pyrazolin-5-one, 3-Isopropoxy 4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- -2-pyrazolin-5-one, 25 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-isopropoxy-2-, pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-isopropoxy-2-pyrazolin-5-one, 30 3-Isopropoxy-4-[(4-oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methyIene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-ChloropynoI-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 35 4-[(5-Chloropyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycaibonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin- 5-one, 40 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 45 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, WO 01/09121 PCT/US00/2O628 -31- 3-Isopropoxy-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-Isopropoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[3-(4-morpholino6thylaminocarbonyIindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,4-DiethoxycarbouylpynoI-2-yI)rnethylene]-3-isopropoxy-2-pyrazoiin-5-one, 10 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-isopropoxy-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-moTphoIinomethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4- {[(4-methyl- l-piperazinylmethyl)pyrrol-2-yl]methylene} -3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-20 5-one, 4-[(4-Diethylaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethy]-4-(piperidinomethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 25 4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)raethylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- 2-30 pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4- {[3-(4-methyl-1 -piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5 -one, 35 3-Ethoxy-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrroI-2-yl]methylene}-2-pyrazolin-5-one, 3-Ethoxy-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-ethoxy-2-pyrazolin-5-40 one, 4-[(4-Diethylaminoethyl-3,5-dimethyIpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethyIpyirol-2-yl)methylene]-3-ethoxy-2-pyrazolin-45 5-one, 3-Ethoxy-4-[(4-oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -32- 4-[(4-Dimethylaminonnethyl-5-methylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5 5-one, 4-[4-(2-Dimethylaminoethylammocarbonylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[3-(2-DimethyIaminoethoxycarbonyIindol-2-yl)rnethylenej-3-ethoxy-2-pyrazolin-5-10 one, 4-[3-(2-Dimethylaminoethylammocarbonylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-15 one, 3-Ethoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[(5-methoxyindol-2-yl)methylene]- 2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yI]methylene}-3-ethoxy -2-pyrazolin-5-one, 20 3-Ethoxy-4-[(indol-3 -yl)methylene]-2-pyrazolin-5 -one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-ethoxy-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-ethoxy-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonyImethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-25 ethoxy -2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyiTol-2-yI)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 30 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinylmethyl)-4,5-tetramethy1enepyrrol-2-yl]methylene}-3- pyrazinyl-2-pyrazolin-5-one, 3 -Pyrazinyl-4- {[3-( 1 -pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-35 pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 40 4-[(4-Diethylaminoethyi-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 45 4-[(5-Chloropyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3-Pyrazinyl-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -33- 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-5 pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazoiin-5-one, 4-[3-(2-Dimethyiaminoethyiaminocarbonyiindoi-2-yi)methyIene]-3-pyrazinyl-2-10 pyrazolin-5-one, 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 15 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethylaniinocarbonylindol-2-yl)methylene]-3-pyrazinyI-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonyIpyrrol-2-yl)methylene]-3-pyrazinyl -2-pyrazolin-5-one, 20 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3-Pyrazinyl-4-[(pyrrol-2-y])methylene]-2-pyrazolin-5-one, 25 4-[(Indol-2-yl)methylene]-3-pyrazinyl -2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]- 3-pyrazinyl-2-pyrazolin-5-one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3- pyrazinyl -2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl] methylene}-3- pyrazinyl -2-pyrazolin-5-one, 30 4-[(5-Ethoxy-4-methoxycarbonyknethyl-3-methoxycarbonylpyrrol-2-yl)methyIene] -3-pyrazinyl -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]- 3- pyrazinyl-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 35 4-[(4-Chloropyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(imidazol-2yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-40 pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2-45 pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -34- 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-(Imidazol-2-yl)-4-[4-(4-morpholinoethylaniinocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imida2ol-2-y!)-4-[3-(4-rnorpho!inoethylaniinocarbonylindol-2-yI)nieihylene]-2-10 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(l-methylindol-3-yI)methylene]-2-pyrazolin-5-one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)metliylene]-3-(imidazol-2-yl) -2-pyrazolin-5-one, 15 3-(Imidazol-2-yl) -4-[(5-raethoxyindol-2-yI)methylene]- 2-pyrazolin-5-one, 3-(Imidazol-2-yl) -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-20 (imidazol-2-yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(indoI-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl))- 2-pyrazolin-5-one, 25 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3- (imidazol-2-yl) - 2-pyrazolin-5-one, 4-{[3-(2-Ammo-2-carboxyethy])indol-2-yl]methyIene}-3-(imidazol-2-yI)-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-30 (imidazol-2-yl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3- (imidazol-2-yI)-2-pyrazoIin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(l-methylcyclopropy])-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methyIene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 35 4-[(5-Chloropyrrol-2-yl)methylene]-3-( 1 -methylcyclopropyl)-2-pyrazolin-5-one, 3-(l-Methylcyclopropyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 40 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4-[4-(2-DimethyIaminoethyIaminocarbonylpyrrol-2-yl)methylene]-3-(l- methylcyclopropyl)-2-pyrazolin-5-one, 4-[(3-EthoxycarbonylindoI-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-45 one, WO 01/09121 PCT/U800/20628 -35- 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-( 1 - methylcyclopropyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 5 3 -(1 -Methylcyclopropyl)-4-[4-(4-morpholinoethoxycarbonylpyiToI-2-yl)methylene] -2-pyrazolin-5-one, 3-(l-Methylcyclopropyl)-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -(1 -Methyl eyclopropyl)-4- [3 -(4-morphol inoethoxyearbonylindol-2-yl)rnethy lene] -10 2-pyrazolin-5-one, 3 -(1 -Methylcyclopropyl)-4-[3 -(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 15 3-(l-Methylcyclopropyl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[3,5 -Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene] -3 -(1 -methylcyclopropyl) -2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methyl ene]-3 -(1 -methylcyclopropyl)-2-pyrazolin-5 -one, 3-(1-Methylcyclopropyl) -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-20 one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-y]]methylene}-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 25 4-[(Indol-3-yl)methylene]-3-( 1 -methylcyclopropyl)-2-pyrazolin-5-one, 4-[(Pyrrol-2-yl)methylene]-3-(1 -methylcyclopropyl)-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene] -3-( 1 -methylcyclopropyl))- 2-pyrazolin-5-one, 30 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-(l -methylcyclopropyl) -2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycaTbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-35 (1-methylcyclopropyl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonyLmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(l- methylcyclopropyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(2-fiiryl)-2-pyrazolin-5-one, 40 4- {[3,5-Dimethyl-4-(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3-(2-furyl)-2-pyrazo lin-5-one, 4- {[3,5-Dimethyl-4-(l -pyrrolidinylmethyl)pyrrol-2-yl]methy]ene} -3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-fuiyl)-2-pyrazolin-45 5-one, WO 01/09121 PCT/US00/2O628 -36- 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethanolarninomethyl-3,5-dimethylpyrrol-2-yJ)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 5 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3-DiethylaminoethyI-4>5-tetrameihyienepyiToI-2-yi)methyiene]-3-(2-furyi)-2- 10 pyrazolin-5-one, 3-(2-Furyl)-4-{[3-(4-methyl-l-.piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 3-(2-Furyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2-pyrazolin-5-one, 15 3-(2-Furyl)-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrro]-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-20 one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5-one, 3-(2-Furyl)-4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 25 4-[(4-Bromopyrrol-2-y])methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 30 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5 one, 4-[4-(2-DimethylaminoethyIaminocarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazoIin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 35 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(2-fiiryl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Fury])-4-[4-(4-morphoImoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-40 one, 3-(2-Furyl)-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Furyl)-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one 3-(2-Furyl)-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5 45 one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 90 fS o cs © tz1 p H U 0H ro © O £ ^ 6 ® PjH lo ^ CN fO CN py< ^ c ? i/"^ to d H ^ (N i——< i ...-J CO 4 4 wn — O —- o a o CS H N C3 d £9 p.. eu n m w ^ •n <N O m © in Tf WO 01/09121 PCT/US0O/2O628 -38- 4- [(4-Diethylaminoethyl-3,5 -dimethy lpyxrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4-Oxo-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2- thienyl)-2-pyrazolin-5-one, 5 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2- thienyl)-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazoIin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(2-thienyi)-2-pyra2oIm-5-one, 10 3-(2-Thienyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-15 pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-20 pyrazolin-5-one, 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 25 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 30 4-[(l -Methylindol-3-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[3,5-Dimethyl-4-eth.oxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4,5-Tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 35 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(2-thienyl) -2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl]methylene}-3-(2- thienyl) -2-pyrazolin-5-one, 4-[(Indol-3 -y l)methylene] -3 -(2-thienyl)-2-pyr azolin-5 -one, 40 4-[(Pyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(2-thienyl) -2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 45 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US0O/2O628 -39- 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3- (2-thienyl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 5 4-[(4-Bromopyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazoIin-5-one, 10 3-Cyclopropoxy-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[4-(2-dimethylaxninoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(3-ethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 15 3-Cyclopropoxy-4-[3-(2-dimethylaminoethoxycarbonylmdol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[3-(2-dimethylaminoethylaminocarbonylindol-2-yl)m6thylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-20 5-one, 3-Cyclopropoxy-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 25 3-Cyclopropoxy-4-[3-(4-morpholinoethylaminocaxbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3 -Cyclopropoxy-4- [3,5 -dimethy 1-4-ethoxycarbonyIpyrro l-2-yl)methylene] -2-pyrazolin-30 5-one, 3-Cyclopropoxy-4-[(5-methoxyindol-2-yl)methyIene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-{[3,5-dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene} -2-pyrazolin-5-one, 35 3 -Cyclopropoxy-4- {[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(Lndol-2-yl)methylene]-2-pyrazolin-5-one, 40 3-Cyc]opropoxy-4-[(3,4-diethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-{[3-(2-Acetaniido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-cyclopropoxy -2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indoI-2-yl]methylene}-3-cyclopropoxy-2-pyrazolin-5-one, 45 3-Cyclopropoxy-4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -40- 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3- cyclopropoxy-2-pyrazolin-5 -one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 5 4-[(5-Chloropyrrol-2-yl)rnethylene]-3-[2-(5-pyrimidinylethyI)]-2-pyrazolin-5-one, 3-[2-(5-pyrimidinylethyl)]-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-EthoxycarbonylpyiTol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5- ntip. 10 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-[2-(5- pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-15 one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)] 2-pyrazolin-5 -one, 4-[3-(2-DimethyIaminoethylaminocarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 20 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]- 3-[2-(5- pyrimidinylethyl)]-2-pyrazolin-5 -one, 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-25 pyrazolin-5-one, 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]- 3-[2-(5- pyrimidinylethyl)]-2-pyrazoIin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 30 4-[(l-Methylindol-3-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] -2 pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyI)] -2-pyrazolin-5-one, 3-[2-(5-pyrimidinylethyl)] -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-35 one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 40 4-[(Indol-3-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 3-[2-(5-pyrirnidinylethyl)]-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin 5-one, 45 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -41- 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yI]methylene}-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 5 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-y])methylene]-3-(2-phenylethyl)-2-p>Tazolirx-5-one, 10 3-(2-phenylethyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[4-(2-Dirnethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-15 pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]- 3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-20 pyrazolin-5-one, 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)- 2-pyrazolin-5 -one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-phenyl ethyl)-2-pyrazoIin-5-one, 25 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]- 3-(2-phenylethyl)-2-pyrazolin-5-one, 30 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4- [(5-Methoxyindol-2-yl)methylene] - 3-(2-phenylethyl) -2-pyrazolin-5 -one, ' 3-(2-phenylethyl) -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene} -3-(2-35 phenylethyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-(2- pheny lethyl)-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 40 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-(2-phenylethyI)-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(2-phenylethyl)-2-pyrazolin-5-one, 4- [(5-Ethoxy-4-methoxycarb onylmethyl-3 -methoxycarbonylpyrrol-2-y l)methylene]-3 -45 (2-phenylethyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -42- 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]- 3- (2-phenylethyl)-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 5 4-[(5-Chloropyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl3-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolm-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolm-5-one. 10 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-[2-(4- hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylind6I-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-15 5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-[2-(4- hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[3-(2-DimethylaminoethylaminocarbonyIindol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 20 3-[2-(4-hydroxyphenyl)ethyl]-4-[4-(4-morpholii)oethoxycarbonylpyiTol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl]-4-[4-(4-morphoIinoethylaminocarbonylpyrrol-2- yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl]-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-25 2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl]-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyiTol-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 30 3-[2-(4-hydroxyphenyl)ethyl]-4-[(5-methoxymdoI-2-yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl]-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene} -3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 35 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin- 5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl]- 2-pyrazolin-5-one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-[2-(4-40 hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene] -3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 45 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrroI-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -43- 3-[2-(4-aminophenyl)ethyl]-4-[(4-bromopyrrol-2-yl)methylene] -2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(4-chloropyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-chloropyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-trifluoromethylpyrrol-2-yl)methylenej-2-pyrazolin-5-5 one, 3-[2-(4-aminophenyl)ethyl]-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]- 2-pyrazolin-5 -one, 10 3-[2-(4-aminophenyl)ethyl]-4-[4-(2-dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(3-ethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyI)ethyl]-4-[3-(2-dimethylaminoethoxycarbonylindol-2-15 yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[3-(2-dimethylaminoethylaminocarbonylindoI-2-yl)methyl ene] -2-pyrazolin-5 -one, 3-[2-(4-aminophenyl)ethyl]- 4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyra2olin-5-one, 20 3-[2-(4-aminophenyl)ethyl]-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene] -2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[3-(4-morpholinoethoxycarbonyllndol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[3-(4-morpholinoethylaminocarbonylindol-2-25 yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-{[3,5-dimethyl-4-(2-dimethylaminoethoxycarbony]) 30 pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-{[3,5-dimethyl-4-(2-dimethylaminoethylamino carbonyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3 - [2-(4-aminophenyl)ethyl] -4- [(pyrrol-2-y l)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(Indol-2-yl)meth.ylene]-2-pyrazolin-5-one, 35 3-[2-(4-ammophenyl)ethyl]-4-[(3,4-diethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-[2-(4- aminophenyl)ethyl]-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(4-aminophenyI)ethyl]-2-40 pyrazolin-5-one, 3-[2-(4-aminophenyI)ethyl]-4-[(5-ethoxy-4-methoxycarbonylmethyl-3- methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 45 4-[(3,5-Dimethyl-4-morpholinomethylpyirol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -44- 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(4- pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyriniidiny])-2-pyrazolin-5-one, 5 4-[(4-Diethylaminomethyl-3>5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5 -Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene] -3 -(4-pyrimidinyl)-2-pyrazolin-5-one, 4- [(4-Diethanolaminomethyl-3,5 -dimethylpyiTol-2-yl)methy]ene]-3 -(4-pyrimidinyI)-2-10 pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4- pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazoIin-5-one, 15 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyriniidinyl)-2-pyrazolin-5-one, 4- {[3-(4-Methyl-l -piperazinyl)methyl-4,5-tetramethylenepyrroI-2-yl]methylene} -3-(4-pyrimidinyl)-2-pyrazoIin-5-one, 3-(4-Pyrimidinyl)-4-{[3-(l-pyiTolidinyl)methyl-4,5-tetramethylenepyirol-2-20 yl]methylene} -2-pyrazolin-5-one, 4-[(3-Piperidmomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(4-pyrimidinyl)pyrazolin-5-one, 25 4-[(4-Diethylaminoethyl-3>5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 30 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazoIin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)niethylene]-3-(5-pyrimidmyl)-2-pyrazolin-5-one, 35 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrrolidinylinethylpyrTol-2-yl)methy]ene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-diethylaminomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-40 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazoIin-5-one, 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-cme, 45 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one5 WO 01/09121 PCT/US00/20628 -45- 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yI)methylene]-3-(5-pyrimidmyl)-2-pyrazolin-5-one, 5 4- {[3-(4-Methyl-1 -piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -3 -(5-pyrimidinyl)-2-pyrazolin-5-one, 3-(5-Pyrimidinyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yljmethylene} -2-pyrazolin-5 -one, 4-[(3-Piperidinomethyl-4,5-tetram.ethy5enepyrco!-2-yI)methy!ene]-3-(5-pyriinidinyl)2-10 pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)raethylene] -3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yI)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 15 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-pyrimidinyl)-2-pyrazoIin-5-6ne, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methyIene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyirol-2-yl)methylene]-3-(5-pyrimidinyl)-2-20 pyrazolin-5-one, 4-[(3,5-DimethyI-4-morphoIinomethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 25 4-[(3,5-Dimethyl-4-(l -pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5 -one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyra2olin-5-one, 4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-30 pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Drniethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methyIene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 35 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5 -one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-40 (2-pyrimidinyl)-2-pyrazolin-5-one, 3-(2-Pyriraidinyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 45 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(2-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -46- 4-[(4-DiethyIaminoethyl-3,5-dimethyIpyirol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl) 5 2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5 one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazoIin-5-one, 10 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(3- pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-15 2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 20 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl) 2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3- pyridazinyl)-2-pyrazolin-5-one, 4-[(3-MoTpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-25 pyridazinyl)-2-pyrazolin-5-one, 4-[(3-DiethylaminomethyI-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3- pyridazinyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 30 3-(3-Pyridazinyl)-4- {[3-(l -pyrrolidinyl)methyl-4,5-tetramethy]enepyrrol-2-yl]methylene} -2-pyrazolin-5 -one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl) 2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(3-pyridazinyl)-2-35 pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridaziny])-2-pyrazolin-5-one, 4-(3>5-Dibromo-4-hydroxybenzylidene)-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-40 2-pyrazolin-5-one, 4- [(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(3 -pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 45 4-[(3,5-Dimethyl-4-morpholinoniethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -47- 4-[(3,5 -Dimethyl-4- {[(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3-(4- pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin- 5 -one, 5 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyridazmyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(piperidinomethyIpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3 5 5 -dimethyl-pyrrol-2-yl)meth3 .'lene]-3-(4-10 pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4- pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Moipholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 15 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 3-(4-Pyridazinyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-20 yl]methylene} -2-pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(4-pyridazinyl)-2-pyrazolin-5-one, 25 4-[(4-Diethylaminoethyl-355-dimethylpyrroI-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethyIaminomethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 30 4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-35 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(5- isoxazolyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin- 5 -one, 40 4- [(4-Diethylaminomethyl-3,5 -dimethylpyrrol-2-yl)methy lene] -3 -(5 -isoxazolyl)-2 -pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3,5-Dimethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethy lenepyrrol-2-yl)methylene]-3-(5-45 isoxazolyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOQ/20628 -48- 3-(5-Isoxazolyl)-4-[(3-morpholinornethyl-435-tetramethylenepyrroI-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 5 3 -(5 -IsoxazolyI)4- {[3 -(4-methyl-1 -piperazinyl)methy 1-4,5 -tetramethylenepyrrol-2-yl]methylene} ~2-pyrazolin-5-one, 3-(5-isoxazolyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 3 -(5-1 soxazolyl)-4- [(3 -piperidinornethyl-4,5-tetramethylenepyrrol-2-yl)methylene] -10 2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)fnethylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 15 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(5-isoxazoIyl)-2-pyra2olin-5-one, 4-[(4-DimethylaminomethyI-5-methylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 20 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 4-[(3,5 -Dimethyl-4- {[(4-m ethyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3-(5 -methyl-3-isoxazolyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(5-methyl-3-25 isoxazolyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 30 4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyI)-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-methyl- 3-isoxazolyl)-2-pyrazolin-5-one, 3-(5-Methyl-3-isoxazolyl)-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-35 yl)methylene]- 2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 3-(5-Methyl-3-isoxazolyl)4-{[3-(4-methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} ~2-pyrazolin-5-one, 40 3-(5-Methyl-3-isoxazolyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-(5-Methyl-3-isoxazolyl)4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene] -2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(5-methyl-3-45 isoxazolyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -49- 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-methyl-3- isoxazolyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 5 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 3-(5-Methyl-3-isoxazolyl)-4-[(4-oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Dirnethy!amir.omethyl-5-methylpyrrol-2-yl)methylene]-3-(j-metjiyl-3-10 isoxazoIyl)-2-pyrazolin-5-one, 3-cyclopropyl-4-(l-3-[(dimethylamino)methyl]-4,5,6,7-tetrahydro-l//-2-indolylmethylidene)-4,5-dihydro-1H-5-pyrazolone, 3-cyclopropyl-4-(l-4-[(l J-dimethylammonio^ethylJ^jS-dimethyl-l/f^-pyrrolylmethylidene^S-dihydro-lH-S-pyrazolone maleate, 15 4-[l-(4-[[2-(dimethylarnino)ethyl](methyl)amino]methyl-3,5-dimethyl-l//-2-pyrrolyl)methylidene]-3-(2-pyrazinyl)-4,5-dihydro-li/-5-pyrazolone 4-(l-4-[2-(diethylamino)ethyl]-3,5-dimethyl-l//-2-pyrrolylmethylidene)-3-(2-pyrazinyl)-4,5-dihydro-l//-5-pyrazolone, 4-l-[4-(3-chloropropanoyl)-3,5-dimethyl-l//-2-pyrrolyl]methylidene-3-(2-20 pyrazinyl)-4,5-dihydro-l//-5-pyrazolone, 4-(l-3-[(dimethylamino)methyl]-4,5,6,7-tetrahydro-l//-2-indolylmethylidene)-3-(2- pyrazinyl)-4,5-dihydro-l//-5-pyrazolone, 4-(l -4-[(dimethylamino)methyl]-3,5-dimethyl-l//-2-pyrrolylmethylidene)-3-(5-methyl-3 -isoxazolyl)-4,5 -dihy dro- IH-5-pyrazolone, 25 3-Cyclopropyl-4-[(4,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Benzyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methoxypheny]oxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Phenyloxymethyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 30 3-(4-Methoxybenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Benzyl-4-{[4-(2-carboxyethyl)-3-methylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-Benzyl-4-{[3-(2-carboxyethyl)-4-methylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 35 3-(4-Methylphenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 2-Amino-4-[)pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-PhenyIethyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Phenylanaino-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 40 3-(4-Methylbenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methylphenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methoxyphenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorobenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chloroph.enylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 45 3-(3-Chlorophenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-{Indol-3-yl)-4-[(pyrrol-2-yl)metliylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -50- 3-(3-Methoxybenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -(3,4-Dimethoxybenzyl)-4- [(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methoxyphenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-PhenylphenyIoxymethyl)-4-[(pyrrol-2-yl)methy]ene]-2-pyrazolin-5-one, 5 3-(2-Phenylpropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Phenylpropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(pyrrol-2-yl)methyIene]-2-pyrazolin-5-one, 4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one, 3-(4-Methylphenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolm-5-one, 10 4-[(3,5-DimethyIpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Nitrophenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazoliii-5-one, 3-(4-Fluorophenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 15 4-[(4,5-Dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-phenylethyl-2-pyrazolin-5-oneJ 4- {[ 1 -(4-Hydroxybutyl)pyrrol-2-yl]methylene} -3-isopropoxy-2-pyrazolin-5-one, 3-Cyclopentyloxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-Tert-butylureido-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(4-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(4-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(l-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 25 3-(4-Aminophenylethyl)-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[(5-methylpyrrol-2-yl)methylene]2-pyrazolin-5-one, 3-(4-Carbamoylphenylethyl)-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 30 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yI)methylene]-3-(4-methoxycarbonylphenylethyl- 2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-35 2-pyrazolin-5-one, 4-[(5-Ethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one( 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one, 3-(EthoxycarbonyImethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazoIin-5-one, 40 3-(4-Methoxyphenylaimnocarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin- 5-one, 4-{(3-(2-Carboxyethyl)-4-methylpyTrol-2-yl]methylene}-3-isopropyl-2-pyrazolin-5-one, 3-CycIopropyl-4-[(pyrrol-2-yl)methylene]-2-ppyrazolin-5-one, 45 3-Cyclobutyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Pyridil)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -51- 3-Cyclopropyl-4-[[l-(3,5-dichlorophenyl)pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Pyrrol-2-yl)methylene]-3-(2J2,3,3-tetramethylcyclopropyl)-2-pyrazolin-5-one> 3-Cyclopropyl-4-[(3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopentyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-oneJ 5 3-(2-Methylcyclopropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-(Benzothiazol-2-yl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4,5-Dimethylpyrrol-2-yl)methylene]-4-(3-pyridyl)]-2-pyrazolin-5-one, 3-Cyclopropyl-4[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Pyrrol-2-yl)-4-[(pyrrol-2-yl)methylene]-2-p>Tazolin-5-one, 10 3-Cyclopropyl-4-[(4-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Benzothiazol-2-yl)-4-[(4-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4- [3,5 -Dimetyl-4-ethylpyrrol-2-yl)methylen e] -3 -(3 -pyridyl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 15 4-[(5-Methylpyrrol-2-yl)methylene]-3-(-3-pyridyl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-Propyl-4-[(pyrrol-2-yl)methyIene]-2-pyrazolin-5-one, 3-Methyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-IsopTopylphenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Phenylammo)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4- {[1 -(4-hydroxybutyl)pyrrol-2-yl]methylcne]-2-pyrazoIin-5-one, 25 4-{[4-(2-Carboxyethyl)-3-methylpyrrol-2-yl]methylene}-3-isopropoxy-2-pyrazolin- 5-one, 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-30 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Acetyl-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-dimetylaminoethyloxycarbonyl)pyrrol-2-yl]methylene} -3-35 isopropoxy-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimetylaminoethylaminocarbonyl)pyrrol-2-yl]methy]ene}-3-isopropoxy-2-pyrazolin-5-one, 4-[(5-Ethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(5-Carboxypyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 40 3-(4-Chlorophenylaminocarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazoIin-5-one, 3-Cyclopropyl-4-[(5-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one, 45 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5- WO 01/09121 PCT/US00/20628 -52- 4-[(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin- 5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 5 4-[(3,4-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3-methylpyrrol-2-y]]methylene}-3-cyclopropyl-2-pyrazolin- 5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 10 3-Cyclopropyl-4-[(5-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4,5-tetrameth.ylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Methoxycarbonylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxycarbonyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropyl-4-[(pyrrol-2-yl)methylene]-2-pyrazoIin-5-one, 15 3-(trans-2-phenylcyclopropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclohexyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropylamino-4-[(4,5-tetramethylenepyrrol-2-yl)rnethylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-morpholinomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 4-[(5-Carboxypyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 4- [(4-Chloropyrrol-2-yl)methylene] -3-ethoxy-2-pyrazolin-5-one, 4- [(4-BromopyrTol-2-yl)methyleneJ -3-ethoxy-2-pyrazolin-5-one, 4-[(5-Chloropyixol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4[(4-Chloropyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 25 4-[(4-Bromopyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 3-Pyrazinyl-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-PyridyI)-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3,5-dimethyl-4-(2-dimethylaminoethyloxycarbonyl)pyrrol-2-30 yl]methylene}-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4(2-dimethylaminoethyloxycarbonyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin- 5-one, 4-[(3,5-Dimethyl-4-dirnethyIaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 35 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one maleate, 4-{[3,5-Dimethyl-4-(2-morpholinoethyraminocarbonyl)pyrrol-2-yl]methylene-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 40 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 4-[(4,5-tetramethylenepyrrol-2-yl)raethylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 4-[(3,5-dimethylpyrrol-2-yl)methylene3-3-(2-furyl)-2-pyrazolin-5-one, 4-[(3,5-dimethyl-4-morpholinomethylpyirol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 45 4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/U SQ0/20628 -53- 3-Cyclopropyl-4-[(3,5-dimethyl-4-trifluoroacetamidomethylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-aminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-(Benzothiazol-2-yl)-4-[(3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Benzothiazol-2-yl)-4-[(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl)methylene] 2-pyrazolin-5 -one, 4- [(3,5-DimethyI-4-ethylpyrrol-2-y])methylene] -3 -pyrazinyl-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyirol-2-yl)methylene]-3-pyrazinyi-2-pyrazoiin-5-one, 10 4-[(4-Carboxypyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-diethanolaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-trifluoroacetamidomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 15 3-Cyclopropyl-4-[(4-ethoxycarbonyl-3-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5 one, 4- {[3,5 -Dimethyl-4-( 1 -pyrrolidmylmethyl)pyrrol-2-yl]methylene } -3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-20 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrroI-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyiTol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 25 4-[(3,5-Dimethyl-4-ethoxycarbonylpyiTol-2-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 4-[(3,4-Di(ethoxycarbonyl)pyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one! 30 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-pyridylethyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methy]ene3-3-(l-methyl-2-phenylethyl)-2-pyrazolin-5-one, 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyTazolin-5-one, 35 3-Ethoxy-4-[(5-nitropyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[(4-nitropyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Carboxypyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene}-3-ethoxy-2-pyrazolin-5-one, 40 4-[(5-Chloro-3-methoxycarbonyl-4-methoxycarbonyimethylpyrrol-2-yl)methylene] 3-ethoxy-2-pyrazolin-5-one, 4-{[3-(2-Carboxyethyl)-4-methylpyrrol-2-yl]methylene}-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-45 one, 3-Ethoxy-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazoIin-5-one, WO 01/09121 PCT/US00/20628 -54- 4-[(3,5-Dimethyl-4-ethoxycarbony]pyrrol-2-yl)methylene]-3-trifluoromethyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 5 3-(3-Aminophenyl)-4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-{[2-(4-morpholinoethyl)aminocarbonylpyn:ol-2-yl]methylene}-2-pyrazolin-5-one, 4-[(4-EthoxycarbonyI-3-phenylpyrroI-2-yl)nieihylene]-3-pyTazinyl-2-pyrazolin-5-10 one, 4- {[4-(4-MethyI-1 -pyperazinylmethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-piperidinomethylpyrroI-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)m6thylene]-3-(5-isoxazolyl)-2-20 pyrazolin-5-one, 4-[(5-Methyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3,5-Dimethyl-4-[N-(2-dimethylaminoethyl)-N-methylaminomethylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 25 3-CycIopropyl-4-[(3-dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene] -2-pyrazo lin-5-one, 4-[(3-DimethylaminomethyI-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl- 2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-2-30 pyrazolin-5-one maleate, 4-{[4-(3-Chloropropionyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazoIin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methy]ene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-[(3,5-Dimethyl-4-dimethylaminomethylpyirol-2-yI)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(4-hydroxypiperidinomethyl)pyrrol-2-yl]niethylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Aminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-40 one maleate, 4-{[4-(4-Benzylpiperidino)methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin- 5-one, 4-{[3,5-Dimethyl-4-(2-hydroxyethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {{3,5-Dimethyl-4-[2-(l -pyrrolidinylethyl)]pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/USQO/20628 -55- 3-Cyclopropyl-4- { {3,5-Dimethyl-4-[2-(l -pyrrolidinylethyl)]pyrrol-2-yl} methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3,5-Dimethyl-4-(2-hydroxyethyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 5 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(3-Diethylaminopropyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(3-hydroxypropyl)pyrrol-2-yl]methy]ene}-3-pyrazinyl-2-10 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminoacetylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one hydrochloride, 4-[(3,5-Dimethyl-4-dimethylaminoacetylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 15 3-Cyclopropyl-4-{[(2-diethylaminoethyl)-3,5-dimethyl-4-pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazoIin-5-one, 4-{[3,5-Dimethyl-4-(4-hydroxybutyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-20 pyrazolin-5-one, 4-{[4-(4-Diethylaminobutyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl-N-oxide)-3,5-dimethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 25 4-{[3,5-dimethyl-4-(l-pyrrolidinylacetyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Diethylaminoacetyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-rsopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 30 4-{[3,5-Dimethyl-4-[3-(l-pyrrolidinylpropyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(Dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazmyI- 2-pyrazolin-5-one, 3-Cyclopropyl-4-[(dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-35 yl)methy!ene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethoxyoxalyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 3-Benzyl-4-[(indol-3-yl)methyIene]-2-pyrazolin-5-one, 3-Benzyl-4- {[1 -(4-hydroxybutyl)indol-3-yl]methylene} -2-pyrazolin-5-one, 40 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenyloxymethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-phenyloxymethyl-2-pyrazolin-5-one, 3-(4-Chlorophenyloxymethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxybenzyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methylphenyloxymethyl)-2-pyrazolin-5-one, 45 4-[(Indol-3-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -56- 4-[(Indol-3-yl)methylene]-3-(4-methylbenzyl)-2-pyrazoliri-5-one, 4-[(Indol-3-yl)methylene]-3-phenylamino-2-pyrazoliii-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methylphenylamino)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylamino)-2-pyrazolin-5-one, 5 3-(4-Chlorobenzyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-{[l-(4-hydroxybutyl)indol-3-yl]methylene}-3-(4-methoxybenzyl)-2-pyrazolin-5-one, 3-(4-Chloropheny]amino)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(lQdol-3-yi)methyiene]-3-(3-methoxybenzyi)-2-pyrazoiin-5-one, 10 3-(3,4-dimethoxybenzyl)-4-[(indol-3-yl)methylene]-2-pyrazoIin-5-one, 3-(4-hydroxybenzyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(3-Chlorophenyloxymethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(Indol-3-yl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylethyl)-2-pyrazolin-5-one, 15 4-[(Indol-3-yl)methylene]-3-(4-phenylphenyloxymethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-phenylpropyl)-2-pyrazolin-5-one, 4-[(Indol-3-yI)methylene]-3-(3-phenylpropyl)-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methylphenylethyl)-2-pyrazolin-5-one, 20 3-Ethoxy-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4- {[1 -(4-Hydroxybutyl)indol-3-yl]methylene} -3 -isopropoxy-2-pyrazolin-5-one, 4- {[1 -(4-Hydroxybutyl)indol-3-yl]methylene} -3 -phenylethyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-nitrophenylethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-propoxy-2-pyrazolm-5-one, 25 3-(4-Fluorophenylamino)4-[(indol-3-yl)methylene]- -2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(2-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3 -Isopropoxy-4- [(7-methylindol-3 -yl)methylene] -2 -pyrazolin-5-one, 4-[(7-Methylindol-3-yl)methy]ene]-3-phenylethyl-2-pyrazolin-5-one, 30 3-Cyclopentyl-4-[(mdol-3-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxycarbonylphenylethyl)-2-pyrazolin-5-one, 3-Isopropoxy-4-[(l-isopropylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 35 3-Isopropyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenylaminocarbonylmethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxycarbonylmethyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylaminocarbonylmethyl)-2-pyrazolin-40 5-one, 3-Cyclopropyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 3-(2-Aminocarbonylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-CycIobutyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 45 3-(2-Dimethylaminocarbonylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[l-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -57- 4-[(Indol-3-yl)methylene]-3-(4-pyridyl)-2-pyrazolin-5-one, 3-Cyclopentyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2,2,3,3-tetramethylcyclopropyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-methylcyclopropyl)-2-pyrazoIin-5-one, 5 3-Cyclohexyl-4-{[l-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one, 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-(4-pyridyl)-2-pyrazolin-5-one, 3-(Benzothiazol-2-yl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 3-Dimethyiamino-4-[(indoi-3-yl)methyiene]-2-pyrazoiin-5-one, 10 4-[(Indol-3 -yl)methylene] -3 -(pyrrol-2-yl)-2-pyrazolin-5 -one, 4-[(Indol-3-yl)methylene]-3-(6-methoxybenzothiazol-2-yl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(7-methylindol-3-yl)methylene]~2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 15 4- [(Indol-3-y l)methylene]-3 -propyl-2-pyrazolin- 5 -one, 4-[(Indol-3-yl)methylene]-3-methyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-trifluoromethyl-2-pyrazolin-5-one, 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one, 4- {[1 -(4-Hydroxybutyl)indol-3-yl]methylene} -3 -methyI-2-pyrazolin-5-one, 20 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-trifluoromethyl-2-pyrazolin-5-one, 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-(tert-butyl)-2-pyrazolin-5-one, 3-Ethoxycarbonyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4- [(Indol-3 -yl)methy lene]-3 -(2-methoxycarbonylethyl)-2-pyrazolin-5 -one, 4-[(Indol-3-yl)methylene]-3-(trans-2-phenyl-l-cyclopropyl)-2-pyrazolin-5-one, 25 3-Cyclobutyl-4-{[l-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one, 4-[(6-Carboxy-l-methylindol-3-yl)methylene]-3-cyclopropyl-2-pyTazolin-5-one, 3-Cyclopropyl-4-[(5-methoxy-l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(l,7-dimethylindol-3-yl)methylene]-2-pyrazolin-5-one, 30 4-[(l-Methylindol-3-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one, 3-Cyclopropylamino-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(6-Carboxy-1 -methylindol-3-yl)methylene]-3 -isopropoxy-2-pyrazolin-5-one, 4-[(l,7-Dimethylindol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-methoxy-l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 35 3-(4-Fluoropheny!amino)-4-[(l-methylindol-3-yl)rnethylene]-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-trifluoroacetamido-2-pyrazolin-5-one, 3-(4-Arninophenylethyl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-Amino-4-[( 1 -methylindol~3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 40 3-Ethoxy-4-[(l-methyIindol-3-yl)methylene]-2-pyrazolin-5-one, 3-(5-Isoxazolyl)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-tert-butyl-2-pyrazolin-5-one, 4-[(6-Carboxy-l-methylindoI-3-yl)methylene]-3-pyrazinyl*2-pyrazolin-5-one, 4-{{l-Methyl-6-[2-(4-raorpholino)ethyl]aniinocarbonylmdol-3-yl}methylene}-3- 45 pyrazinyl-2-pyrazolin-5-one, 4-[(Indol-2-yI)methylene]-3-isopropoxy-2-pyrazolin-5-one, WO 01/09121 PCT/US0O/2O628 -58- 3-(4-Hydroxyphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methoxycarbonylphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Carbamoylphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-Cyclopropyl-4-[(indol-2-yl)methy]ene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-dimethylaminomethylindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(i-methyiindoi-2-yi)methyIene]-2-pyrazoIin-5-one, 10 4-[(Indol-2-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-nitroindol-2-yl)methylene]-2-pyrazoIin-5-one, 4-[(Indol-2-yl)methylene]-3-isopropylamino-2-pyrazolin-5-one, 3-(4-Carboxyphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 15 4-[(Indol-2-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 3-Isopropoxy-4-[(3-methylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-{[3-(2-methoxycarbonyl-2-acetamidoethyl)indol-2-yl]methylene}- 2-pyrazolin-5-one, 3-Ethoxy-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-Ethoxy-4- {[3-(4-morpholinomethyl)indol-2-yl]methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-(4-niorpholinomethyl)indol-2-yl]methylene}-2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 25 4-[(4-Chloro-6,7-dihydroindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(4-Chloro-6,7-dihydroindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-dihydroindoI-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethylindol-2-yl)raethylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-benzyl-2-pyrazolin-5-one, 30 3-Benzyl-4-{[l-(4-hydroxybutyl)-7-azaindol-3-yl]methylene}-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-methoxyphenyloxymethyl)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Amino-4-[(7-azaindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-methoxybenzyl)-2-pyrazolin-5-one, 35 4-[(7-Azaindol-3-yl)methylene]-3-phenylamino-2-pyrazolin-5-one, 4-[(7-Azaindol-3-y])methylene]-3-(4-methylbenzyl)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one, 4- {[ 1 -(4-Hydroxybutyl)-7-azaindol-3-yl]methylene} -3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one, 40 4-[(7-Azaindol-3-yl)methylene]-3-isopropyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-cyclopropyl-2-pyrazoIin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-cyclobutyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)metbylene]-3-phenyl-2-pyrazolin-5-one, 45 4- [(7-Azaindol-3 -yl)methylene]-3 -(4-fluorophenylamino)-2-pyrazolin-5 -one, 4-[(7-Azaindol-3-yl)methylene]-3-propyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -59- 4-[(7-Azaindol-3-yl)methylene]-3-methyI-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-trifluoromethyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(tert-butyl)-2-pyrazolin-5-one, 4- {[ 1 -(4-Hydroxybutyl)-7-azaindol-3 -yl]methylene} -3-trifluoromethyl-2-pyrazolin-5 5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-isopropylphenylamino)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(3-methylphenylamino)-2-pyrazolin-5-one, 4- {[ 1 -(4-Hydroxybutyl)-7-azaindol-3-yl]methylene} -3-(3-methylphenylamino)-2-pyrazolin-5-one, 10 4-[(7-Azaindol-3-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one, 3-Benzyl-4-[(4-dimethylaminophenyl)methylene]-2-pyrazolin-5-one, 4-[(4-Dimethylaminophenyl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Dimethylaminophenyl)methylene]-3-phenylethyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-dimethylaminophenyl)methylene]-2-pyrazolin-5-one, 15 3-Isopropoxy-4-[(3-methylpyrazol-4-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-methylpyrazol-4-yl)methylene]-2-pyrazolin-5-one, 4-[(Imidazol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(imidazol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Imidazol-4-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 20 3-Cyclopropyl-4-[(thien-2-yl)methylene]-2-pyrazolin-5-one, 4[(Indol-3-yl)methylene]-3-isopropyl-l-methyl-2-pyrazolin-5-one, 3-Isopropoxy-4-[(pyrrol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(8-Hydroxyquinolin-5-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl) 25 2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin- 5 -one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]metliylene}-3-(2-fiiryl)-2-pyrazolin-5-one, 30 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl) 2-pyrazolin-5 -one, 4- {[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-(5-pyrimidinyl) 35 2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)- 2-pyrazolin- 5 -one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 40 3-Cyclopropyl-4-[(4-diethylaminoraethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[4-(2-cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3,5-dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-2-45 pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -60- 3-Cyclopropyl-4-{{3)5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yI}methylene}-2-pyrazolin-5-one, 4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3 -cyclopropyl-2-pyrazolin-5-one, 5 3-Cyclopropyl-4-[(4-diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4-{[4-(l-pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yljmethylene} -2-pyrazolin-5-one, 3 -Cyclopropyl-4- { {3-i sopropyl-5-methy 1-4- [2-( 1 -pyrroiidinylethyl) jpyrrol-2-10 yI}methylene}-2-pyrazolin-5-one, 3 -Cyclopropyl-4- {[4-(2-cyclopropylaminoethyl)-3 -isopropyl-5 -methylpyrrol-2-y!]methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene}-2-pyrazolin-5-one, 15 3 -Cycl opropy 1-4- {[3 -isopropyl-5 -methyl-4-(4-piperidinobutyl)pyrrol-2-yljmethylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4- { {4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5- . methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-{[4-(4-dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-20 yl]methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-cyclopropyl-4-(l-pirrolidinylmethyl)-5-methylpyrrol-2-yl]methylene} -2-pyrazolin-5-one} 25 3-Cyclopropyl-4- {{3-cyclopropyl-5-methyl-4-[2-(l -pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-2 pyrazolin-5-one, 3-Cyclopropyl-4- { {3-cyclopropyl-4-[2-di(methoxyethyl)arainoethyl]-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 30 3-Cyclopropyl-4-{[3-cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -2-pyrazolin-5 -one, 3-Cyclopropyl-4- {{3-cyclopropyl-4-[3-(2,5-dimethyl-l -pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-35 2-yl]methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4- { (3-cyclopropyl-5-methyl-4-[4-(l -pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 40 4- {[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazohn-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene} -3-45 pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -61- 4- {[4-(2-Carboxyethyl)-3,5-dimethyIpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5 -one, 5 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazo Iin-5-one, 4-{[4-(2-CycIopropyiaminoethyi)-3-isopropyl-5-methylpyrroi-2-yl]methylene}-3-10 pyrazinyl-2-pyrazoIin-5-one, 3-Pyrazinyl-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 3-Pyrazinyl-4- {{4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene}-2-pyrazolin-5-one, 4- {[4-(4-DimethylaminobutyI)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-20 pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4- { {3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-2-pyrazinyl-2-pyrazolin-5-one, 25 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-furyl)-40 2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyixol-2-yl]methylene}-3-(2-furyl)-2-pyrazoIin-5-one, 45 4- {{3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -62- 4-[(4-Diethylaminomethyl-3-isopropyl-5-rnethylpyrrol-2-yl)methylene]-3-(2-fuiyl)- 2-pyrazolin-5-one, 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]rnethylene}-3-(2-furyl)-2-pyrazolin-5-one, 5 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyciopropyiaxninoethyi)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-10 furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5 -one, 3-(2-Furyl)-4-{[3-isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methyIene}-2-pyrazolin-5-one, 15 3 -(2-Furyl)-4- {{4-[3 -(4-pyridylmethylamino)propyl]-3 -isopropyl-5 -methylpyrrol-2-yl} methylene}-2-pyrazolin-5-one, 4- {[4-(4-Dimethylaminobutyl)-3-isopropyl-5 -methylpyrrol-2-yl]methylene} -3 -(2-fiiryl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-20 furyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyirolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3-(2-furyl)-2-pyr£izolin-5-one, 25 4- {[3-Gyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3-(2-furyl)-2-pyrazolin-5-one, 4- {{3-Cyclopropyl-4- [3 -(2,5-dimethyl-1 -pyrrolidinyl)propyl] -5 -methylpyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl} methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutyIaminobutyl)pyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 35 4-[(3,5-Dimethyl-4-(l-pyrrolidinyLmethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2- thienyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-40 thienyl)-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-phenyIaminoethyl)pyrrol-2-yl]methylene} -3-(2- thienyl)-2-pyrazolin-5-one, 45 4- { {3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(2-thienyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -63- 4- {[4-(2-CarboxyethyI)-3,5-dimethylpyrrol-2-yl]methylene} -3-(2- thienyl)-2-pyrazoIin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 5 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4- { {3-Isopropyl-5-methyl-4-[2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl} methylene} -3 -(2-thienyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaimnoethyl)-3-isopropyl-5-methylpyrroi-2-yi]methylene}-3-(2-10 thienyl)-2-pyrazolin-5-one, 4-{{4-[3-(l-Pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 15 4- { {4-[3-(4-Pyridylmethylammo)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyiTol-2-yl)methylene]-3-(2-20 thienyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyI)ethyl]pyrrol-2-yl}methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrroI-2-yl}methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 25 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{[3-CycIopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 35 4-[(3!5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazo lin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-40 pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 45 4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(4-pyrimidiny l)-2-pyrazolin-5 -one, WO 01/09121 PCT/US00/20628 -64- 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 5 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin- 5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yI}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-cyclopropyiaminoethyi)-3-isopropyi-5-methyipyrroi-2-yi]methy]ene}-3-(4-10 pyrimidinyl)-2-pyrazolin-5-one, 3-(4-Pyrimidinyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene}-2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 15 4- {{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol^2-yl} methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-20 pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene} -3-(4-pyrimidinyl)-2-pyrazolin-5-one, 25 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dirnethyl-l-pyrrolidinyl)propyl]-5-methylpyixol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5 -one, 35 4-[(3,5-Dimethyl-4-(l-pyirolidinylmethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dirnethyIpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(5-40 pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 45 4- {{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -65- 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methy]pyirol-2-yl)niethylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 5 4- {[4-(l -Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-cyciopropylaminoethyl)-3-isopropyi-5-methylpyrrol-2-yl]rnethy!ene}-3-(5-10 pyrimidinyl)-2-pyrazolin-5-one, 3-(5-Pyrimidinyl)-4- {{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methyIpyrrol-2-yl} methylene} -2-pyrazolin-5 -one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 15 4- { {4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -3-(5 -pyrimidinyl) -2-pyrazolin-5 -one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylammomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-20 pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 25 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4- {{ 3-Cyclopropyl-5-methyl-4-[4-( 1 -pyrrolidinyl)butyl]pyrrol-2-yl} methylene} -3-(5 -pyrimi dinyl)-2-pyrazolin-5 -one, 4- {[3-Cyclopropyl-5 -methyl-4-(4-cyclobutylaminobutyl)pyirol-2-yl]methylene} -3-(5 -pyrimidinyl)-2-pyrazolin-5 -one, 35 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin- 5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrTol-2-yl]methylene}-3-(2-40 pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenyIaminoethyl)pyrrol-2-yI]methylene}-3-(2-pyrimidinyl)-2-pyrazolin- 5-one, 45 4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrroI-2-yl}methylene}-3-(2-pyrrmidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -66- 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 5 4- {[4-( 1 -Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3 -(2-pyrimidinyl)-2-pyrazolin-5-one, 4- {{3 -Isopropyl-5-methyl-4- [2-( 1 -pyrrolidinylethyl)]pyrrol -2-yl} methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-(2-cyciopropylaminoethyi)-3 -isopropyl-5-methylpyrrol-2-yl]methy"iene} -3-(2-10 pyrimidinyl)-2-pyrazolin-5-one, 3-(2-Pyrimidinyl)-4- { {4-[3-(l -pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 15 4- {{4-[3 -(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-(4-Dimethylaminobutyl)-3 -isopropyl-5 -methylpyrrol-2-yl]methylene} -3 -(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-20 pyrimidinyl)-2-pyrazolin-5-one, 4- { {3-Cyclopropyl-5-methyl-4-[2-( 1 -pyrrolidinyl)ethyl]pyrro 1-2-yl} methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene} -3 -(2-pyrimidinyl)-2-pyrazolin-5-one, 25 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-(2-pyrimidinyl)-2-pyr£izolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- { {3-Cyclopropyl-5-methyl-4-[4-(l -pyrrolidinyl)butyl]pyrrol-2-yl}methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- {[3 -Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 35 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(3-40 pyridazinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5 -one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 45 4- {{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -67- 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 5 4- {[4-( 1 -PirroIidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-(3-pyridaziny l)-2-pyrazo!in-5 -one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(2-cyciopropyiaminoethyi)-3-isopropyi-5-methyipyrroi-2-yijmethyiene}-3-(3-10 pyridazinyl)-2-pyrazolin-5-one, 3-(3-Pyridazinyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one, 4- {[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene} -3-(3-pyridazinyl)-2-pyrazolin-5 -one, 15 4- {{4-[3-(4-PyridyLmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(3-20 pyridazinyl)-2-pyrazolin-5-one, 4-{{3-CycIopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyn:ol-2-yl}methylene}-3-(3 -pyridazinyl)-2-pyrazolin-5 -one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 25 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyI]-5-methylpyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-30 yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one5 4- {{3 -Cyclopropyl-5 -methyl-4-[4-( 1 -pyrrolidinyl)buty l]pyrrol-2-yl} methylene} -3 -(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cycIobutylaminobutyl)pyrrol-2-yl]methylene}-3-(3 -pyridazinyl)-2-pyrazolin-5 -one, 35 4-[(3,5-Dimethyl-4-(l-pyrrolidmylmethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-40 pyridazinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5 -one, 45 4- { {3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methyIene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -68- 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5 -one, 4- {[4-(l -Pirrolidinylmethyl)-3 -isopropyl-5 -methylpyrrol-2-yl]methylene} -3-(4-pyridazinyl)-2-pyrazolin-5 -one, 5 4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 4- { {3-Isopropyl-5-metbyl-4-[2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl} methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(2-cyclopropyiaminoethyi)-3-isopropyi-5-methylpyrroi-2-yiJmethylene}-3-(4 . 10 pyridazinyl)-2-pyrazolin-5-one, 3-(4-Pyridazinyl)-4-{{4-[3-(l-pyrrolidmyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidmobutyl)pyrroI-2-yl]iriethylene}-3-(4-pyridazinyl)-2-pyrazolin-5 -one, 15 4- { {4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-20 pyridazinyl)-2-pyrazolin-5-one, 4- { {3-Cyclopropyl-5-methyl-4-[2-( 1 -pyrrolidinyl)ethyl]pyrrol-2-yl} methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 25 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl} methyl ene} -3 -(4-pyridazinyl)-2-pyrazolin-5 -one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyI)pyrrol-2-30 yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl) -2-pyrazolin-5 -one, 35 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrroI-2-yl)methylene]-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(l,2,4-40 triazm-3-yl)-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene} -3-( 1,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(l,2,4-triazin-3 yl)-2-pyrazolin- 5 -one, 45 4- {{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene} -3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -69- 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(l,2,4-triazin-3 -yl)-2-pyrazolin-5 -one, 5 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methy]-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[4-(2-cyciopropyiaminoethyi)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-10 (l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{{4-[3-(l-Pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4- {[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene} -3-(l ,2,4-triazin-3-yl)-2-pyrazolin-5-one, 15 4- {{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methyIpyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-metliylpyrrol-2-yl)methylene]-3-(l,2,4-20 triazin-3-yl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(1,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene} -3-(l ,2,4-triazin-3-yl)-2-pyrazolin-5-one, 25 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3 -(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4- { {3-Cyclopropyl-4-[3-(2,5-dimethyl-1 -pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrTol-2-30 yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4- {{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyI)butyI]pyrrol-2-yl} methylene} -3-(1,2,4-triazin-3 -yl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(1,2,4-triazin-3-yl)-2-pyrazolin-5-one, 35 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(l-pyrrolidinylethyl)]-3-trif]uoromethylpyrrol-2-yl}methyIene}- 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethy lamino ethyl)-5 -methyl-3-trifluoromethylpyrrol-2-yl] methylene} -3 -40 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(4-pyridiylmethylaminoethyl)]-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-trifluoromethylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {[4-(2-Aminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -70- 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(l-pyrrolidinylethyl)]-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-4-[2-(4-pyridiylmethylaminoethyl)]-3-tert-butylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-(l -Imidazoyl)etliyl]-5-methyl-3-tert-butyipyrroi-2-yi}methyIene} -3-10 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-tert-butylylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3-ethyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4-{{3-Ethyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrroI-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Ethyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]rnethylene}-3-pyrazinyl-2-pyra2olin-5-one, 4- {{3-Ethyl-5-methyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl]methylene} -3-20 pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-ethylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-ethylpyirol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4- {[3-CycIobutyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyra2;olin-5-one, 4-{{3-Cyclobutyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclobutyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-30 pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclobutyl-5-methyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-on.e, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-cyclobutylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{[4-(2-Aminoethyl)-5-methyl-3-cyclobutylpyiTol-2-yl]methy]ene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopentyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopentyl-5-methyl-4-[2-(l-pyrroIidinylethyl)]pyrrol-2-yl}methylene}-3-40 pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopentyl-4-(2-ethylaminoethy])-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopentyl-5-methyl-4-[2-(4-pyridiylmethylaminoethyI)]pyrrol-2-yl]methy lene} -3 -pyrazinyl-2-pyrazolin-5 -one, 45 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-cyclopentylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -71- 4-{[4-(2-Aminoethyl)-5-methyl-3-cyclopentylpyrrol-2-yl]methylene}-3-pyrazinyl-2 pyrazolin-5-one 4-{[3-Cyclohexyl-4-(2-diethylarninoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- {{3-Cyclohexyl-5-methyl-4-[2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclohexyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{3-Cyciohexyi-5-methyi-4-[2-(4-pyridiylmethyiaminoethyl)]pyrroi-2-10 yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-cyclohexylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-cyclohexylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-phenyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2 20 pyrazolin-5-one, 4- {{ 5-Methyl-3-phenyl-4-[2-(4-pyiidiylmethylaminoethyl)]pyrrol-2-yl} methylene} - 3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-phenylpyrrol-2-yl}methylene}-3- . pyraziny l-2-pyrazolin-5 -one, 25 4-{[4-(2-Aminoethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene} 3-pyrazinyl-2-pyrazolLn-5-one, 4-{{5-Methyl-3-(4-methoxyphenyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-30 yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(4-methoxyphenyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4- { {4-[2-(l -Imidazoyl)ethyl]-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyTazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-40 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-pyridyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 45 4- {{5-Methyl-3-(2-pyridyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/2O628 -72- 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(2-pyridyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-pyrazinyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-pyTazinylpyrrol-2-yl]njethylene}-3-10 pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3-pyrazinyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-y 1} m ethylene} -3 -pyrazinyl-2-pyrazolin-5 -one, 4- {{4- [2-( 1 -Imidazoyl)ethyl]-5 -methyl-3 -pyrazinylpyrrol-2-yl} methylene} - 3 -pyrazinyl-2-pyrazolin-5-one, 15 4- {[4-(2-Cyclopropylaminoethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3 20 pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminoethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(2-imidazoyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}- 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene} -3-30 pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3-(2- pyrimidinyl)-4-[2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl}methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminoethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 35 4-{ {5-Methyl-3-(2- pyrimidinyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl} methylene} -3 -pyrazinyl-2-pyrazolin-5 -one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl}methylene}-3 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-40 yljmethyl ene} -3 -pyrazinyl-2-pyra2olin-5 -one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3 -(3 -i soxazolyl)-4-[2 -(1 -pyrTolidinylethyl)]pyrrol-2-yl} methylene} -3 pyrazinyl-2-pyrazolin-5-one, 45 4- {[4-(2-Ethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -73- 4-{{5-Methyl-3-(3-isoxazolyl)-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{4-[2-( 1 -Imidazoyl)ethyl]-5-methyl-3-(3 -isoxazolyl)pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 5 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(2-furyl)pyiTol-2-yl]methylene}-3-pyrazinyl-2-pyrazoIin-5-one, 4-{{5-Methyl-3-(2-fuiyl)-4-[2-(l-pyrrolidinylethyl)]pyrroI-2-yl} methylene}-3-10 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl- 2-pyrazolin-5-one, 4- {{5-Methyl-3-(2-furyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 15 4- {{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(2-fuiyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(2-fiiryl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-20 3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Hydroxymethyl-3-isopropyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4- {{5-Hydroxymethyl-3-isopropyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-hydroxymethyl-3-isopropylpyrrol-2-yl}methylene}- 3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-30 yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one: 4-{[4-(2-Diethylaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl- 2-pyrazolin-5 -one, 4-{{3,5-Dicyclopropyl-4-[2-(l-pyrrolidinylethyl)]pyiTol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4- {[4-(2-Ethylaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {{3,5-Dicyclopropyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene} - 3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-3,5-dicyclopropylpyrrol-2-yl}methylene}-3-pyrazinyl 40 2-pyrazolin-5-one, 4- {[4-(2-Cyclopropylaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3 pyrazinyl-2-pyrazolin-5-one, 45 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene} 3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/2O628 -74- 4-{{5-Methyl-4-[2-(l-pyrrolidinylmethyl)]-3-trifluoromethylpyirol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 5 4- {{5-Methyl-4-[2-(4-pyridiylmethylaminomethyl)]-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-( 1 -Imidazoyl)methyl]-5-methyl-3-trifluoromethylpyrrol-2-yl} methylene} - 3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-trif!uoromethylpyrrol-2-y!]methylene}-3-10 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Dimethylaminomethyl)-5-methyl-3 -tert-butylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5 -one, 15 4-{{5-Methyl-4-[2-(l-pyrrolidinylmethyl)]-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(4-pyridiylmethylaminomethyl)]-3-tert-butylpyrrol-2-20 yl]methylene} -3-pyrazinyl-2-pyrazolin-5 -one, 4-{{4-[2-(l-Irnidazoyl)methyl]-5-methyl-3-tert-butylpyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-tert-butylylpyrrol-2-yI]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4-{[4-(2-Diethylaminomethyl)-3-ethyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl 2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-3-ethyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {3-Ethyl-5-methyl-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl}methylene} -3-30 pyrazinyl-2-pyrazolin-5-one, 4-{[3-Ethyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2 pyrazolin-5-one, 4- { {3 -Ethyl-5 -methyl-4- [2-(4-pyridiylmethy laminomethyl)]pyrrol-2-yl]methylene } ■ 3-pyrazinyl-2-pyrazolin-5-one, 35 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-ethylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Aminomethyl)-5 -methyl-3-ethylpyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4- {[3-Cyclobutyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene} -3-40 pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclobutyl-4-(2-dimethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclobutyl-5-methyl-4-[2-(l-pyirolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {[3-Cyclobuty]-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -75- 4- {{3 -Cyclobutyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-cyclobutylpyrrol-2-yl}methyl6ne}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- {[4-(2-Aminomethyl)-5 -methyl-3 -cyclobutylpyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopentyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{[3-Cyclopentyl-4-(2-dimethylaminorDethyl)-5-methylpyrrol-2-yl]methylene}-3-10 pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclbpentyl-5-methyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopentyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 15 4- {{3-Cyclopentyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yljmethylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-cyclopentylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-cyclopentylpyrrol-2-yl]methylene}-3-pyrazinyl-20 2-pyrazolin-5-one 4-{[3-Cyclohexyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazoIin-5-one, 4-{[3-Cyclohexyl-4-(2-dimethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 25 4- { {3-Cyclohexyl-5-methyl-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclohexyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazmyl-2-pyrazolin-5-one, 4-{{3-Cyclohexyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-30 yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-cyclohexylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Aminomethyl)-5-methyl-3 -cyclohexylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 35 4- {[4-(2-Diethylaminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{{5-Methyl-3-phenyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-40 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-phenyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-phenylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -76- 4-{[4-(2-Aminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazoliri-5-one, 5 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrroI-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {5 -Methyl-3 -(4-methoxyphenyl)-4- [2-( 1 -pyrrolidinylmethy I)]pyrrol-2-yl) methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(4-methoxyphenyI)pyrrol-2-yl]methylene}-10 3-pyrazinyl-2-pyrazolin- 5 -one, 4-{{5-Methyl-3-(4-methoxyphenyl)-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl} methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl}methylene}-3-pyrazinyI-2-pyrazolin-5-one, 15 4-{[4-(2-Aminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrroI-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-20 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-pyridyl)-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2-pyridyI)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4- { {5-Methyl-3-(2-pyridyl)-4-[2-(4-pyridylmethylarninomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {4- [2-( 1 -Imidazoyl)methyl] -5 -methyl-3 -(2-pyridyl)pyrrol-2-yl} methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-30 2-pjrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 35 4-{{5-Methyl-3-pyrazinyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-pyrazinyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-40 yl}methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-pyrazinylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazoIin- 5 -one, 4- {[4-(2-Cyclopropylaminomethyl)-5-methyl-3 -pyrazinylpyrrol-2-yl] methylene} -3 -pyrazinyl- 2-pyrazolin-5-one> 45 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methyIene}-3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -77- 4-{[4-(2-Dimethylaminornethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methy]ene}- 3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(l-pyrroIidinylmethyl)]pyrrol-2-yl}methylene} 3-pyrazinyl-2-pyrazolin-5-one, 5 4- {[4-(2-Ethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methyIene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(2-imidazoyl)pyrrol-2-yl}methylene}-3 10 pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Cyclopropylaminomethyl)- 5 -methyl-3 -(2-imidazoyl)pyrrol-2-. yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene}- 3-pyrazinyl-2-pyrazolin-5-one, 15 4- {[4-(2-Dimethylaminomethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-(2- pyrimidinyl)-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene}-3-20 pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-(2- pyrimidinyl)-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl}methylene} 3-pyrazinyl-2-pyrazolin-5-one, 25 4- {[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-30 pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3-(3-isoxazolyl)-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl}methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 35 4- {{5-Methyl-3-(3-isoxazolyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5 -one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(3-isoxazolyl)pyrroI-2-yl}methylene}-3 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-40 yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-fiiryl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5 -one, 45 4-{{5-Methyl-3-(2-furyl)-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -78- 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{S-Methyl-S-^-furyl^-p-^-pyridiyhnethylaminomethytyJpyrroW-ylJmethylene^S-pyrazinyl^-pyrazolin-S-one, 4- {{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(2-furyl)pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{[4-(2-Diethylaminomethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- { {5-Hydroxymethyl-3-isopropyl-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminomethyl)- 5 -hydroxymethyl-3-isopropylpyrrol-2-yl]methy lene} - 3-pyrazinyl-2-pyrazolin-5-one, 4- {{5 -Hydroxymethyl-3 -i sopropyl-4- [2-(4-pyridiylmethylammomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolrn-5-one, 4- {{4-[2-(l -Imidazoyl)methyl]-5-hydroxymethyl-3-isopropylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Cyclopropylaminomethyl)-5 -hydroxymethyl-3 -isopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4- {{3,5 -Dicyclopropyl-4- [2-( 1 -pyrrolidinylmethyl)]pyrrol-2-yl} methylene } -3-pyrazinyL-2-pyrazolin-5-one, 4-{[4-(2-EthyIaminomethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{3,5 -Dicyclopropyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-3,5-dicyclopropylpyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-[(4-Cyclopropylaminomethyl-3,5-dicyclopropylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5 -one, 4-{[3-Cyclopropylaminomethyl-5-methyl-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopropylaminomethyl-5-methyl-4-(2-hydroxyethyl)pyrrol-2-yl]methylene}-3-pyrazinyI-2-pyrazolin-5-one, 4-{[3-dimethylaminomethyl-5-methyI-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, and 4-{[3-hydroxymethyl-5-methyl-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one. WO 01/09121 PCT/US00/20628 -79- Compounds of formula I may exist as salts with pharmaceutical^ acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulphates, methanesulphonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g., (+)-tartrates, (-)-tartrates or mixtures thereof 5 including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. These salts may be prepared by methods known to those skilled in the art. Certain compounds of formula I which have acidic substituents may exist as salts with phaimaceutically acceptable bases. The present invention includes such 10 salts. Example of such salts include sodium salts, potassium salts, lysine salts and arginine salts. These salts may be prepared by methods known to those skilled in the art. Certain compounds of formula I and their salts may exist in more than one crystal form and the present invention includes each crystal form and mixtures thereof. 15 Certain compounds of formula I and their salts may also exist in the form of solvates, for example hydrates, and the present invention includes each solvate and mixtures thereof. Certain compounds of formula I may contain one or more chiral centers, and exist in different optically active forms. When compounds of formula I contain one 20 chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. The enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which maybe separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for 25 example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is 30 converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. WO 01/09121 PCT/USOO/20628 -80- Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation. When a compound of formula I contains more than one chiral center it may 5 exist in diastereoisomeric forms. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of compounds of formula I and mixtures thereof. 10 Certain compounds of formula I may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each tautomer and/or geometric isomer of compounds of formula I and mixtures thereof. Certain compounds of formula I may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about 15 an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers. The present invention includes each conformational isomer of compounds of formula I and mixtures thereof. Certain compounds of formula I may exist in zwitterionic form and the present invention includes each zwitterionic form of compounds of formula I and mixtures 20 thereof. The compounds of this invention are useful as inhibitors of serine/threonine and tyrosine kinases. In particular, compounds of this invention are useful as inhibitors of tyrosine kinases that are important in hyperproliferative diseases, especially in the process of angiogenesis. For example, certain of these compounds 25 are inhibitors of such receptor kinases as KDR, Flt-1, FGFR, PDGFR, c-Met, or IGF-l-R. Since these compounds are anti-angiogenic, they are important substances for inhibiting the progression disease states where angiogenesis is an important component. Certain compounds of the invention are effective as inhibitors of such serine/threonine kinases as erk, MAP kinases, cdks, Plk-1 or Raf-1. These 30 compounds are useful in the treatment of cancer, and hyperproliferative disorders. In addition, certain compounds are effective inhibitors of non-receptor kinases such -81- as src, lyn, lck, fyn, blk, hck. These compounds are useful in the treatment of cancer, hyperproliferative disorders and immunologic diseases. Described but not claimed is a method of inhibiting the kinase activity of tyrosine kinases and serine/threonine kinases comprising the administration of a compound represented by formula I to said kinase in sufficient concentration to inhibit the enzyme activity of said kinase. Described herein are uses of these compounds in pharmaceutical comppsitions with a pharmaceutically effective amount of the above-described compounds and a pharmaceutically acceptable carrier or excipient. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the invention and a pharmaceutically acceptable carrier or diluent. These pharmaceutical compositions can be administered to individuals to slow or halt the process of angiogenesis in angiogenesis-aided diseases, or to treat edema, effusions, exudates, or ascites and other conditions associated with vascular hyperpermeability. Certain pharmaceutical compositions can be administered to individuals to treat cancer and hyperproliferative disorders by inhibiting serine/threonine kinases such as cdk, Plk-1, erk, etc. DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention have antiangiogenic properties. These antiangiogenic properties are due at least in part to the inhibition of protein tyrosine kinases essential for angiogenic processes. For this reason, these compounds can be used as active agents against such disease states; as arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, virally-dnduced angiogenic disorders, fractures, Crow-Fukase syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma and retinopathies such as those associated with diabetic retinopathy, retinopathy of prematurity, or age-related macular degeneration. In addition, some of these compounds can be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders such as thyroid 140979 l.DOC INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 MAR 2004 WO 01/09121 PCT/US00/20628 -82- hyperplasia (especially Grave's disease), and cysts (such as hypervascularity of ovarian stroma characteristic of polycystic ovarian syndrome (Stein-Leventhal syndrome)) since such diseases require a proliferation of blood vessel cells for growth and/or metastasis. 5 Further, some of these compounds can be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, brain tumor-associated cerebral edema, high-altitude, trauma or hypoxia induced cerebral or pulmonary edema, ocular and macular edema, ascites, and other diseases where 10 vascular hyperpermeability, effusions, exudates, protein extravasation, or edema is a manifestation of the disease. The compounds will also be useful in treating disorders in which protein extravasation leads to the deposition of fibrin and extracellular matrix, promoting stromal proliferation (e.g. keloid, fibrosis, cirrhosis and carpal tunnel syndrome). Increased VEGF production potentiates inflammatory 15 processes such as monocyte recruitment and activation. The compounds of this invention will also be useful in treating inflammatory disorders such as inflammatory bowel disease (IBD) and Crohn's disease. VEGF's are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and the formation of edema. 20 Indeed, vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be mediated via VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia results in a marked upregulation of VEGF in numerous tissues, hence situations involving infarct, occlusion, ischemia, anemia, or circulatory impairment typically invoke 25 VEGF/VPF mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromolecular extravasation, which is often accompanied by diapedesis, can result in excessive matrix deposition, aberrant stromal proliferation, fibrosis, etc. Hence, VEGF-mediated hyperpermeability can significantly contribute to disorders with these etiologic features. 30 It is envisaged that the disorders listed above are mediated to a significant extent by protein tyrosine kinase activity involving the KDR/VEGFR-2 and/or the WO 01/09121 PCT/US00/20628 -83- Flt-l/VEGFR-1 tyrosine kinases. By inhibiting the activity of these tyrosine kinases, the progression of the listed disorders is inhibited because the angiogenic or vascular hyperpermeability component of the disease state is severely curtailed. The action of certain compounds of this invention, by their selectivity for specific 5 tyrosine kinases, result in a minimization of side effects that would occur if less selective tyrosine kinase inhibitors were used. Certain compounds of the invention are also effective inhibitors of FGFR, PDGFR, c-Met and IGF-l-R. These receptor kinases can directly or indirectly potentiate angiogenic and hyperproliferative responses in various disorders, hence their inhibition can impede disease 10 progression. The compounds of this invention have inhibitory activity against protein kinases. That is, these compounds modulate signal transduction by protein kinases. Compounds of this invention inhibit protein kinases from serine/threonine and tyrosine kinase classes. In particular, these compounds selectively inhibit the 15 activity of the KDR/FLK-l/VEGFR-2 tyrosine kinases. Certain compounds of this invention also inhibit the activity of additional tyrosine kinases such as Flt-1/VEGFR-1, FGFR, PDGFR, IGF-1R, c-Met, Src-subfamily kinases such as Lck, Src, fyn, yes, etc. Additionally, some compounds of this invention significantly inhibit serine/threonine kinases such as PKC, MAP kinases, erk, CDKs, Plk-1, or 20 Raf-1 which play an essential role in cell proliferation and cell-cycle progression. The potency and specificity of the generic compounds of this invention towards a particular protein kinase can often be altered and optimized by variations in the nature, number and arrangement of the substituents (i.e., R„ R2, R3, R4, Rs, R^ and R7) of and conformational restrictions. In addition the metabolites of certain 25 compounds may also possess significant protein kinase inhibitory activity. The compounds of this invention, when administered to individuals in need of such compounds, inhibit vascular hyperpermeability and the formation of edema in these individuals. These compounds act, it is believed, by inhibiting the activity of KDR tyrosine kinase which is involved in the process of vascular 30 hyperpermeability and edema formation. The KDR tyrosine kinase may also be referred to as FLK-1 tyrosine kinase, NYK tyrosine kinase or VEGFR-2 tyrosine WO 01/09121 PCT/US00/20628 -84- kinase. KDR tyrosine kinase is activated when vascular endothelial cell growth factor (VEGF) or another activating ligand (such as VEGF-C, VEGF-D, VEGF-E or HTV Tat protein) binds to a KDR tyrosine kinase receptor which lies on the surface of vascular endothelial cells. Following such KDR tyrosine kinase activation, 5 hyperpermeability of the blood vessels occurs and fluid moves from the blood stream past the blood vessel walls into the interstitial spaces, thereby forming an area of edema. Diapedesis also often accompanies this response. Similarly, excessive vascular hyperpermeability can disrupt normal molecular exchange across the endothelium in critical tissues and organs (e.g., lung and kidney), thereby 10 causing macromolecular extravasation and deposition. Following this acute response to KDR stimulation which is believed to facilitate the subsequent angiogenic process, prolonged KDR tyrosine kinase stimulation results in the proliferation and chemotaxis of vascular endothelial cells and formation of new vessels. By inhibiting KDR tyrosine kinase activity, either by blocking the 15 production of the activating ligand, by blocking the activating ligand binding to the KDR tyrosine kinase receptor, by preventing receptor dimerization and transphosphorylation, by inhibiting the enzyme activity of the KDR tyrosine kinase (inhibiting the phosphorylation function of the enzyme) or by some other mechanism that interrupts its downstream signaling (D. Mukhopedhyay et al., 20 Cancer Res. 58:1278-1284 (1998) and references therein), hyperpermeability, as well as associated extravasation, subsequent edema formation and matrix deposition, and angiogenic responses, may be inhibited and minimized. One group of preferred compounds of this invention have the property of inhibiting KDR tyrosine kinase activity without significantly inhibiting Flt-1 25 tyrosine kinase activity (Flt-1 tyrosine kinase is also referred to as VEGFR-1 tyrosine kinase). Both KDR tyrosine kinase and Flt-1 tyrosine kinase are activated by VEGF binding to KDR tyrosine kinase receptors and to Flt-1 tyrosine kinase receptors, respectively. Since Flt-1 tyrosine kinase activity may mediate important events in endothelial maintenance and vascular function, an inhibition of this 30 enzyme activity may lead to toxic or adverse effects. At the very least, such inhibition is unnecessary for blocking the angiogenic responses, induction of WO 01/09121 PCT/US00/20628 -85- vascular hyperpermeability and the formation of edema, so it is wasteful and of no value to the individual. Certain preferred compounds of this invention are unique because they inhibit the activity of one VEGF-receptor tyrosine kinase (KDR) that is activated by activating ligands but do not inhibit other receptor tyrosine kinases, 5 such as Fit-1, that are also activated by certain activating ligands. The preferred compounds of this invention are, therefore, selective in their tyrosine kinase inhibitory activity. The compounds of the present invention are also useful in the treatment of ulcers - bacterial, fungal, Mooren ulcers and ulcerative colitis. 10 The compounds of the present invention are also useful in the treatment of conditions wherein undesired angiogenesis, edema, or stromal deposition occurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS, parapoxvirus, psoriasis, Kaposi's sarcoma, protozoan infections and toxoplasmosis, endometriosis, ovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, systemic 15 lupus, sarcoidosis, synovitis, inflammatory bowel disease, Crohn's disease, sickle cell anaemia, Lyme's disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rendu disease, chronic inflammation, chronic occlusive pulmonary disease, asthma, rheumatoid arthritis and osteoarthritis, and edema following burns, trauma, radiation, or stroke. 20 The compounds of the present invention are also useful in the treatment of ocular conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, optic pits, chronic retinal detachment, post-laser complications, conjunctivitis, Stargardt's disease and Eales disease in addition to retinopathy and macular degeneration. 25 The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease. The compounds of the present invention are also useful in the treatment of cancer related indications such as solid tumors, sarcomas (especially Ewing's 30 sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, WO 01/09121 PCT/US00/2Q628 -86- hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites. The compounds of the present invention are also useful in the treatment of Crow-Fukase (POEMS) syndrome and diabetic conditions such as glaucoma, 5 diabetic retinopathy and microangiopathy. It is envisaged that the disorders listed above are mediated to a significant extent by protein tyrosine kinase activity involving the VEGF receptors (e.g. KDR and Flt-1). By inhibiting the activity of these receptor tyrosine kinases, the progression of the listed disorders is inhibited because the angiogenic component of 10 the disease state is severely curtailed. The action of the compounds of this invention, by their selectivity for specific tyrosine kinases, result in a minimization of side effects that would occur if less selective tyrosine kinase inhibitors were used. In another aspect the present invention provides compounds of formula I as defined initially above (including the provisos) for use as medicaments, particularly 15 as inhibitors of protein kinase activity for example tyrosine kinase activity, serine kinase activity and threonine kinase activity. In yet another aspect the present invention provides the use of compounds of formula I as defined initially above (including the provisos) in the manufacture of a medicament for use in the inhibition of protein kinase activity. 20 In this invention, the following definitions are applicable: " Physiologically acceptable salts" refers to those salts which retain the biological effectiveness and properties of the free bases and which are obtained by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as sulfonic acid, carboxylic 25 acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid and the like. "Alkyl" refers to a saturated aliphatic hydrocarbon, including straight-chain and branched-chain groups having 1 to 6 carbons or cyclic hydrocarbons having 3 to 6 carbons. 30 "Alkoxy" refers to an "O-alkyl" group, where "alkyl" is defined as described above. WO 01/09121 PCT/US00/20628 -87- Pharmaceutical Formulations The compounds of this invention can be administered to a human patient by themselves or in pharmaceutical compositions where they are mixed with suitable carriers or excipient(s) at doses to treat or ameliorate vascular hyperpermeability, 5 edema and associated disorders. Mixtures of these compounds can also be administered to the patient as a simple mixture or in suitable formulated pharmaceutical compositions. A therapeutically effective dose further refers to that amount of the compound or compounds sufficient to result in the prevention or attenuation of inappropriate neovascularization, progression of hyperproliferative 10 disorders, edema, VEGF-associated hyperpermeability and/or VEGF-related hypotension. Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, latest edition. Routes of Administration 15 Suitable routes of administration may, for example, include oral, eyedrop, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections. 20 Alternatively, one may administer the compound in a local rather than a systemic manner, for example, via injection of the compound directly into an edematous site, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody. 25 Composition/Formulation The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes. 30 Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more WO 01/09121 PCT/US00/20628 -88- physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. 5 For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. 10 For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. 15 Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such 20 as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. 25 Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for 30 identification or to characterize different combinations of active compound doses. WO 01/09121 PCT/U S00/20628 -89- Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or 5 lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. 10 For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner. For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable 15 propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of e.g. gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound 20 and a suitable powder base such as lactose or starch. The compounds may be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or 25 emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. 30 Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. WO 01/09121 PCT/US00/20628 -90- Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly 5 concentrated solutions. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases 10 such as cocoa butter or other glycerides. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with 15 suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt. An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, 20 a water-miscible organic polymer, and an aqueous phase. The cosolvent system may be the VPD co-solvent system. VPD is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant polysorbate 80, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. The VPD co-solvent system (VPD:5W) consists of VPD diluted 1:1 with a 5% dextrose in water solution. This 25 co-solvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of 30 polysorbate 80; the fraction size of polyethylene glycol may be varied; other WO 01/09121 PCT/US00/20628 -91- biocompatible polymers may replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples 5 of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethysulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and 10 are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed. The pharmaceutical compositions also may comprise suitable solid or gel 15 phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols. Many of the organic molecule compounds of the invention may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible 20 salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms. Effective Dosage Pharmaceutical compositions suitable for use in the present invention include 25 compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent development of or to alleviate the existing symptoms of the subject being treated. Determination of the effective amounts is well within the capability of those skilled in the art. 30 For any compound used in the method of the invention, the therapeutically effective dose can be estimated initially from cellular assays. For example, a dose WO 01/09121 PCT/US00/20628 -92- can be formulated in cellular and animal models to achieve a circulating concentration range that includes the IC50 as determined in cellular assays (i.e., the concentration of the test compound which achieves a half-maximal inhibition of a given protein kinase activity). In some cases it is appropriate to determine the IC50 5 in the presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound. Such information can be used to more accurately determine useful doses in humans. Further, the most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma. 10 A therapeutically effective dose refers to that amount of the compound that results in amelioration of symptoms in a patient. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the maximum tolerated dose (MTD) and the EDS0 (effective dose for 50% maximal response). The dose ratio 15 between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between MTD and EDJ0. Compounds which exhibit high therapeutic indices are preferred. The data obtained from these cell culture assays and animal studies can be used in formulating a range of dosage for use in humans. The dosage of such compounds lies preferably within a range of circulating concentrations that 20 include the ED50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition. (See e.g. Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics", Ch. 1 pi). In the treatment of crises, 25 the administration of an acute bolus or an infusion approaching the MTD may be required to obtain a rapid response. Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the kinase modulating effects, or minimal effective concentration (MEC). The MEC will vary for each 30 compound but can be estimated from in vitro data; e.g. the concentration necessary to achieve 50-90% inhibition of protein kinase using the assays described herein. WO 01/09121 PCT/XJS0O/2O628 -93- Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using the MEC value. Compounds 5 should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90% until the desired amelioration of symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration. 10 The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician. Packaging The compositions may, if desired, be presented in a pack or dispenser device 15 which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and 20 labeled for treatment of an indicated condition. In some formulations it may be beneficial to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid energy milling. The use of compounds of the present invention in the manufacture of 25 pharmaceutical compositions is illustrated by the following description. In this description the term "active compound" denotes any compound of the invention but particularly any compound which is the final product of one of the preceding Examples. a) Capsules 30 In the preparation of capsules, 10 parts by weight of active compound and 240 parts by weight of lactose can be de-aggregated and blended. The mixture can be WO 01/09121 PCT/USOO/20628 -94- filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of active compound. b) Tablets Tablets can be prepared from the following ingredients. 5 Parts bv weieht Active compound 10 Lactose 190 Maize starch 22 Polyvinylpyrrolidone 10 10 Magnesium stearate 3 The active compound, the lactose and some of the starch can be de-aggregated, blended and the resulting mixture can be granulated with a solution of the polyvinylpyrrolidone in ethanol. The dry granulate can be blended with the magnesium, stearate 15 and the rest of the starch. The mixture is then compressed in a tab letting machine to give tablets each containing a unit dose or a part of a unit dose of active compound. c) Enteric coated tablets Tablets can be prepared by the method described in (b) above. The tablets can be enteric coated in a conventional manner using a solution of 20% cellulose acetate 20 phthalate and 3% diethyl phthalate in ethanolrdichloromethane (1:1). d) Suppositories In the preparation of suppositories, 100 parts by weight of active compound can be incorporated in 1300 parts by weight of triglyceride suppository base and the mixture formed into suppositories each containing a therapeutically effective amount 25 of active ingredient. In the compositions of the present invention the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. For example, the compounds of this invention can be administered in combination with one or more additional pharmaceutical agents that inhibit or prevent the 30 production of VEGF, attenuate intracellular responses to VEGF, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or WO 01/09121 PCT/US00/20628 -95- inhibit or prevent the formation of edema or neovascularization. The compounds of the invention can be administered prior to, subsequent to or simultaneously with the additional pharmaceutical agent, whichever course of administration is appropriate. The additional pharmaceutical agents include but are not limited to anti-edemic 5 steroids, NSAEDS, ras inhibitors, anti-TNF agents, anti-IL-1 agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX-2 inhibitors, NO synthase inhibitors, PKC inhibitors and PI3 kinase inhibitors. The compounds of the invention and the additional pharmaceutical agents act either additively or synergistically. Thus, the administration of such a combination of substances that inhibit angiogenesis, 10 vascular hyperpermeability and/or inhibit the formation of edema can provide greater relief from the deleterious effects of a hyperproliferative disorder, angiogenesis, vascular hyperpermeability or edema than the administration of either substance alone. In the treatment of malignant disorders combinations with antiproliferative or cytotoxic chemotherapies or radiation are anticipated. 15 The present invention also comprises the use of a compound of formula I as a medicament. Both the Src and Syk families of kinases play pivotal roles in the regulation of immune function. The Src family currently includes Fyn, Lck, Fgr, Fes, Lyn, Src, Yes, Hck, and Blk. The Syk family is currently understood to include only Zap and 20 Syk. The Janus family of kinases is involved in the transduction of growth factor and proinflammatory cytokine signals through a number of receptors. Although BTK and ITK, members of the Tec family of kinases, play a less well understood role in immunobiology, their modulation by an inhibitor may prove therapeutically beneficial. The kinases RIP, IRAK-1, IRAK-2, NIK, TPL-2/COT, IKK-1 and IKK-25 2 are involved in the signal transduction pathways for the key pro-inflammatory cytokines TNF and IL-1. By virtue of their ability to inhibit one or more of these kinases, compounds of formula I may function as immunomodulatory agents useful for the maintenance of allografts and the treatment of autoimmune disorders. Through their ability to regulate T cell activation or the potentiation of an 30 inflammatory process, these compounds could be used to treat such autoimmune diseases. Transplants due to rejection phenomena, either host versus graft for solid WO 01/09121 PCT/US00/20628 -96- organs or graft versus host for bone marrow, are limited by the toxicity of currently available immunosuppressive agents and would benefit from an efficacious drug with improved therapeutic index. Gene targeting experiments have demonstrated the essential role of Src in the biology of osteoclasts, the cells responsible for bone 5 resorption. Compounds of formula I, through their ability to regulate Src, may also be useful in the treatment of osteoporosis, osteopetrosis, Paget's disease, tumor-induced hypercalcemia and in the treatment of bone metastases. A number of protein kinases have been demonstrated to be protooncogenes. Chromosome breakage (at the ltk kinase break point on chromosome 5), 10 translocation as in the case of the Abl gene with BCR (Philadelphia chromosome), truncation in instances such as c-Kit or EGFR, or mutation (e.g., Met) result in the creation of dysregulated proteins converting them from protooncogene to oncogene products. In other tumors, oncogenesis is driven by an autocrine or paracrine ligand/growth factor receptor interactions. Members of the src-family kinases are 15 typically involved in downstream signal transduction thereby potentiating the oncogenesis and themselves may become oncogenic by over-expression or mutation. By inhibiting the protein kinase activity of these proteins the disease process may be disrupted. Vascular restenosis may involve process of FGF and/or PDGF -promoted smooth muscle and endothelial cell proliferation. The ligand stimulation 20 of FGFR, PDGFR, IGF1-R and c-Met in vivo is proangiogenic, and potentiates angiogenesis dependent disorders. Inhibition of FGFr, PDGFr, c-Met, or IGF1-R kinase activity may be an efficacious strategy for inhibiting these phenomena. Thus compounds of formula I which inhibit the kinase activity of normal or aberrant c-kit, c-met, c-fms, src-family members, EGFr, erbB2, erbB4, BCR-Abl, PDGFr, FGFr, 25 IGF1-R and other receptor or cytosolic tyrosine kinases may be of value in the treatment of benign and neoplastic proliferative diseases. In many pathological conditions (for example, solid primary tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inappropriate ocular neovascularization, psoriasis and atherosclerosis) disease progression is 30 contingent upon persistent angiogenesis. Polypeptide growth factors often produced by the disease tissue or associated inflammatory cells, and their corresponding WO 01/09121 PCT/US0O/2O628 -97- endothelial cell specific receptor tyrosine kinases (e.g., KDR/VEGFR-2, Flt-1/VEGFR-l, Tie-2/Tek and Tie) are essential for the stimulation of endothelial cell growth, migration, organization, differentiation and the establishment of the requisite new functional vasculature. As a result of the "vascular permeability 5 factor" activity of VEGF in mediating vascular hyperpermeability, VEGF-stimulation of a VEGFR kinase is also believed to play an important role in the formation of tumor ascites, cerebral and pulmonary edema, pleural and pericardial effusions, delayed-type hypersensitivity reactions, tissue edema and organ dysfunction following trauma, bums, ischemia, diabetic complications, 10 endometriosis, adult respiratory distress syndrome (ARDS), post-cardiopulmonary bypass-related hypotension and hyperpermeability, and ocular edema leading to glaucoma or blindness due to inappropriate neovascularization. In addition to VEGF, recently identified VEGF-C and VEGF-D, and virally-encoded VEGF-E or HTV-Tat protein can also cause a vascular hyperpermeability response through the 15 stimulation of a VEGFR kinase. Tie-2 is expressed also in a select population of hematopoietic stem cells in which it may play a role in their recruitment, adhesion, regulation and differentiation {Blood, 4317-4326 (1997)); this Tie-2 expressing population may serve as circulating angiogenic endothelial progenitors. Certain agents according to formula I capable of blocking the kinase activity of endothelial 20 cell specific kinases could therefore inhibit disease progression involving these situations. The compounds of formula I or a salt thereof or pharmaceutical compositions containing a therapeutically effective amount thereof may be used in the treatment of benign and neoplastic proliferative diseases and disorders of the immune system. 25 Such diseases include autoimmune diseases, such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, Crohn's disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, organ transplant rejection (eg. kidney rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancers such as lung, breast, stomach, 30 bladder, colon, pancreas, ovarian, prostate and rectal cancer and hematopoietic malignancies (leukemia and lymphoma), and diseases involving inappropriate WO 01/09121 PCT/U S00/20628 -98- vascularization for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human beings. In addition, such inhibitors may be useful in the treatment of disorders involving VEGF mediated edema, ascites, effusions, and 5 exudates, including for example macular edema, cerebral edema, acute lung injury and adult respiratory distress syndrome (ARDS). The compounds of the present invention may also be useful in the prophylaxis of the above diseases. A further aspect of the present invention provides the use of a compound of 10 formula I or a salt thereof in the manufacture of a medicament for treating vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or disorders of the immune system in mammals, particularly human beings. The present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or 15 disorders of the immune system which comprises the administration of a therapeutically effective amount of a compound of formula I to a mammal, particularly a human being, in need thereof. The in vitro potency of compounds in inhibiting these protein kinases may be determined by the procedures detailed below. 20 The potency of compounds can be determined by the amount of inhibition of the phosphorylation of an exogenous substrate (e.g., synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by a test compound relative to control. KDR Tyrosine Kinase Production Using Baculovirus System: The coding sequence for the human KDR intra-cellular domain (aa789-1354) 25 was generated through PCR using cDNAs isolated from HUVEC cells. A poly-His6 sequence was introduced at the N-terminus of this protein as well. This fragment was cloned into transfection vector pVL1393 at the Xba 1 and Not 1 site. Recombinant baculovirus (BV) was generated through co-transfection using the BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque 30 purified and verified through Western analysis. For protein production, SF-9 cells WO 01/09121 PCT/US00/2O628 -99- were grown in SF-900-II medium at 2 x 106/ml, and were infected at 0.5 plaque forming units per cell (MOI). Cells were harvested at 48 hours post infection. Purification of KDR SF-9 cells expressing (His)6KDR(aa789-1354) were lysed by adding 50 ml of 5 Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, ImM PMSF, lOjig/ml aprotinin, 1 |i g/ml leupeptin) to the cell pellet from 1L of cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4°C. The cell lysate was applied to a 5 ml NiCl2 chelating sepharose column, equilibrated with 50 mM HEPES, pH7.5, 0.3 M NaCl. KDR was 10 eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) which measures kinase activity. The purified KDR was exchanged into 25mM HEPES, pH7.5, 25rnM NaCl, 5 mM DTT buffer and stored at -80°C. Human Tie-2 Kinase Production and Purification 15 The coding sequence for the human Tie-2 intra-cellular domain (aa775-l 124) was generated through PCR using cDNAs isolated from human placenta as a template. A poly-His6 sequence was introduced at the N-terminus and this construct was cloned into transfection vector pVL 1939 at the Xba 1 and Not 1 site. Recombinant BV was generated through co-transfection using the BaculoGold 20 Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified through Western analysis. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2 x 106/ml, and were infected at MOI of 0.5. Purification of the His-tagged kinase used in screening was analogous to that described for KDR. 25 Human Flt-1 Tyrosine Kinase Production and Purification The baculoviral expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. A nucleotide sequence encoding poly-His6 was placed 5' to the nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was 30 generated through PCR using cDNA libraries isolated from HUVEC cells. The histidine residues enabled affinity purification of the protein as a manner analogous WO 01/09121 PCT/US00/2O628 -100- to that for KDR and ZAP70. SF-9 insect cells were infected at a 0.5 multiplicity and harvested 48 hours post infection. EGFR Tyrosine Kinase Source EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 p.1) and the 5 EGF ligand was acquired from Oncogene Research Products/Calbiochem (Cat # PF011-100). Expression of ZAP70 The baculoviral expression vector used was pVL1393. (Pharmingen, Los Angeles, Ca.) The nucleotide sequence encoding amino acids M(H)6 LVPR^S was 10 placed 5' to the region encoding the entirety of ZAP70 (amino acids 1-619). The nucleotide sequence encoding the ZAP70 coding region was generated through PCR using cDNA libraries isolated from Jurkat immortalized T-cells. The histidine residues enabled affinity purification of the protein (vide infra). The LVPR^S bridge constitutes a recognition sequence for proteolytic cleavage by thrombin, enabling 15 removal of the affinity tag from the enzyme. SF-9 insect cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours post infection. Extraction and purification of ZAP70 SF-9 cells were lysed in a buffer consisting of 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100,1 mMPMSF, 1 p.g/ml leupeptin, 10 jig/ml 20 aprotinin and 1 mM sodium orthovanadate. The soluble lysate was applied to a chelating sepharose HiTrap column (Pharmacia) equilibrated in 50 mM EEPES, pH 7.5, 0.3 M NaCl. Fusion protein was eluted with 250 mM imidazole. The enzyme was stored in buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT. 25 Lck source Lck or truncated forms of Lck may be commercially obtained ( e.g. from Upstate Biotechnology Inc. (Saranac Lake, N.Y) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods. 30 WO 01/09121 PCT/US00/20628 -101- Enzyme Linked Immunosorbent Assay (ELISA) For PTKs Enzyme linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. The ELISA were conducted according to known protocols which are described in, for example, Voller, et al, 5 1980, "Enzyme-Linked Immunosorbent Assay," In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, pp 359-371 Am. Soc. of Microbiology, Washington, D.C. The disclosed protocol was adapted for determining activity with respect to a specific PTK. For example, preferred protocols for conducting the ELISA 10 experiments is provided below. Adaptation of these protocols for determining a compound's activity for other members of the receptor PTK family, as well as nonreceptor tyrosine kinases, are well within the abilities of those in the art. For purposes of determining inhibitor selectivity, a universal PTK substrate (e.g., random copolymer of poly(Glu4 Tyr), 20,000-50,000 MW) was employed together 15 with ATP (typically 5 p.M) at concentrations approximately twice the apparent Km in the assay. The following procedure was used to assay the inhibitory effect of compounds of this invention on KDR, Flt-1, Flt-4/VEGFR-3, Tie-2, EGFR, FGFR, PDGFR, IGF-l-R, c-Met and ZAP70 tyrosine kinase activity: 20 Buffers and Solutions: PGTPoly (Glu,Tyr) 4:1 Store powder at -20°C. Dissolve powder in phosphate buffered saline (PBS) for 50mg/ml solution. Store 1ml aliquots at -20°C. When making plates dilute to 250|j.g/ml in Gibco PBS. 25 Reaction Buffer: lOOmM Hepes, 20mM MgCl2, 4mM MnCl2, 5mM DTT, 0.02%BSA, 200jiM NaV04, pH 7.10 ATP: Store aliquots of lOOmM at -20°C. Dilute to 20^M in water Washing Buffer: PBS with 0.1% Tween 20 Antibody Diluting Buffer: 0.1% bovine serum albumin (BSA) in PBS 30 WO 01/09121 PCT/US00/20628 -102- TMB Substrate: mix TMB substrate and Peroxide solutions 9:1 just before use or use K-Blue Substrate from Neogen Stop Solution: IM Phosphoric Acid 5 Procedure 1. Plate Preparation: Dilute PGT stock (50mg/ml, frozen) in PBS to a 250|ig/ml. Add 125fil per well of Corning modified flat bottom high affinity ELISA plates (Corning #25805-96). Add 125jutl PBS to blank wells. Cover with sealing tape and incubate overnight 37°C. 10 Wash lx with 250jal washing buffer and dry for about 2hrs in 37°C dry incubator. Store coated plates in sealed bag at 4°C until used. 2. Tyrosine Kinase Reaction: -Prepare inhibitor solutions at a 4x concentration in 20% DMSO in water. -Prepare reaction buffer 15 -Prepare enzyme solution so that desired units are in SOpl, e.g. for KDR make to 1 ng/pl for a total of 50ng per well in the reactions. Store on ice. -Make 4x ATP solution to 20(iM from lOOmM stock in water. Store on ice -Add 50jxl of the enzyme solution per well (typically 5-50 ng enzyme/well depending on the specific activity of the kinase) 20 -Add 25}il 4x inhibitor -Add 25 pi 4x ATP for inhibitor assay -Incubate for 10 minutes at room temperature -Stop reaction by adding 50(il 0.05N HC1 per well -Wash plate 25 **Final Concentrations for Reaction: 5(iM ATP, 5% DMSO 3. Antibody Binding -Dilute lmg/ml aliquot ofPY20-HRP (Pierce) antibody(a phosphotyrosine antibody)to 50ng/ml in 0.1% BSA in PBS by a 2 step dilution (lOOx, then 200x) -Add 1 OOjal Ab per well. Incubate 1 hr at room temp. Incubate lhr at 4C. 30 -Wash 4x plate WO 01/09121 PCT/US00/20628 -103- 4. Color reaction -Prepare TMB substrate and add 1 OOjil per well -Monitor OD at 650nm until 0.6 is reached -Stop with 1M Phosphoric acid. Shake on plate reader. 5 -Read OD immediately at 450nm Optimal incubation times and enzyme reaction conditions vary slightly with enzyme preparations and are determined empirically for each lot. For Lck, the Reaction Buffer utilized was 100 mM MOPSO, pH 6.5, 4 mM MnCl2, 20 mM MgCl2, 5 mM DTT, 0.2% BSA, 200 mM NaV04 under the analogous assay 10 conditions. Compounds of formula I may have therapeutic utility in the treatment of diseases involving both identified, including those not mentioned herein, and as yet unidentified protein tyrosine kinases which are inhibited by compounds of formula I. All compounds exemplified herein significantly inhibit KDR kinase at 15 concentrations of 50 micromolar or below. Some compounds of this invention also significantly inhibit other PTKs such as lck at concentrations of 50 micromolar or below. Cdc2 source The human recombinant enzyme and assay buffer may be obtained 20 commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods. Cdc2 Assay The protocol used was that provided with the purchased reagents with minor modifications. In brief, the reaction was carried out in a buffer consisting of 50mM 25 Tris pH 7.5, lOOmM NaCl, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and lOmM MgCl2 (commercial buffer) supplemented with fresh 300 (J.M ATP (31 p.Ci/ml) and 30 jag/ml histone type IIIss final concentrations. A reaction volume of 80|iL, containing units of enzyme, was run for 20 minutes at 25 degrees C in the presence or absence of inhibitor. The reaction was terminated by the addition of 30 120fiL of 10% acetic acid. The substrate was separated from unincorporated label by spotting the mixture on phosphocellulose paper, followed by 3 washes of 5 WO 01/09121 PCT/US00/20628 -104- minutes each with 75mM phosphoric acid. Counts were measured by a betacounter in the presence of liquid scintillant. Certain compounds of this invention significantly inhibit cdc2 at concentrations below 50 uM. 5 PKC kinase source The catalytic subunit of PKC may be obtained commercially (Calbiochem). PKC kinase assay A radioactive kinase assay was employed following a published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. 10 Biochemical and Biophysical Research Communication 3:166, 1220-1227 (1990)). Briefly, all reactions were performed in a kinase buffer consisting of 50 mM Tris-HC1 pH7.5, lOmM MgCI2,2mM DTT, ImM EGTA, 100 hM ATP, 8 fiM peptide, 5% DMSO and 33P ATP (8Ci/mM). Compound and enzyme were mixed in the reaction vessel and the reaction initiated by addition of the ATP and substrate 15 mixture. Following termination of the reaction by the addition of 10 stop buffer (5 mM ATP in 75 mM phosphoric acid), a portion of the mixture was spotted on phosphocellulose filters. The spotted samples were washed 3 times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. Incorporation of radiolabel was quantified by liquid scintillation counting. 20 Erk2 enzyme source The recombinant murine enzyme and assay buffer may be obtained commercially (New England Biolabs, Beverly MA. USA) or purified from known natural or recombinant sources using conventional methods. Erk2 enzyme assay 25 In brief, the reaction was carried out in a buffer consisting of 50 mM Tris pH 7.5, ImM EGTA, 2mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl2 (commercial buffer) supplemented with fresh 100 jjM ATP (31 nCi/ml) and 30pM myelin basic protein under conditions recommended by the supplier. Reaction volumes and method of assaying incorporated radioactivity were as described for the 30 PKC assay (vide supra). WO 01/09121 PCT/USOO/20628 -105- In Vitro Models for T-cell Activation Upon activation by mitogen or antigen, T-cells are induced to secrete IL-2, a growth factor that supports their subsequent proliferative phase. Therefore, one may measure either production of IL-2 from or cell proliferation of, primary T-cells or 5 appropriate T-cell lines as a surrogate for T-cell activation. Both of these assays are well described in the literature and their parameters well documented (in Current Protocols in Immunology, Vol 2, 7.10.1-7.11.2). In brief, T-cells may be activated by co-culture with allogenic stimulator cells, a process termed the one-way mixed lymphophocyte reaction. Responder and 10 stimulator peripheral blood mononuclear cells are purified by Ficoll-Hypaque gradient (Pharmacia) per directions of the manufacturer. Stimulator cells are mitotically inactivated by treatment with mitomycin C (Sigma) or gamma irradiation. Responder and stimulator cells are co-cultured at a ratio of two to one in the presence or absence of the test compound. Typically 10s responders are mixed 15 with 5 x 104 stimulators and plated (200 p.1 volume) in a U bottom microtiter plate (Costar Scientific). The cells are cultured in RPMI 1640 supplemented with either heat inactivated fetal bovine serum (Hyclone Laboratories) or pooled human AB serum from male donors, 5 x 10"5M 2mercaptoethanol and 0.5% DMSO, The cultures are pulsed with 0.5 ^Ci of 3H thymidine (Amersham) one day prior to 20 harvest (typically day three). The cultures are harvested (Betaplate harvester, Wallac) and isotope uptake assessed by liquid scintillation (Betaplate, Wallac). The same culture system maybe used for assessing T-cell activation by measurement of IL-2 production. Eighteen to twenty-four hours after culture initiation, the supematants are removed and the IL-2 concentration is measured by 25 ELISA (R and D Systems) following the directions of the manufacturer. In-vivo Models of T-Cell Activation The in vivo efficacy of compounds can be tested in animal models known to directly measure T-cell activation or for which T-cells have been proven the 30 effectors. T-cells can be activated in vivo by ligation of the constant portion of the T-cell receptor with a monoclonal anti-CD3 antibody (Ab). In this model, BALB/c WO 01/09121 PCT/US00/20628 -106- mice are given 10|ig of anti-CD3 Ab intraperitoneally two hours prior to exsanguination. Animals to receive a test drug are pre-treated with a single dose of the compound one hour prior to anti-CD3 Ab administration. Serum levels of the proinflammatory cytokines interferon-y (IFN- y) and tumor necrosis 5 factor-a(TNF-a), indicators of T-cell activation, are measured by ELISA. A similar model employs in vivo T-cell priming with a specific antigen such as keyhole limpet hemocyanin (KLH) followed by a secondary in vitro challenge of draining lymph node cells with the same antigen. As previously, measurement of cytokine production is used to assess the activation state of the cultured cells. Briefly, 10 C57BL/6 mice are immunized subcutaneously with 100 fig KLH emulsified in complete Freund's adjuvant (CFA) on day zero. Animals are pre-treated with the compound one day prior to immunization and subsequently on days one, two and three post immunization. Draining lymph nodes are harvested on day 4 and their cells cultured at 6 x 106per ml in tissue culture medium (RPMI1640 supplemented 15 with heat inactivated fetal bovine serum (Hyclone Laboratories) 5 x 10"5 M 2-mercaptoethanol and 0.5% DMSO) for both twenty-four and forty-eight hours. Culture supematants are then assessed for the autocrine T-cell growth factor Interleukin-2 (IL-2) and/or IFN-y levels by ELISA. Lead compounds can also be tested in animal models of human disease. 20 These are exemplified by experimental auto-immune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models which mimic aspects of human multiple sclerosis have been described in both rats and mice (reviewed FASEB J. 5:2560-2566, 1991; murine model: Lab. Invest. 4(3):278, 1981; rodent model:J. Immunol 146(4): 1163-8, 1991 ). Briefly, mice or rats are immunized with an 25 emulsion of myelin basic protein (MBP), or neurogenic peptide derivatives thereof, and CFA. Acute disease can be induced with the addition of bacterial toxins such as bordetella pertussis. Relapsing/remitting disease is induced by adoptive transfer of T-cells from MBP/ peptide immunized animals. CIA may be induced in DBA/1 mice by immunization with type II collagen 30 (J. Immunol: 142(7):2237-2243). Mice will develop signs of arthritis as early as ten days following antigen challenge and may be scored for as long as ninety days after WO 01/09121 PCT/US00/20628 -107- immunization. In both the EAE and CIA models, a compound may be administered either prophylactically or at the time of disease onset. Efficacious drugs should reduce severity and/or incidence. Certain compounds of this invention which inhibit one or more angiogenic 5 receptor PTK, and/or a protein kinase such as lck involved in mediating inflammatory responses can reduce the severity and incidence of arthritis in these models. Compounds can also be tested in mouse allograft models, either skin (reviewed in Ann. Rev. Immunol., 10:333-58, 1992; Transplantation: 57(12): 10 1701-17D6, 1994) or heart (Am.J.Anat.:l 13:273,1963). Briefly, full thickness skin grafts are transplanted from C57BL/6 mice to B ALB/c mice. The grafts can be examined daily, beginning at day six, for evidence of rejection. In the mouse neonatal heart transplant model, neonatal hearts are ectopically transplanted from C57BL/6 mice into the ear pinnae of adult CBA/J mice. Hearts start to beat four to 15 seven days post transplantation and rejection may be assessed visually using a dissecting microscope to look for cessation of beating. Cellular Receptor PTK Assays 20 The following cellular assay was used to determine the level of activity and effect of the different compounds of the present invention on KDR/VEGFR2. Similar receptor PTK assays employing a specific ligand stimulus can be designed along the same lines for other tyrosine kinases using techniques well known in the art. 25 VEGF-Induced KDR Phosphorylation in Human Umbilical Vein Endothelial Cells (HUVEC) as Measured by Western Blots: 1. HUVEC cells (from pooled donors) were purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer directions. Only early passages (3-8) were used for this assay. Cells were cultured in 100 mm dishes 30 (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using complete EBM media (Clonetics). WO 01/09121 PCT/US00/20628 -108- 2. For evaluating a compound's inhibitory activity, cells were trypsinized and seeded at 0.5-1.0 x 105 cells/well in each well of 6-well cluster plates (Costar; Cambridge, MA). 3. 3-4 days after seeding, plates were 90-100% confluent. Medium was 5 removed from all the wells, cells were rinsed with 5-10ml of PBS and incubated 18- 24h with 5ml of EBM base media with no supplements added (i.e., serum starvation). 4. Serial dilutions of inhibitors were added in 1ml of EBM media (25jiM, 5^M, or lfiM fmal concentration to cells and incubated for one hour at 37 10 C. Human recombinant VEGF16S (R&D Systems) was then added to all the wells in 2 ml of EBM medium at a final concentration of 50ng/ml and incubated at 37 C for 10 minutes. Control cells untreated or treated with VEGF only were used to assess background phosphorylation and phosphorylation induction by VEGF. All wells were then rinsed with 5-10ml of cold PBS containing ImM Sodium 15 Orthovanadate (Sigma) and cells were lysed and scraped in 200(j.l of RIP A buffer (50mM Tris-HCl) pH7, 150mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, ImM EDTA) containing protease inhibitors (PMSF ImM, aprotinin lug/ml, pepstatin 1 fig/ml, leupeptin lug/ml, Na vanadate ImM, Na fluoride ImM) and l|ig/ml of Dnase (all chemicals from Sigma Chemical Company, St Louis, MO). 20 The lysate was spun at 14,000 rpm for 30min, to eliminate nuclei. Equal amounts of proteins were then precipitated by addition of cold (-20 C) Ethanol (2 volumes) for a minimum of 1 hour or a maximum of overnight. Pellets were reconstituted in Laemli sample buffer containing 5% -mercaptoethanol (BioRad; Hercules, CA) and boiled for 5min. The proteins were resolved by 25 polyacrylamide gel electrophoresis (6%, 1.5mm Novex, San Deigo, CA) and transferred onto a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), the proteins were probed overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, 30 NY) at 4 C. After washing and incubating for 1 hour with HRP-conjugated F(ab)2 of WO 01/09121 PCT/USOO/20628 -109- goat anti-rabbit or goat-anti-mouse IgG the bands were visualized using the emission chemiluminescience (ECL) system (Amersham Life Sciences, Arlington Height, IL). Certain examples of the present invention significantly inhibit cellular VEGF-induced KDR tyrosine kinase phosphorylation at concentrations of less than 50 nM. 5 In vivo Uterine Edema Model This assay measures the capacity of compounds to inhibit the acute increase in uterine weight in mice which occurs in the first few hours following estrogen stimulation. This early onset of uterine weight increase is known to be due to edema caused by increased permeability of uterine vasculature. Cullinan-Bove and Koss 10 (.Endocrinology (1993), 735:829-837) demonstrated a close temporal relationship of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus. These results have been confirmed by the use of neutralizing monoclonal antibody to VEGF which significantly reduced the acute increase in uterine weight following estrogen stimulation (WO 97/42187). Hence, this system can serve as a 15 model for in vivo inhibition of VEGF signaling and the associated hyperpermeability and edema. Materials: All hormones were purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) as lyophilized powders and prepared according to supplier instructions. 20 Vehicle components (DMSO, Cremaphor EL) were purchased from Sigma (St. Louis, MO). Mice (Balb/c, 8-12 weeks old) were purchased from Taconic (Germantown, NY) and housed in a pathogen-free animal facility in accordance with institutional Animal Care and Use Committee Guidelines. 25 Method: Day 1: Balb/c mice were given an intraperitoneal (i.p.) injection of 12.5 units of pregnant mare's serum gonadotropin (PMSG). Day 3: Mice received 15 units of human chorionic gonadotropin (hCG) i.p. 30 Day 4: Mice were randomized and divided into groups of 5-10. Test compounds were administered by i.p., i.v. or p.o. routes depending on solubility and WO 01/09121 PCT/US00/20628 -110- vehicle at doses ranging from 1-100 mg/kg. Vehicle control group received vehicle only and two groups were left untreated. Thirty minutes later, experimental, vehicle and 1 of the untreated groups were given an i.p. injection of 17 -estradiol (500 |ig/kg). After 2-3 hours, the 5 animals were sacrificed by C02 inhalation. Following a midline incision, each uterus was isolated and removed by cutting just below the cervix and at the junctions of the uterus and oviducts. Fat and connective tissue were removed with care not to disturb the integrity of the uterus prior to weighing (wet weight). Uteri were blotted to remove fluid by pressing between two sheets of filter paper with a one liter glass 10 bottle filled with water. Uteri were weighed following blotting (blotted weight). The difference between wet and blotted weights was taken as the fluid content of the uterus. Mean fluid content of treated groups was compared to untreated or vehicle treated groups. Significance was determined by Student's test. Non-stimulated control group was used to monitor estradiol response. 15 Results demonstrate that certain compounds of the present invention inhibit the formation of edema when administered systemically by various routes. Certain compounds of this invention which are inhibitors of angiogenic receptor tyrosine kinases can also be shown active in a Matrigel implant model of neovascularization. The Matrigel neovascularization model involves the formation 20 of new blood vessels within a clear "marble" of extracellular matrix implanted subcutaneously which is induced by the presence of proangiogenic factor producing tumor cells (for examples see: Passaniti, A., et al, Lab. Investig. (1992), 67(4), 519-528; Anat. Rec. (1997), 249(1), 63-73; Int. J. Cancer (1995), 63(5), 694-701; Vase. Biol. (1995), 15(11), 1857-6). The model preferably runs over 3-4 days and 25 endpoints include macroscopic visual/image scoring of neovascularization, microscopic microvessel density determinations, and hemoglobin quantitation (Drabkin method) following removal of the implant versus controls from animals untreated with inhibitors. The model may alternatively employ bFGF or HGF as the stimulus. 30 Certain compounds of this invention which inhibit one or more oncogenic, protooncogenic, or proliferation-dependent protein kinases, or angiogenic receptor WO 01/09121 PCT/US0O/2O628 -111- PTK also inhibit the growth of primary murine, rat or human xenograft tumors in mice, or inhibit metastasis in murine models. EXEMPLIFICATION The core structure of the compounds of the invention was synthesized via a 5 base catalyzed aldol condensation followed by an elimination reaction. Scheme I is a general representation of this reaction. The appropriate starting materials, II and III, for making the compounds of general formula IV of the present invention synthesized in accordance with general Scheme I are commercially available and/or can be made according to methods well-known in the art and/or are enabled by the 10 description provided herein. O N H n. hi. iv. Scheme I: General synthesis of 4-[(substituted) methylene]-2-pyrazolin-5-ones. I. 4-[(Pyrrol-2-yl)methylene]-2-pyrazolin-5-ones (V). Example 1: 3-Cyclopropyl-4-[(4,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-25 5-one. A reaction mixture of 3-cyclopropyl-2-pyrazolin-5-one (790 mg, 6.3 mmol), 4,5-dimethylpyrrole-2-carboxaldehyde (800 mg, 6.5 mmol), and piperidine 100 mg, in ethanol 50 mL was stirred at 90°C for 3.5 h. The solvent was removed under WO 01/09121 PCT/US00/20628 -112- reduced pressure. The solid residue was purified by flash column chromatography using (3 : 7) ethyl acetate : hexane as the mobile phase, then further purified by recrystallization from toluene. Example 40: 3-Tert-butylureido-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one. 5 A reaction mixture of 3-amino-4-[(pyrrol-2-yl)methylene]-2-pyrazoline-5- one (1.7 mmol) and /er/-butylisocyanate (1 mL) in ethyl acetate 5 mL was stirred at 80°C for 2 h. The product was collected by filtration and recrystallized from ethanol. Example 88: 4-{[4-(2-Dimethylaminoethoxycarbonyl)-3,5-dimethylpyrrol-2-10 yl]methylene}-3-isopropoxy-2-pyrazolin-5-one. A mixture of 4-[(4-carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one (200 mg, 0.68 mmol) in dichloromethane (20 ml) and a drop of DMF, was treated with oxalyldichloride (0.2 ml). The stirring was continued for 24 h and a solution of dimethylaminoethanol (0.6g, 6.7 mmol) in 15 dichloromethane (5ml) was added. The stirring was continued for 24 h. The solvent was evaporated to dryness, the solid residue was treated with NaHC03 (5%) and extracted with dichloromethane. The solid obtained after elimination of the solvent was recrystallized from n-heptane. Example 194: 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrole-2-yl]methylene}-20 3-pyrazinyl-2-pyrazolin-5-one N-oxide A mixture of Example 176 (0.2 g, 0.54 mmol) and m-chloroperbenzoic acid (0.2 g, 1.1 mmol) in chloroform (50 ml) was stirred at room temperature over 48 hrs. The solvent was removed to dryness and the residue purified by flash chromatography (dichloromethane/ethanol 9:1). Yield 30%, mp 192°C (ethanol) 25 Table 1: Other compounds synthesized having structural formula V. Example Substituent on Ring A R1 Recrystallization Solvent % Yield Method 1 4,5-dimethyl cyclopropyl toluene 30 see Example 1 2 none benzyl toluene : heptane 64 see Example 1 3 none 4-methoxy-phenyloxy methyl methanol 36 see Example 1 4 none phenyloxy methyl NA 33 see Example 1 WO 01/09121 PCT/US00/20628 -113- 5 none 4-chloro-phenyloxy methyl ethanol 33 see Example 1 6 none 4-methoxy benzyl ethanol 21 see Example 1 7 4-(2-carboxyethyl)-3-methyl benzyl NA see Example 1 8 3-(2-carboxyethyl)-4-methyl benzyl isopropanol see Example 1 9 none 4-methyl-phenyloxy-methyl methanol 42 see Example 1 10 none amino isopropanol 90 see Example 1 11 none isopropoxy isopropanol 52 see Example 1 12 none phenylethyl NA 86 see Example 1 13 none phenylamino isopropanol 86 see Example 1 14 none 4- methylbenzyl methanol 60 see Example 1 15 none 4- methylphenyl -amino methanol 86 see Example 1 16 none 4-methoxy-phenylamino DMF: water 92 see Example 1 17 none 4- chlorobenzyl ethanol 56 see Example 1 18 none 4- chlorophenyl-amino ethanol 90 see Example 1 19 none 3- chlorophenyl-oxymethyl NA - 50 see Example 1 20 none indol-3-yl ethanol 90 see Example 1 21 none 3- methoxybenz yl methanol 21 see Example 1 22 none 3,4-dimethoxy-benzyl ethanol 83 see Example 1 23 none 4-methoxy-phenylethyl ethanol 91 see Example 1 24 none 4-phenyl-phenyloxy methyl methanol 72 see Example 1 25 none 2- phenylpropyl heptane 10 see Example 1 26 none 3- phenylpropyl toluene :heptane 60 see Example 1 27 none 4-hydxoxy-phenylethyl methanol 76 see Example 1 28 3,5-dimethyl phenylethyl methanol 51 see Example 1 29 none 4-methyl-phenylethyl ethanol 53 see Example 1 30 3,5-dimethyl isopropoxy heptane 55 see Example 1 31 none ethoxy ethanol 76 see Example 1 WO 01/09121 PCT/US00/20628 -114- 32 none 4-nitro-phenylethyl toluene 48 see Example 1 33 none 4-fluoro-phenylamino isopropanol 66 see Example 1 34 none 4-chloro-phenylethyl ethanol 60 see Example 1 35 4,5-dimethyl isopropoxy methanol 55 see Example 1 36 3,5-dimethyl-4-ethyl isopropoxy toluene 47 see Example 1 37 3,5-dimethyl-4-ethyl phenylethyi heptane 49 see Example 1 38 l-(4-hydroxy-butyl) isopropoxy NA 80 see Example 1 39 none cyclopentylo xy methanol 75 see Example 1 40 none tert-butylureido ethanol 87 see Example 40 41 4-methyl isopropoxy toluene 34 see Example 1 42 4-methyl 4-amino-phenylethyl NA 27 see Example 1 43 1-methyl isopropoxy toluene 55 see Example 1 44 5-methyl isopropoxy methanol: water 30 see Example 1 45 3,5-dimethyl-4-ethyl 4- aminophenyl ethyl toluene 50 see Example I 46 5-methyl ethoxy methanol 58 see Example 1 47 3,5-dimethyl-4-ethyl 4-carbamoyl-phenylethyl DMF: water 82 see Example 1 48 3,5-dimethyI-4-ethyl 4-methoxy carbonyl-phenylethyl methanol 70 see Example 1 49 3,5-dimethyl-4-ethoxycarbonyl isopropoxy ethanol 81 see Example 1 50 3,5-dimethyl-4-ethoxycarbonyl 4-amino-phenylethyl ethanol 62 see Example 1 51 5-ethyl isopropoxy heptane 48 see Example 1 52 3,5-dimethyl-4-ethyl 4-hydroxy-phenvlethyl isopropanol 35 see Example 1 53 none ethoxy carbon yl-methyl ethanol 35 see Example 1 54 none 4-methoxy-phenylamino-carbonylmeth yl methanol 46 see Example 1 55 3 (2 -carboxy ethy 1)-4-methyl isopropyl ethanol 32 see Example 1 56 none cyclopropyl ethanol 50 see Example 1 57 none cyclobutyl ethanol 65 see Example 1 58 none 3-pyridyl ethanol 50 see Example 1 59 l-(3,5-dichloro-phenyl) cyclopropyl ethanol 30 see Example 1 WO 01/09121 PCT/US00/20628 -115- 60 none 2,2,3,3- tetramethyl-cyclopropyl toluene 55 see Example 1 61 3,5-dimethyl cyclopropyl toluene 33 see Example 1 62 none cyclopentyl toluene 66 see Example 1 63 none 2-methyl cyclopropyl hexane 44 see Example 1 64 none benzothiazol-2-yl DMF: water 60 see Example 1 65 4,5-dimethyl 3-pyridyl ethanol 35 see Example 1 66 3,5-dimethyl-4-ethyl cyclopropyl ethanol 50 see Example 1 67 none PVTrol-2-yI methanol 88 see Example 1 68 4-methyl cyclopropyl ethanol 35 see Example 1 69 4-methyl benzothiazol-2-yl ethanol 48 see Example 1 70 3,5-dimethyl 3-pyridyl ethanol 24 see Example 1 71 3,5-dimethyl-4-ethyl 3-pyiidyl ethanol 51 see Example 1 72 5-methyl cyclopropyl ethanol 50 see Example 1 73 5-methyl 3-pyridyl ethanol 47 see Example 1 74 5-ethyl cyclopropyl ethanol: water 21 see Example 1 75 3,5-dimethyl-4-ethoxycarbonyl cyclopropyl ethanol 83 see Example 1 76 5-phenyl isopropoxy methanol 66 see Example 1 77 none propyl NA 49 see Example 1 78 none methyl NA 6 see Example 1 79 none 4-isopropyl-phenylamino NA 50 see Example 1 80 none 3- phenylamino NA 80 see Example 1 81 ' 1-(4-hy droxy-butyl cyclopropyl ethanol 34 see Example 1 82 4-(2-carboxyethyl)-3-methyl isopropoxy ethanol 46 see Example 1 WO 01/09121 PCT/USOO/20628 -116- 83 4-carboxy-3,5-dimethyl isopropoxy NA 41 see Example 1 84 4,5-tetramethylene isopropoxy ethanol 77 see Example 1 85 3,4-dimethyl-4-morpholino methyl isopropoxy NA 30 see Example 1 86 3,5-dimethyl-4-dimethylamino methyl isopropoxy heptane 30 see Example 1 87 4-acetyl-3,5-dimethyl isopropoxy ethanol 62 see Example 1 88 3,5-dimethyl-4-(2-dimethyl aminoethyloxy carbonyl) isopropoxy heptane 40 See Example 88 89 3,5-dimethyl-4-(2-dimethyl aminoethyl aminocarbonyl) isopropoxy toluene: heptane 41 See Example 88 90 5-ethoxy carbonyl isopropoxy methanol 79 see Example 1 91 5-carboxy isopropoxy toluene 83 see Example 1 92 none 4- chlorophenyl aminocarbon yl methyl DMF/water 50 see Example 1 93 5-phenyl cyclopropyl ethanol 72 see Example 1 94 3,5-dimethyl-4-ethyl tetrahydrofur an-3-yl toluene 44 see Example 1 95 4-carboxy-3,5-dimethyl cyclopropyl ethanol 69 see Example 1 96 3,5-dimethyl-4-ethoxycarbonyl 3-pyridyl ethanol 86 see Example 1 97 3,5-dimethyl-4-morpholino methyl cyclopropyl NA 34 see Example 1 98 3,4-dimethyl pyrazinyl methanol 60 see Example 1 99 4-(2-carboxy ethyl)-3-methyl cyclopropyl methanol 51 see Example 1 100 3,5-dimethyl-4-dimethyl amino methyl cyclopropyl NA 67 see Example 1 101 5-ethoxy carbonyl cyclopropyl ethanol 91 see Example 1 102 4,5-tetramethylene cyclopropyl ethanol 84 see Example 1 103 none 2-methoxy carbonyl ethyl ethanol 56 see Example 1 104 none ethoxycarbon yl NA 40 see Example 1 105 none isopropyl NA 44 see Example 1 106 none trans-2-phenyl cyclopropyl toluene 46 see Example 1 107 none cyclohexyl toluene 32 see Example 1 108 4,5 -tetramethy lene cyclopropyl amino ethanol 50 see Example 1 WO 01/09121 PCT/US00/20628 -117- 109 5-morpholino methyl cyclopropyl ethylacetate 72 see Example 1 110 5-carboxy cyclopropyl ethanol 50 see Example 1 111 4-chloro ethoxy ethanol 88 see Example 1 112 4-bromo ethoxy ethanol 70 see Example 1 113 5-chloro ethoxy NA 37 see Example 1 114 4-chloro cyclopropyl ethanol 42 see Example 1 115 4-bromo cyclopropyl ethanol 50 see Example 1 116 4,5-tetramethylene pyrazinyl ethanol 85 see Example 1 117 4,5-tetramethylene 3-pyridyl ethanol 84 see Example 1 118 4-carboxy-3,5-dimethyl pyrazinyl DMF 66 see Example 1 119 3,5-dimethyl-4-(2- dimethylamino cthyloxycarbonyl) cyclopropyl NA 71 see Example 88 120 3,5-dimethyl-4-(2-dimethylamino ethyloxy carbonyl pyrazinyl NA 20 see Example 88 121 3,5-dimethyl-4-dimethylamino methyl pyrazinyl toluene 76 see Example 1 122 3,5-dimethyM-dimethylamino methyl maleate pyrazinyl ethanol 98 Maleate salt formed from free base of Example 121. (See footnote) 123 3,5-dimethyl-4-(2-morpholino ethylamino carbonyl) pyrazinyl toluene 20 see Example 1 124 3,5-dimethyl 2-pyridyl ■ ethanol 36 see Example 1 125 3,5-dimethyl-4-ethyl 2-pyridyl ethanol 50 see Example 1 126 4,5-tetramethylene 2-pyridyl ethanol 58 see Example 1 127 3,5-dimethyl 2-furyl ethanol 51 see Example 1 128 3,5-dimethyl-4-morpholino methyl pyrazinyl NA 28 see Example 1 129 3,5-dimethyl 2-thieny] ethanol 25 see Example 1 130 4-ethoxycarbonyl cyclopropyl ethanol 68 see Example 1 131 3,5-dimethyl-4- trifluoro acetamidomethyl cyclopropyl ethanol 70 see Example 1 132 4-aminomethyl-3,5-dimethyl cyclopropyl ethanol 30 see Example 1 133 3,5-dimethyl benzothiazol-2-yl ethanol 40 see Example 1 134 3,5-dimethyl-4-morpholino methyl benzothiazol- 2-yl ethanol 40 see Example 1 135 3,5-dimethyl-4-ethyl pyrazinyl ethanol 74 see Example 1 136 4-ethoxycarbonyl pyrazinyl toluene 26 see Example 1 WO 01/09121 PCT/US00/20628 -118- 137 4-carboxy pyrazinyl methanol 70 see Example 1 138 3,5-dimethyl-4-diethanolamino methyl pyrazinyl ethanol 50 see Example 1 139 3,5-dimethyl-4- trifluoro acetamidomethyl pyrazinyl NA 78 see Example 1. 140 4-ethoxycarbonyl -3-phenyl cyclopropyl ethanol 68 see Example 1 141 3,5-dimethyl-4-( 1 -pyrrolidinyl methyl) pyrazinyl toluene 23 see Example 1 142 3,5-dimethyl-4-dimethylamino methyl 2-furyl toluene 20 see Example 1 143 3,5-dimethyl-4-dimethylamino methyl 2-thienyl toluene 48 see Example 1 144 3,5-dimethyl-4-dimethylamino methyl 3-pyridyl toluene 51 see Example 1 145 3,5-dimethyl-4-ethoxycarbonyl phenyl ethanol 89 see Example 1 146 3,5-dimethyl-4-ethyl phenyl methanol 34 see Example 1 147 3,4-di(ethoxy carbonyl) ethoxy ethanol 54 see Example 1 148 4-ethoxycarbonyl ethoxy methanol 30 see Example 1 149 3,5-dimethyl-4-ethoxycarbonyl 2-(3-pyridyl)ethyl ethanol 81 see Example 1 150 3,5-dimethyI-4-ethoxycarbonyl l-methyl-2-phenylethyl ethanol 52 see Example 1 151 4-carboxy-3,5-dimethyl ethoxy DMF: water 81 see Example 1 152 5-nitro ethoxy ethanol 64 see Example I 153 4-nitro ethoxy toluene 95 see Example 1 154 4-carboxy ethoxy NA 40 see Example 1 155 3,5-dimethyl-4-(2-dimethyl aminoethyl amino carbonyl) ethoxy heptane 86 see Example 88 156 5-chloro-3-methoxycarbonyl-4-methoxy carbonylmethyl ethoxy ethanol 46 see Example 1 157 3-(2-carboxyethyl)-4-methyI ethoxy NA 54 see Example 1 158 3,5-dimethyl-4-ethoxycarbonyl ethoxy ethanol 82 see Example 1 159 4,5-tetramethylene ethoxy heptane 80 see Example 1 160 3,5-dimethyl-4-ethoxycarbonyl trifluoro-methyl ethanol 45 see Example 1 WO 01/09121 PCT/US00/20628 -119- 161 3,5-dimethyl-4-ethoxycarbonyl 5-isoxazolyl DMF: water 74 see Example 1 162 3,5-dimethy 1-4-ethoxycarbonyl 3-amino-phenyl ethanol 76 see Example 1 163 4-morpholino ethyl aminocarbonyl ethoxy NA 30 see Example 88 164 4-ethoxycarbonyl-3-phenyl pyrazinyl toluene 70 see Example 1 165 4-(4-methyl-l-pyperazinyl methyl)-3,5-dimethyl pyrazinyl DMF 58 see Example 1 166 4-diethylamino methyl- 3,5-dimethyl pyrazinyl NA 20 see Example 1 167 3,5-dimethyl-4-piperidino methyl pyrazinyl toluene 25 see Example 1 168 3,5-dimethyl-4-piperidinomethyl 5-isoxazolyl NA 35 see Example 1 169 3,5-dimethyl-4-dimethylamino methyl 5-isoxazolyl NA 30 see Example 1 170 5-methyl-4-dimethylamino methyl pyrazinyl toluene-heptane 75 see Example 1 171 3,5-Dimethyl-4-[N-(2-dimethyl-aminoethyl)-N-methylaminomethyll pyrazinyl methanol 40 See example 1 WO 01/09121 PCT/USOO/20628 r -120- 172 3 -dimethy lamino-methyl-4,5-tetramethylene cyclopropyl NA 30 See example 1 173 3 -dimethylamino-methyl-4,5-tetramethylene pyrazinyl NA 30 See example 1 174 3,5-dimethyl-4-dimethylamino-methyl maleate cyclopropyl ethanol 90 Maleate salt form from free base of Example 100. (See footnote) 175 4-(3-chloro propionyl)-3,5-dimethyl pyrazinyl toluene 88 See example 1 176 4-(2-diethylamino-ethyl)-3,5-dimethyl pyrazinyl ethanol 95 See example 1 177 3,5-dimethyl-4-(dimethylamino-methyl) 5-methyl-3-isoxazolyl toluene/heptane 40 See example 1 178 3,5-Dimethyl-4-(4- hydroxypiperidinomethyl) pyrazinyl methanol 40 See example 1 179 4-Aminomethyl-3,5-dimethyl maleate pyrazinyl methanol 76 See example 1 180 4-(4-Benzylpiperidinomethyl)-3,5-dimethyl pyrazinyl toluene 80 See example 1 181 3,5-Dimethyl-4-(2-hydroxy ethyl) pyrazinyl NA 80 See example 1 182 3,5-Dimethyl-4- [2-( 1 -pyrrolidinylethyl)l pyrazinyl toluene 67 See example 1 183 3,5-Dimetliyl-4- [2-( 1 -pyrrolidinylethyl)! cyclopropyl toluene 20 See example 1 184 3,5-Dimethyl-4-(2-hydroxyethyl) cyclopropyl NA 23 See example 1 185 3,5-Dimethyl-4-(2-ethylaminoethyl) pyrazinyl NA 35 See example 1 186 4-(3-Diethyl aminopropyl)-3,5-dimethyl pyrazinyl ethanol 52 See example 1 187 3,5-Dimethyl-4-(3-hydroxypropyl) pyrazinyl ethanol 82 See example 1 188 3,5-Dimethyl-4-dimethyl aminoacetyl hydrochloride pyrazinyl ethanol/ethylether 51 See example 1 189 3,5-Dimethyl-4-dimethyl aminoacetyl ethoxy ethanol/ ethylether 44 See example 1 190 4-(2-dietbylaminoethyl)-3,5-Dimethyl cyclopropyl heptane 54 See example 1 191 3,5-Dimethyl-4-(2-dimethylaminoethyl) pyrazinyl toluene 48 See example 1 192 3,5-Dimethyl-4-(4-hydroxybutyl) pyrazinyl methanol 58 See example 1 193 4-(4-Diethylaminobutyl)-3,5-dimethyl pyrazinyl toluene 60 See example 1 194 4-(2-Diethylamino-ethyl-N-oxide)-3,5 dimethyl pyrazinyl Ethanol 30 See example 194 WO 01/09121 PCT/Us00/20628 -121- 195 3,5-Dimethyl-4-( 1 -pyrrolidinylacetyl) pyrazinyl NA 57 See example I 196 4-Diethylaminoacetyl-3,5-dimethyl pyrazinyl NA 52 See example 1 197 3-Isopiopyl-5-methyl pyrazinyl Ethanol 44 See example 1 198 3,5-Dimethyl-4- [3-(I-pyrrolidinylpropyl)! pyrazinyl Ethanol 30 See example 1 199 4-Dimethyl aminomethyl-3-isopropyl-5-methyI pyrazinyl Toluene 40 See example 1 200 4-Dimethyl amijioniethyl-3-isopropyl-5-methyl cyclopropyl Toluene 40 See example 1 201 3,5-DimethyI-4-(2-ethoxyoxaIyl) pyrazinyl Ethanol 40 See example I 202 3,5-Dimethyl-4-(2-ethylaminoelhyl) cyclopropyl NA 60 See example 1 203 3,5-Dimethyl-4-(2-cyclopropylaminoethyl) pyrazinyl Toluene 40 See example I 204 3,5-Dimethyl-4-[2-(4-pyridyl-methylamino) elhyll pyrazinyl NA 40 See example 1 205 3,5-Dimethyl-4-(2-cyclopropylaminoethyl') cyclopropyl Toluene 36 See example 1 206 3,5-Dimethyl-4-(2-diethylaminoethvl) 2-pyrimidinyl Toluene 35 See example 1 207 3,5-Dimethyl-4-(2-diethylaminoethvl) 3-pyridazinyl Toluene 40 See example 1 208 3,5-Dimethyl-4-(2-dicthvlaminoethyl) 4-pyrimidinyl Toluene 50 See example 1 209 3,5-Dimethyl-4-(2-diethylaminoethyl 4-pyridazinyl Toluene 30 See example 1 Table 1 A: Physical data for compounds synthesized having stractural formula V. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 1 220-222 68.10 68.27 6.59 6.61 18.32 18.30 2 182-184 71.69 72.00 5.21 5.40 16.72 16.47 3 177-180 64.63 64.06 5.08 5.02 14.13 14.00 4 163-165 67.40 66.88 4.90 4.88 15.72 15.53 5 218-222 59.71 59.87 4.00 4.24 13.92 13.85 6 179-180 68.55 68.45 5.03 5.44 14.99 14.99 7 270-272 67.64 67.17 5.67 5.82 12.45 12.38 8 (0.3 H,01* 226-228 66.58 66.10 5.72 5.65 12.26 12.27 9 207-210 68.31 68.20 5.37 5.44 14,93 14.96 10 265-270 54.53 55.07 4.57 4.47 . 31.80 31.98 11 172-174 60.26 60.37 5.97 5.80 19.16 18.97 12 145-147 72.43 72.29 5.69 5.70 15.83 16.17 WO 01/09121 PCT/US00/20628 -122- 13 285-287 66.65 66.66 4.79 4.71 22.20 22.12 14 254-255 72.43 72.36 5.69 5.53 15.83 15.84 15 256-258 67.65 67.31 5.29 5.12 21.03 20.96 16 288-290 63.81 63.90 4.99 4.53 19.84 19.75 17 178-180 63.05 63.26 4.23 4.10 14.70 14.59 18 (0.25 H,0)* 245-247 57.74 57.69 3.97 3.81 19.23 18.95 19 165-167 59.71 59.69 4.00 4.05 13.92 13.80 20 300-305 69.55 69.67 4.37 4.61 20.27 20.39 21 169-171 68.31 68.27 5.37 5.36 14.93 14.92 22 164-165 65.58 65.58 5.50 5.63 13.49 13.44 23 137-139 69.13 69.15 5.80 5.69 14.22 14.30 24 (0.25 H,01* 192-194 72.50 72.56 5.07 5.36 12.07 12.02 25 130-131 73.09 73.16 6.13 6.25 15.04 14.83 26 169-170 73.09 73.46 6.13 6.32 15.04 14.42 27 253-255. 68.31 68.48 5.37 5.01 14.93 14.74 28 186-187 73.69 73.89 6.52 6.49 14.32 14.25 29 153-154 73.09 73.38 6.13 5.95 15.04 14.85 30 176-177 63.14 63,20 6.93 6.77 16.99 16.98 31 211-213 58.53 58.81 5.40 5.27 20.48 20.52 32 224-226 61.92 62,02 4.54 4.75 18.05 1831 33 272-273 62.21 62,45 4.10 4.33 20.73 20.81 34 193-194 64.11 64.27 4.71 4.85 14.02 14.07 35 195-197 63.14 63,26 6.93 6.76 16.99 17.04 36 188-190 65.43 65.59 7.68 7.00 15.26 15.29 37 168-170 74.73 74,40 7.21 7.10 13.07 13.11 38 138-140 61.84 61.87 7.27 7.17 14.42 14.31 39 201-203 63.65 63,65 6.16 6.19 17.13 17.24 40 266-268 56.71 57,04 6.22 6.06 25.43 25.69 41 215-217 61.78 61,77 6.48 6.40 18.01 17.96 42 (0.75 H,0)* 178-180 66.32 66.78 6.33 6.01 18.19 17.85 43 199-201 61.78 61.97 6.48 6.36 18.01 17.91 44 128-130 61.78 61,42 6.48 6.32 18.01 17.78 45 183-185 71.40 71.38 7.19 7.28 16.65 16.62 46 197-199 64.35 64.69 7.33 6.96 16.08 16.03 47 297-299 69.21 69.08 6.64 6.68 15.37 15.31 48 177-179 69.64 69.70 6.64 6.57 11.07 11.10 49 226-228 60.18 60.06 6.63 6.46 13.16 13.02 50 186-188 66.30 66.20 6.36 6.25 14.73 14.68 51 119-121 63.14 63.14 6.93 6.95 16.99 17.00 52 260-262 71.19 71.01 6.87 6.96 12.45 12.36 53 124-126 58.29 58.49 5.29 5.04 16.99 16.99 54 240-242 62.95 62.96 4.97 5.00 17.27 17.11 55 229-231 62.26 62.20 6,62 6.37 14.52 14.36 56 158-160 65.65 65.78 5.51 5.50 20.88 20.78 57 150-152 66.95 67.09 6.08 5.76 19.52 19.45 58 222-224 65.53 65.57 4.23 4.29 25.51 23.62 59 188-190 58.97 59.06 3.78 3.92 12.13 11.98 60 160-162 70.01 70.28 7.44 7.35 16.33 16.22 61 193-195 68.09 68.34 6.59 6.39 18.32 18.18 WO 01/09121 PCT/USQO/20628 -123- 62 (0.2 toluene)* 127-129 69.82 69.73 6.75 6.64 16.96 17.20 63 132-133 66.95 67.11 6.08 6.03 19.52 19.73 64 340-342 61.20 61.38 3.42 3.70 19.03 19.19 65 220(d) 67.65 67.47 5.29 5.30 21.04 20.94 66 206-210 70.01 69.65 7.44 7.46 16.33 16.23 67 245-247 63.70 63.76 4.45 4.64 24.76 24.64 68 212-215 66.95 66.72 6.08 5.63 19.52 19.29 69 (0.5 H,0)* 327-329 60.55 60.90 4.12 4.09 17.65 17.42 70 235-238 67.65 67.66 5.29 5.40 21.04 20.98 71 270-272 69.36 69.41 6.16 6.21 19.03 18.98 72 170-172 66.95 67.05 6.08 6.08 19.52 19.42 73 210-212 66.65 66.73 4.79 4.82 22.21 22.10 74 163-165 68.10 68.15 6.59 6.63 18.32 18.27 75 240-242 63.77 63.77 6.35 6.35 13.94 13.90 76 212-214 69.14 69.27 5.80 5.88 14.23 14.20 77-80 l3C and "H NMR and analytical LC/MS data consistent with assigned structure 81 134-136 65.91 65.60 7.00 6.99 15.37 15.03 82 267-269 59.01 59.12 6.27 6.22 13.76 13.66 83 >300 57.72 57.81 5.88 5.84 14.42 14.25 84 206-207 65.91 66.04 7.01 6.78 15.37 15.34 85 162-164 62.41 62.36 7.56 7.46 16.17 15.94 86 173-175 63.13 63.27 7.95 7.73 18.41 18.34 87 209-210 62.27 61.86 6.62 6.58 14.52 14.25 88 165-167 59.65 59.82 7.23 7.05 15.46 15.34 89 192-194 59.82 59.92 7.53 7.26 19.38 19.21 90 205-207 57.72 57.96 5.88 5.62 14.42 14.43 91 235-237 51.24 51.78 5.38 5.49 14.94 14.95 92 240-242 58.45 58.07 3.98 3.96 17.04 16.64 93 208-210 73.62 73.60 5.45 5.62 15.15 15.14 94 163-165 66.87 66.70 7.36 7.10 14.62 14.59 95 312(d) 61.53 61.08 5.53 5.38 15.37 - 15.11 96 247-249 63.89 64.05 5.36 5.48 16.56 16.70 97 175-177 65.82 65.62 7.36 7.43 17.06 16.75 98 245-250 62.91 63.30 4.90 5.10 26.20 26.29 99 290(d) 62.70 62.66 5.96 5.83 14.62 14.47 100 176-178 67.10 67.21 7.74 7.49 19.56 19.53 101 250-152 61.52 61.73 5.53 5.46 15.37 15.40 102 227-230 70.56 70.62 6.71 6.61 16.46 16.52 103 134-136 58.29 58.71 5.29 5.44 16.99 17.03 104 177-179 56.64 56.85 4.75 4.56 18.01 17.56 105 120-122 65.01 65.12 6.44 6.44 20.67 20.59 106 173-175 74.42 74.20 5.60 5.77 14.46 14.77 107 176-178 69.11 69.21 7.04 7.08 17.27 17.24 108 240-243 66.64 66.62 6.71 6.39 20.72 20.80 109 184-186 63.98 64.21 6.71 6.69 18.65 18.74 110 220(d) 54.75 55.17 4.97 4.90 15.96 16.21 111 237-239 50.12 50.54 4.21 3.90 17.53 17.59 112 242-244 42.28 42.45 3.55 3.39 14.79 14.58 113 170-172 50.12 49.98 4.21 4.21 17.53 18.10 114 220(d) 56.06 56.46 4.27 4.37 17.83 17.54 115 210(d) 47.16 47.60 3.59 3.85 15.00 14.57 WO 01/09121 PCT/US00/20628 -124- 116 253-255 65.51 65.83 5.15 5.25 23.87 23.86 117 264-267 69.84 69.61 5.51 5.53 19.16 19.13 118 225-228 56.71 56.59 4.94 4.79 22.00 21.94 119 172-174 62.77 62.61 7.02 6.71 16.26 16.06 120 223-225 58.30 58.79 5.92 6.10 21.47 20.89 121 220-222 63.50 63.57 6.26 6.25 25.39 25.55 122 206-210 55.01 54.51 5.71 5.64 18.32 18.30 123 178-180 59.56 60.03 5.95 5.82 23.15 22.87 124 228-230 67.65 68.00 5.29 5.46 21.04 21.12 125 184-186 69.36 69.19 6.16 6.09 19.03 19.33 126 214-216 69.84 69.94 5.51 5.41 19.16 19.33 127 235-237 65.87 65.88 5.13 5.24 16.46 16.51 128 274-277 62.28 62.26 6.05 5.90 22.93 22.94 129 235-237 61.96 62.01 4.82 4.91 15.48 15.44 130 192-194 61.52 61.73 5.53 5.53 15.37 15.43 131 278-280 54.23 54.40 4.83 4.92 15.81 15.68 132 217-219 63.61 63.84 7.11 6.90 21.19 21.22 133 295-297 63.33 63.55 4.37 4.45 17.38 17.44 134 285(d) 62.15 62.03 5.54 6.02 16.47 16.91 135 264-267 65.06 65.10 5.80 5.71 23.71 23.51 136 155-157 59.74 59.30 4.46 4.40 21.24 21.20 137 230-232 54.26 54.58 3.77 3.34 24.34 23.99 138 242-244 58.44 58.81 6.36 j 6.28 21.52 21.84 139 302-305 51.45 51.30 3.93 4.26 21.17 20.88 140 218-220 68.75 69.07 5.48 5.53 12.02 11.96 141 235-237 64.02 64.11 6.41 6.54 23.58 23.01 142 209-211 65.36 65,37 6,45 6.89 17.93 16.53 143 208-210 61.32 61.43 6.20 6.18 16.83 16.64 144 220-224 66.85 67.24 6.54 6.54 21.65 21.11 145 216-217 67.64 67.71 5.68 5.80 12.45 12.53 146 274-275 73.70 73.80 6.53 6.53 14.32 14.39 147 132-134 55.01 55.24 5.48 5.32 12.03 12.03 148 212-216 56.31 56.25 5.45 5.20 15.15 15.02 149 180-182 65.56 65.10 6.05 5.96 15.29 15.20 150 168-170 69.64 69.91 6.64 6.43 11.07 11.10 151 310-312 56.31 56.30 5.45 5.15 15.15 15.17 152 208-210 48.00 48.37 4.03 4.19 22.39 22.65 153 287-289 48.00 48.37 4.03 4.04 22.39 22.64 154 290-293 53.01 52.63 4.45 4.47 16.86 16.59 155 158-160 58.61 58.82 6.94 6.48 16.08 16.05 156 225-227 48.72 49.00 4.36 4.18 11.36 11.35 157 255-257 57.72 57.65 5.88 5.97 14.42 14.32 158 232-234 59.01 59.06 6.27 6.30 13.76 13.68 159 178-180 64.85 64.61 6.61 6.95 16.20 15.99 160 252-254 51.07 51.17 4.29 4.34 12.76 12.60 161 255-257 58.53 58.63 4.91 5.08 17.06 16.96 162 214-216 64.76 64.91 5.72 5.74 15.90 15.74 163 197-199 56.50 56.22 6.41 6.37 19.38 18.96 164 255-257 65.11 65.37 4.42 4.49 18.08 18.11 165 295-297 63.31 63.62 6.64 6.66 25.84 25.96 166 242-244 64.75 64.66 6.86 6.73 23.85 23.74 167 240-242 65.91 65.61 6.64 6.74 23.06 22.69 168 215-217 63.79 63.57 6.44 6.56 19.38 19.82 169 161-163 56.45 56.96 6.51 6.45 20.57 20.29 WO 01/09121 PCT/US0O/2O628 -125- 170 193-195 61.92 62.18 5.85 5.74 27.08 26.80 171 205-207 62.96 62.48 7.13 6.73 25.70 25.40 172 182-185 69.20 69.21 7.74 7.82 17.93 17.41 173 210-212 65.12 64.66 6.33 6.02 23.98 23.50 174 199-201 59.68 59.31 6.51 6.37 13.92 14.42 175 213(d) 57.92 58.32 4.61 4.82 19.08 19.26 176 210-212 65.55 65.24 7.15 7.18 22.93 22.94 177 242-244 62.37 61.87 6.47 6.55 21.39 21.06 178 (0.5 H,0)* 255-57 61.68 61.48 6.47 6.45 21.58 21.68 179 (0.5 H,0) 205-8 54.15 54.27 5.02 4.97 19.94 19.63 180 (0.25) 211-14 70.64 70.56 6.69 7.06 18.30 17.93 181 306-8 61.72 61.64 5.50 5.45 22.49 22.41 182 (0.17 H,0) 190-92 65.36 64.97 6.67 6.55 22.86 23.20 183 197-200 69.90 69.87 8.02 8.12 17.16 16.86 184 244-46 65.91 65.52 7.00 6.98 15.37 15.05 185 192-94 HKMN and EM data consistent with assigned structure 186 (3 . H,0) 208.10 58.05 58.21 7.88 7.39 19.73 19.47 187 273-75 62.75 63.01 5.88 5.76 21.52 21.33 188 (C1H.2 H,0) >300 (d) 50.83 51.14 5.88 5.70 19.76 20.10 189 198 60.36 59.86 6.97 6.90 17.60 17.36 190 133 69.48 69.19 8.59 8.47 17.05 16.74 191 216 . 60.60 60.43 6.73 6.32 23.56 23.14 192 222 63.70 63.85 6.24 6.23 20.63 20.53 193 184 66.98 66.70 7.66 7.40 21.30 20.85 194 192 62.75 62.46 6.79 6.73 21.96 21.64 195 (0.5 H,0) 220 61.94 61.66 5.93 5.72 21.68 21.54 196 (0.5 H,0) 199 61.62 61.78 6.41 6.13 21.56 22.06 197 244 65.07 65.02 5.80 5.79 23.71 23.99 198 202-04 66.64 66.24 6.92 6.99 22.20 22.00 199 227 64.75 64.90 6.86 6.99 23.85 23.88 200 190-92 68.75 68.86 8.33 8.46 17.82 17.51 201 223 58.85 58.96 4.66 4.73 19.06 19.03 202 (0.4 H,0) 150 66.37 66.46 8.12 7.90 18.21 17.80 203 210-218 63.81 63.95 6.42 6.45 23.50 23.12 204 (0.2 H,0) 203-205 65.23 65.05 5.82 5.84 24.20 23.77 205 (0.4 H20) 158-160 67.64 67.93 7.81 7.74 17.53 17.40 206 (0.2 H,0) 144-146 64.91 64.87 7.19 7.30 22.71 22.53 207 (0.2 H-,0) 218-220 64.91 64.79 7.19 7.00 22.71 22.78 208 220 65.55 65.45 7.15 7.13 22.93 22.53 WO 01/09121 PCT/US00/2Q628 -126- I 209 I 212-216 I 65.55 I 65.49 I 7.15 1 7.38 1 22.93 I 22.31 [ * The molecular weight calculated for the elemental analysis includes the solvent in the amount indicated. Footnote: Maleate salts were formed by the addition of an ethanolic solution of maleic acid to the free base in ethanol at room temperature, followed by cooling, and filtration of the crystalline 5 product. II. 4-[(IndoI-3-yl)methylene3-2-pyrazolin-5-ones (VI). Example 210: 3-Benzyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one. A reaction mixture of 3-benzyl-2-pyrazoline-5-one (905 mg, 5.2 mmol), 3-indole carboxaldehyde (800 mg, 5.6 mmol) and piperidine (100 mg) in ethanol (50 mL) was stirred at 90°C for 3 h. After cooling overnight, the product was collected 25 by filtration, then purified by reciystallization from ethanol. Table 2: Other compounds synthesized having structural formula VI. Example Substituent on Indole R1 Recrystallization Solvent % Yield Method 210 none benzyl ethanol 76 see Example 210 211 l-(4-hydroxy- butYf) benzyl methanol 51 see Example 210 212 none 4-methoxy-phenyloxymethyl isopropanol 67 see Example 210 213 none phenyloxymethyl isopropanol 94 see Example 210 214 none 4-chloro-phenyloxymethyl ethanol 65 see Example 210 215 none 4-methoxybenzyl ethanol 90 see Example 210 216 none 4-methyl-phenyloxymethyl ethanol 93 see Example 210 217 none phenylethyl ethanol 84 see Example 210 218 none isopropoxy methanol 81 see Example 210 219 none 4-methylbenzyl ethanol 95 see Example 210 220 none phenylamino isopropanol 52 see Example 210 WO 01/09121 PCT/USOO/20628 -127- 221 none 4-methylphenyl-amino methanol 60 see Example 210 222 none 4- methoxyphenyl-amino ethanol 96 see Example 210 223 none 4-chlorobenzyl ethanol 77 see Example 210 224 l-(4-hydroxy butyl) 4-methoxybenzyl DMF: water 89 see Example 210 225 none 4-chlorophenyl-amino DMF : water 86 see Example 210 226 none 3-methoxybenzyl DMF : water 99 see Example 210 227 none 3,4-dimethoxy-benzyl DMF; water 88 see Example 210 228 none 4-hydroxybenzyl DMF : water 56 see Example 210 229 none 3-chloro-phenyloxymethyl isopropanol 89 see Example 210 230 none indol-3-yl methanol 58 see Example 210 231 none 4-methoxy-phenylethyl isopropanol 88 see Example 210 232 none 4-phenyl-phenyloxymethyl NA 91. see Example 210 233 none 2-phenylpropyl methanol 60 see Example 210 234 none 3-phenylpropyl ethanol 76 see Example 210 235 none 4-hydroxy-phenylethyl methanol 51 see Example 210 236 none 4-methyl-phenylethyl ethanol 86 see Example 210 237 none ethoxy ethanol 90 see Example 210 238 l-(4-hydroxy-butyl) isopropoxy toluene: heptane 43 see Example 210 239 l-(4-hydroxy-butyl) phenylethyl methanol 80 see Example 210 240 none 4-nitro-phenylethyl isopropanol 83 see Example 210 241 none propoxy DMF : water 43 see Example 210 242 none 4-fluoro-phenylamino ethyl acetate 65 see Example 210 243 none 4-amino-phenylethyl methanol: water 74 see Example 210 244 2-methyl isopropoxy methanol 40 see Example 210 245 7-methyl isopropoxy • ethanol 98 see Example 210 246 7-methyl phenylethyl DMF : water 97 see Example 210 247 none cyclopentyl ethanol 56 see Example 210 248 1-methyl isopropoxy ethanol 81 see Example 210 249 none 4-methoxy-carbonyl-phenylethyl ethanol 77 see Example 210 250 1-isopropyl isopropoxy toluene: heptane 71 see Example 210 251 1-methyl 4-hydroxy-phenylethyl ethanol 50 see Example 210 252 none isopropyl ethanol 76 see Example 210 WO 01/09121 PCT/US00/20628 -128- 253 none 4-chlorophenyl aminocarbonyl methyl DMF: water 40 see Example 210 254 none eth oxy carbonyl-methyl methanol 40 see Example 210 255 none 4-methoxy-phenylamino-carbonylmethyl DMF : water 40 see Example 210 256 none cyclopropyl DMF: water 50 see Example 210 257 none 3-pyridyl ethanol 50 see Example 210 258 none 2-amino-carbonylethyl methanol 55 see Example 210 259 none cyclobutyl ethanol 79 see Example 210 260 none 2- (dimethylamino carbonyl)ethyl ethanol 97 see Example 210 261 l-(4-hydioxy butyl) cyclopropyl ethanol 80 see Example 210 262 none 4-pyridyl ethanol 91 see Example 210 263 none cyclopentyl ethanol 75 see Example 210 264 none 2,2,3,3-tetramethyl-cyclopropyl ethanol 32 see Example 210 265 none 2-methyl-cyclopropyl ethanol 34 see Example 210 266 l-(4-hydroxy-butyl) cyclohexyl toluene 41 see Example 210 267 l-(4-hydroxy-butyl) 4-pyridyl ethanol 50 see Example 210 268 none benzothiazol-2-yl ethanol 50 see Example 210 269 none 2-pyridyl 67 see Example 210 270 none dimethylamino ethanol 77 see Example 210 271 none pyrrol-2-yl ethanol 83 see Example 210 272 none 6-methoxybenzo thiazol-2-yl ethanol 60 see Example 210 273 1-methyl cyclopropyl ethanol 76 see Example 210 274 7-methyl cyclopropyl ethanol 60 see Example 210 275 1-methyl 3-pyridyl ethanol 64 see Example 210 276 none propyl NA 63 see Example 210 277 none methyl NA 68 see Example 210 278 none trifluoromethyl NA 14 see Example 210 279 l-(4-hydroxy-butyl) hydrogen NA 62 see Example 210 280 l-(4- hydroxy-butyl) methyl NA 36 see Example 210 281 l-(4-hydroxy-butyl) trifluoromethyl NA 7 see Example 210 WO 01/09121 PCT/US00/20628 -129- 282 . l-(4- hydroxy-butyl) Terf-butyl NA 50 see Example 210 283 none ethoxycarbonyl ethanol 74 see Example 210 284 none 2-methoxy carbonylethyl ethanol 79 see Example 210 285 none trans-2-phenyl-l-cyclopropyl ethanol 92 see Example 210 286 l-(4-hydroxy butyl cyclobutyl ethanol 26 see Example 210 287 6-carboxy-l-methyl cyclopropyl ethanol 26 see Example 210 288 5-methoxy-1-methyl cyclopropyl ethanol 75 see Example 210 289 1-methyl pyrazinyl ethanol 82 see Example 210 290 1,7-dimethyl cyclopropyl ethanol 97 see Example 210 291 1-methyl tetrahydrofuran-3-yl ethanol 78 see Example 210 292 1-methyl cyclopropyl amino ethanol 54 see Example 210 293 6-carboxy-l-methyl isopropoxy DMF : water 45 see Example 210 294 1,7-dimethyl isopropoxy methanol 53 see Example 210 295 5-methoxy-1 -methyl isopropoxy ethanol 72 see Example 210 296 1-methyl 4-fluorophenyl amino methanol 80 see Example 210 297 1-methyl trifluoro acetamido methanol 70 see Example 210 298 1-methyl 4-aminophenyl ethyl toluene 64 see Example 210 299 1-methyl amino ethanol 80 see Example 210 300 none 4-chlorophenyl ethyl ethanol 85 see Example 210 301 1-methyl ethoxy ethanol 80 see Example 210 302 1-methyl 5-isoxazolyl DMF: water 83 see Example 210 303 1-methyl tertbutyl ethanol 92 see Example 210 304 6-carboxy -1 -methyl pyrazinyl DMF 98 see Example 210 305 l-methyl-6- [2-(4-morpholino) ethyljamino carbonyl pyrazinyl NA 20 see Example 210 Table 2A: Physical data for compounds synthesized having stractural formula VI. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 210 292-295 75.73 75.74 5.02 5.28 13.94 13.85 WO 01/09121 PCT/USOO/20628 -130- 211 217-220 73.97 73.93 6.20 6.14 11.25 11.18 212 266-268 69.35 69.23 4.65 5.05 12.13 12.03 213 284-286 71.91 71.86 4.76 4.78 13.24 13.34 214 264-267 64.87 64.78 4.01 4.12 11.94 11.93 215 265-270 72.49 72.64 5.17 5.21 12.68 12.72 216 288-291 72.49 72.52 5.17 5.36 12.68 12.74 217 268-270 76.17 76.12 5.43 5.55 13.32 13.59 218 263-265 66.90 66.75 5,61 5.46 15.60 15.48 219 280-282 76.17 76.34 5,43 5.23 13.32 13.30 220 265-267 71.50 71.48 4.66 4.62 18.53 18.35 221 (0.75 H,0)* 255-257 69.11 69.30 5.30 5.07 16.98 16.99 222 265-267 68.66 68.65 4.85 4.98 16.85 16.67 223 274-277 67.96 67.77 4.20 4.39 12.51 12.33 224 204-206 71.44 71.39 6.24 6.14 10.41 10.32 225 248-250 64.19 64.01 3.89 4.15 16.63 16.59 226 288-290 72.49 72.46 5.17 5.16 12.68 12.81 227 282-284 69.79 69.68 5.29 5.29 11.62 11.75 228 295-300 71.91 71.20 4.76 4.76 13.24 13.44 229 265-268 64.87 64.91 .4.01 4.16 11.94 11.92 230 (0.5 CHjOH)* 288-292 71.91 71.45 4.71 4.69 16.36 13.36 231 266-268 73.02 72.78 5.54 5.70 12.16 12.09 232 (0.75 H,0)* 295-296 73.78 73.58 5.07 5.21 10.32 10.20 233 253-255 76.57 76.06 5.81 6.09 12.75 12.60 234 218-220 76.57 76.52 5.81 5.93 12.75 12.62 235 (1.0 CH,OH)* 271-275 69.40 69.40 5.82 5.72 11.56 11.38 236 244-245 76.57 76.73 5.81 5.72 12.75 12.64 237 248-250 65.87 65.94 5.13 5.01 16.46 16.45 238 210-212 66.84 66.76 6.79 6.83 12.30 12.21 239 205-207 74.39 74.32 6.50 6.58 10.84 10.92 240 295-297 66.65 66.65 4.47 4.85 15.54 15.75 241 246-247 66.90 66.95 5.61 5.56 15.60 15.61 242 (0.75 Ethyl Acetate)* 251-252 65.28 64.88 4.92 4.91 14.50 14.53 243 244-246 72.70 72.45 5.49 5.67 16.95 16.71 244 (0.25 CH,OHT 262-264 66.99 66.78 6.22 6.09 14.42 14.46 245 254-256 67.82 67.78 6.04 5.76 14.83 14.82 246 302-304 76.57 75,96 5.81 5.59 12.75 12.84 247 277-279 69.13 68.95 5.80 5.79 14.22 14.36 248 239-240 67.82 67.75 6.04 6.10 14.83 14.77 249 259-260 70.76 70.62 5.13 5.43 11.25 11.24 250 161-163 69.43 69.40 6.75 6.80 13.49 13.48 251 255-257 73.04 72.89 5.50 5.72 12.17 12.11 252 264-266 71.12 71.17 5.96 5.87 16.58 16.65 253 305-307 63.41 63.17 3.99 4.07 14.79 14.57 WO 01/09121 PCT/US00/20628 -131- 254 235-237 64.63 64.81 5.08 5.04 14.13 14.22 255 (0.5 H,Or >300 65.78 65.64 4.99 4.81 14.61 14.61 256 300-305 71.69 71.39 5.21 5.22 16.72 16.75 257 305-307 70.82 70.71 4.36 4.36 19.43 19.50 258 280-281 61.58 61.86 5.29 5.44 18.36 18.12 259 >300 72.43 72.30 5.69 5.71 15.84 15.85 260 258-260 65.79 65.66 5.84 5.50 18.05 17.82 261 215-216 70.56 70.29 6.54 6.45 12.99 12.99 262 >300 70.82 70.76 4.19 4.78 19.43 19.29 263 300-304 73.09 72.79 6.13 6.06 15.04 14.98 264 (0.25 H,0)* 296-298 73.16 73.43 6.86 6.89 13.47 13.36 265 294-296 72.43 72.57 5.69 5.73 15.84 15.85 266 226-227 72.29 72.10 7.44 7.56 11.49 11.54 267 224-225 68.27 68.65 5.73 5.91 15.16 15.25 268 >300 66.26 65.96 3.51 3.64 16.27 16.25 269 278-280 70.82 71.07 4.19 4.35 19.43 19.53. 270 258-260 66.12 66.26 5.54 5.50 22.03 21.87 271 300-302 69.55 68.91 4.37 4.54 20.28 20.23 272 >300 64.16 64.20 3.77 3.94 14.96 14.69 273 245-247 72.43 72.34 5.69 5.72 15.83 15.78 274 286-288 72.73 72.14 5.69 5.91 15.83 15.60 275 (0.5 H,01* 230-232 69.44 69.89 4.85 4.84 17.99 18.10 276-282 ,3C and 'H NMR and analytical LC/MS data consistent with assigned structure 283 250(d) 63.59 63.42 4.62 5.00 14.83 14.83 284 267-269 64.63 64.58 5.08 5.29 14.13 14.14 285 280-282 75.99 76.11 5.31 5.32 12.66 12.65 286 220-222 71.19 71.16 6.87 6.85 12.45 12.46 287 237-240(d) 66.00 66.00 4.88 4.85 13.58 13.43 288 236-238 67.09 67.48 5.96 6.00 13.80 13.76 289 263-265 67.31 67.58 4.32 4.48 23.09 23.31 290 258-260 72.15 72.33 6.22 6.06 14.85 15.11 291 208-210 69.13 69.18 5.80 5.85 14.23 14.25 292 160-164(d) 68.55 68.25 5.75 5.86 19.98 19.71 293 330-332 62.38 62.37 5.23 5.31 12.84 12.87 294 245-247 68.67 68.86 6.44 6.21 14.13 14.14 295 238-239 65.16 65.31 6.11 6.10 13.41 13.46 296 218-219 67.09 66.65 4.82 4.99 16.12 16.10 297 252-253 53.58 53.80 3.30 3.51 16.66 16.67 298 192-193 74.29 74.26 5.98 5.85 15.27 15.38 299 246-247 63.73 63.51 5.10 5.32 22.88 22.54 WO 01/09121 PCT/US00/20628 -132- 300 271-272 68.67 68.59 4.61 5.04 j 12.01 11.81 301 194-196 66.90 66.94 5.61 5.72 15.60 15.62 302 271-272 65.75 66.02 4.14 4.34 19.17 19.00 303 201-203 70.28 70.02 7.44 7.41 13.29 13.17 304 >300 60.47 60.96 4.54 4.33 20.02 19.85 305 240-241 61.52 61.67 5.59 5.67 20.92 20.91 * The molecular weight calculated for the elemental analysis includes the solvent in the amount indicated. Footnote: Maleate salts were formed by the addition of an ethanolic solution of maleic acid to the 5 free base in ethanol at room temperature, followed by cooling, and filtration of the crystalline product. III. 4-[{Indol-2-yl)methylene]-2-pyrazolin-5-one (VII). Table 3: Compounds synthesized having structural formula VII. Example Substituent on Indole R' Recrystallization Solvent % Yield Method 306 none isopropoxy ethanol 81 see Example 210 307 none 4-hydroxy-phenylethyl ethanol 45 see Example 210 308 none 4-amino-phenylethyl NA 20 see Example 210 309 none 4-methoxy-carbonyl-phenylethyl toluene 75 see Example 210 310 none 4-carbamoyI-phenylethyl DMF: water 90 see Example 210 311 none cyclopropyl ethanol 35 see Example 210 WO 01/09121 PCT/US00/20628 -133- 312 3- dimethylamino methyl cyclopropyl NA 20 see Example 210 313 none 3-pyridyl ethanol 62 see Example 210 314 5-methoxy isopropoxy methanol 78 see Example 210 315 1-methyl isopropoxy DMF: water 89 see Example 210 316 none tetrahydrofura n-3-yl ethylacetate 30 see Example 210 317 5-methoxy cyclopropyl ethanol 33 see Example 210 318 5-nitro cyclopropyl DMF 84 see Example 210 319 none isopropyl amino methanol 80 see Example 210 320 none 4- carboxyphenyl ethyl DMF: water 65 see Example 210 321 none phenyl ethanol 55 see Example 210 322 3-methyl isopropoxy methanol 76 see Example 230 323 3-(2-methoxy carbonyl-2-acetamido ethyl) isopropoxy toluene: heptane 40 see Example 210 324 none ethoxy ethanol 55 see Example 210 325 3-(4-morpholino methyl) ethoxy ethanol 65 see Example 210 326 3-(4-morpholino methyl) cyclopropyl ethylacetate 46 see Example 210 327 5-methoxy pyrazinyl NA 91 see Example 210 WO 01/09121 PCT/US00/20628 -134- 328 5-methoxy 2-pyridyl NA 90 see Example 210 329 4-chloro-6,7-dihydro ethoxy ethanol ■ 54 see Example 210 330 4-chloro-6,7-dihydro pyrazinyl toluene 83 see Example 210 331 4-0X0-1,5,6,7-tetrahydro pyrazinyl toluene 40 see Example 210 332 3-dimethyl aminomethyl ethoxy toluene- heptane 41 see Example 210 Table3A: Physical data for compounds synthesized having structural formula VII. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 306 221-223 66.90 67.11 5.61 5.53 15.60 15.68 307 242-245 72.49 72.34 5.17 5.15 12.68 12.36 308 187-189 72.71 72.99 5.49 5.48 16.96 16.35 309 210-212 70.76 70.99 5.13 5.00 11.25 11.11 310 (0.25 H,0)* 263-265 69.44 69.51 5.09 5.05 15.43 15.21 311 (0.75 H,0)* 238-240 68.04 67.68 5.55 5.11 15.87 15.75 312 (0.25 H-,0)* 202(d) 69.10 69.13 6.60 6.46 17.91 17.56 313 fo.5 H,or 155-157 68.67 68.68 4.40 4.48 18.84 18.56 314 219-220 64.20 64.48 5.72 5.76 14.04 14.08 315 254-255 67.83 67.89 6.05 6.09 14.83 14.83 316 180-183 68.31 68.49 5.37 5.57 14.94 14.80 317 221-224 68.31 68.34 5.37 5.35 14.94 14.82 318 316-320 60.80 60.70 4.08 4.35 18.91 19.01 319 245-247 67.14 67.08 6.01 6.03 20.88 20.94 320 >300 70.18 69.87 4.77 4.87 11.69 11.76 321 210-211 75.25 75.17 4.56 4.75 14.62 14.62 322 241-243 67.83 ' 67.97 6.05 6.05 14.83 14.89 323 205-206 61.16 61.51 5.87 5.93 13.58 13.27 324 265-267 65.87 65.91 5.13 5.27 16.46 16.52 325 205-206 64.39 64.64 6.26 6.35 15.81 15.82 326 203-180 68.55 68.53 6.32 6.31 15.99 15.80 327 272-274 63.94 64.29 4.10 4.00 21.93 22.10 328 170-172 67.91 68.06 4.43 4.43 17.60 17.74 329 177-203 57.64 57.87 4.84 4.79 14.40 14.35 WO 01/09121 PCT/US00/20628 -135- 330 (0.4 toluene)* 206-209 62.27 62.20 4.22 4.47 19.31 19.27 331 (0.1 toluene)* 300-303 63.36 63.49 4.36 4.41 22.12 21.96 332 185-187 65.37 65.13 6.45 6.35 17.94 17.70 * The molecular weight calculated for the elemental analysis includes the solvent in the amount indicated. IV. 4-[(7-Azaindol-3-yl)methyJene]-2-pyrazolin-5-ones (VIII). 5 Table 4: Compounds synthesized having structural formula VHI. Example Substituent on azaindole R' Recrystallization Solvent % Yield Method 333 none benzyl DMF : water 71 see Example 210 334 1.(4- . hydroxy-butyl) benzyl ethyl acetate 30 see Example 210 335 none 4-methoxy-phenyloxymethyl DMF: water 80 see Example 210 336 none isopropoxy methanol 61 see Example 210 337 none amino DMF: water 92 see Example 210 338 none 4-methoxybenzyl DMF: water 96 see Example 210 339 none phenylamino DMF : water 77 see Example 210 340 none 4-methylbenzyl ethanol 95 see Example 210 341 none 4-hydroxy-phenylethyl ethanol 84 see Example 210 342 l-(4-hydroxy-butyl) 4-hydroxy-phenylethyl methanol 80 see Example 210 343 none isopropyl ethanol 30 see Example 210 344 none cyclopropyl ethanol 50 see Example 210 345 none cyclobutyl . ethanol 74 see Example 210 346 none 3-pyridyl ethanol 40 see Example 210 347 none phenyl NA 56 see Example 210 WO 01/09121 PCT/US00/20628 -136- 348 none 4-fluoro-phenylamino NA 14 see Example 210 349 none propyl NA 24 see Example 210 350 none methyl NA 77 see Example 210 351 none trifluoromethyl NA 17 see Example 210 352 none ten-butyl NA 80 see Example 210 353 l-(4-hydroxy-butyl) trifluoromethyl NA 6 see Example 210 354 none 4-isopropyl-phenylamino NA 30 see Example 210 355 none 3-methyl phenylamino NA 70 see Example 210 356 l-(4-hydroxy-butyl) 3-methyl-phenylamino NA 30 see Example 210 357 none phenylethyl DMF : water 63 see Example 210 Table 4A: Physical data for compounds synthesized having stractural formula VIII. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 333 274-277 71.50 71.63 4.66 4.88 18.53 18.17 334 176-179 70.56 70.67 5.92 5.87 14.96 14.78 335 300-302 65.69 65.62 4.35 4.85 16.12 15.77 336 258-260 62.21 61.57 5.22 5.12 20.72 20.57 337 (i H,or >300 53.82 53.92 4.48 4.34 28.54 28.22 338 273-276 68.66 68.05 4.85 4.89 16.85 16.67 339 (1 H,0)* 249-252 63.54 63.45 4.70 4.75 21.79 21.68 340 (0.5 H,0)* >300 70.07 70.54 5.22 5.07 17.21 17.24 341 270-272 68.66 68.25 4.85 5.04 16.86 16.71 342 211-212 68.30 67.97 5.98 6.11 13.85 13.80 343 300(d) 66.12 65.91 5.54 5.57 22.03 21.89 344 (0.25 H,0)» 245-246 65.48 65.20 4.90 4.76 21.82 21.47 345 300-302 66.52 66.51 5.39 5.22 20.69 20.88 346 212-215 66.50 65.84 3.83 4.07 24.20 23.93 347 280-282 70.80 70.50 4.20 4.10 19.40 19.10 348-356 ,3C and 'H NMR and analytical LC/MS data consistent with assigned structure 357 317-319 | 72.13 | 71.69 1 5.09 | 5.04 | 17.70 | 17.65 * The molecular weight calculated for the elemental analysis includes the solvent in the amount 5 indicated. Footnote: Maleate salts were formed by the addition of an ethanolic solution of maleic acid to the free base in ethanol at room temperature, followed by cooling, and filtration of the crystalline product. WO 01/09121 PCT/US00/20628 -137- V. 4- (Phenylmethylene)-2-pyrazolin-5-ones (IX). Example Substituent on Ring A R1 Recrystallization Solvent % Yield Method 358 4-dimethyI-amino benzyl ethanol 32 see Example 210 359 4-dimethyl-amino isopropoxy toluene: heptane 51 see Example 210 360 4-dimethyl-amino phenylethyl NA 45 see Example 210 361 4-dimethyl-amino cyclopropyl ethanol 77 see Example 210 10 Table 5A: Physical data for compounds synthesized having structural formula IX. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 358 253-255 74.73 74.20 6.27 6.13 13.75 13.34 359 197-198 65.91 66.33 7.01 6.86 15.37 15.27 360 224-225 75.20 75.08 6.62 6.56 13.15 13.19 361 280-289 70.56 70.33 6.71 6.80 16.46 16.20 15 VI. 4-[(Pyrazol-4-yl)methylene]-2-pyrazolin-5-ones (X). X. WO 01/09121 PCT/USQO/20628 -138- Table 6: Compounds synthesized having structural formula X. Example Substituent on Ring A R1 Recrystallization Solvent % Yield Method 362 3-methyl isopropoxy ethyl acetate 80 "see Example 210 363 3-methyl cyclopropyl toluene 51 see Example 210 Table 6A: Physical data for compounds synthesized having structural formula X. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 362 228-230 56.39 56.06 6.02 5.91 23.91 23.77 363 265-267 61.09 61.30 5.59 5.83 25.91 25.71 5 VII. 4-[(Imida2ol-2-yl)methyIene]-2-pyrazolin-5-ones (XI). 10 15 Table 7A: Physical data for compounds synthesized having structural formula XI. Example MP. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 364 212-214 54.53 54.96 5.49 4.61 25.43 25.67 365 264-266 59.39 59.52 4.98 . 5.00 27.71 27.37 20 25 Table 7: Compounds synthesized having structural formula XI. Example Substituent j on Ring A R1 Recrystallization Solvent % Yield Method 364 none 1 isopropoxy toluene 45 see Example 210 365 none | cyclopropyl ethanol 42 see Example 210 WO 01/09121 PCT/USOO/2Q628 -139- Vm. 4-[(Imidazol-4-yl)methylene]-2-pyrazolin-5-ones (XII) IX. XII. Table 8: Compound synthesized having structural formula XII. Example Substituent on Ring A R' Recrystallization Solvent % Yield Method 366 none isopropoxy ethanol 81 see Example 210 10 Table 8A: Physical data for compounds synthesized having structural formula XII. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 366 259-260 54.53 54.84 5.49 5.68 25.43 25.37 15 IX. 4-[(Thien-2-yl)methylene]-2-pyrazolin-5-ones (XIII). \ 20 XIII. 25 Table 9: Compound synthesized having structural formula XIII. Example Substituent on Ring A R1 Recrystallization Solvent % Yield Method 367 none cyclopropyl ethanol 20 see Example 210 WO 01/09121 PCT/US00/2Q628 -140- Table 9A: Physical data for compounds synthesized having structural formula xin. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 367 275-277 60.53 60.68 4.61 4.74 12.83 12.50 X. 4- [(Indol-3 -yl)methylene]-l -methyl-2-pyrazolin-5-ones (XIV). XIV. CH3 Table 10: Compound synthesized having structural formula XTV. Example Substituent on indole R1 Recrystallization Solvent % Yield Method 368 none isopropyl ethanol 54 see Example 210 Table 1 OA: Physical data for compounds synthesized having structural formula XIV. Example Mp. (°C) Elemental Analysis Carbon Hydrogen Nitrogen Calculated Found Calculated Found Calculated Found 368 241-242 71.88 71.73 6.41 6.47 15.72 15.71 WO 01/09121 PCT/USOO/20628 -141- XV. Table 11 : Compound synethesized laving structural formu la XV. Example Substituent on pyrrole R' Recrystallization Solvent % Yield Method 369 none isopropoxy methanol 70 see Example 210 Table 11 A: Physical data for compounds synthesized having structural formula XV. Example Mp., °C Elemental analysis Carbon Hydro gen Nitrogen Calculated Found Calculated Found Calculated Found 369 252-255 60.26 60.35 5.98 5.82 19.17 19.13 10 XII.. 4-[(Quinolin-5-yl)methylene]-2-pyrazoline-5-ones (XVI) XVI. WO 01/09121 PCT/USOO/20628 -142- Table 12. Compound synthesized laving structural formu a XVI. Example Subst. on quinoline R' Recrystallization Solvent % Yield Method 370 8-hydroxy isopropoxy methanol 40 see Example 210 Table 12A: Physical data for compounds synthesized having structural formula XVI. Example Mp., °C Elemental analysis Carbon Hydrogen Nitro? en Calculated Found Calculated Found Calculated Found 370 >300 64.64 64.43 5.09 5.01 14.13 13.98 5 X. Synthesis of Starting Materials. A. Synthesis of 3-ketoesters (XIX). The general method used to synthesize 3-ketoesters is shown in Scheme II. CH CH CI R1 O XV II. XVIII. 1. base 2. 3% H C1 3. anhydrous ethanol and heat H3CH 2C. 10 XIX. 15 Scheme II: Synthesis of 3-ketoesters WO 01/09121 PCT/US0O/2O628 -143- Example 371: Ethyl 3-(2,2,3,3-tetramethylcyclopropyl)-3-oxopropionate. Pyridine (5 g, 0.063 mol) and 2,2,3,3-tetramethylcyclopropyl carbonyl chloride (5 g, 0.031 mol) were added to an ice-cold solution of 2,2-dimethyl-l,3-dioxane-4,7-dione (4.7 g, 0.032 mol) in anhydrous dichloromethane (37 mL) under a 5 nitrogen atmosphere. The temperature was maintained at 0°C for 1 h, then was allowed to raise to room temperature overnight. The mixture was then transferred to a separatory funnel, washed twice with 3% hydrochloric acid and twice with water. The organic layer was dried over magnesium sulfate, then filtered and concentrated under reduced pressure to give 5 g of a dark red oil. The oil was refluxed for 3 h in 10 anhydrous ethanol (60 mL). The solvent was evaporated and the product was purified by distillation. Example 377: Ethyl 3-(6-methoxybenzothiazol-2-yl)-3-oxopropionate. Ethyl acetate (7.2 g, 0.082 mol) was added to sodium hydride (1.5 g of a 50 % dispersion in oil, 0.032 mol), keeping the temperature below 25°C. 2-15 Ethoxycarbony-2-(6-methoxy)benzothiazole (5.25 g, 0.022 mol) was added. The mixture was warmed to reflux gently and then stirred at room temperature overnight. The reaction was quenched with ice water (50 mL) and the pH was adjusted to 7.7 with concentrated hydrochloric acid. The product precipitated out and was collected by filtration, washed with water, then dried. 20 Example 378: Ethyl 4-(4-phenylphenyloxy)-3-oxobutanoate. Sodium hydride (5.0 g, 0.114 mole) and 4-phenylphenol (15.3 g, 0.09 mol) were stirred at 0°C in 75 mL of dimethyl formamide (hereinafter "DMF") for 2 h. Ethyl 4-chloroacetoacetate (5.0 g, 0.03 mol) in DMF (75 mL) was added. The mixture was stirred for 1 h at 0°C and for 12 h at room temperature, then neutralized 25 with 50 % phosphoric acid and extracted with dichloromethane. The product was purified by silica gel chromatography using (8 : 2) toluene : ethanol as the mobile phase. WO 01/09121 PCT/US00/20628 -144- Table 13: Compounds synthesized having structural formula XIX. Example R' % Yield b.p. rc) m.p. (°C) Method 371 2,2,3,3-tetramethyI-cyclopropyl 67 68 (0.2 mmHg NA see Example 371 372 2-methylcyclopropyl 50 62-4 (0.2 mmHg NA see Example 371 373 trans-2-phenyl-cyclopropyl 64 138-40 (0.2 mmHg NA see Example 371 374 tetrahydrofuian-3-yl 60 82-6 (0.2 mmHg NA see Example 371 375 3-methoxy-phenylmethyl 62 132 (0.2 mmHg) NA see Example 371 376 phenylethyl 55 110(0.2 mmHg NA see Example 371 377 6-methoxy-benxothiazol-2-yl 65 NA 160 see Example 377 378 4-phenylphenoxy-methyl 33 NA 83 see Example 378 379 3-chloro-phenoxymethyl 32 147 (8 mmHg) NA see Example 378 380 pyrazinyl 71 NA 82 see Example 377 B. Synthesis of Ethyl Cyclopentyloxythiocarbonylacetate. XX. XXI. XXII. 10 Scheme III: Synthesis of ethyl alkyloxy or aryloxy carbonimidoyl acetate hydrochloride (R9 is a substituted or unsubstituted aliphatic or aromatic group). 15 WO 01/09121 PCT/US00/20628 -145- Example 381: Synthesis of ethyl cyclopentyloxycarbonimidoyl acetate hydrochloride (XXII). A mixture of dry ethyl cyanoacetate (14 g, 0.12 mol) and dry cyclopentanol (12 g, 0.15 mol) was saturated at 0°C with hydrogen chloride gas for 3 hours, kept 5 at 0°C overnight, then diluted with diethylether. The product precipitated out and was collected by filtration and washed with ether. Yield 22.4 g, (77%) m.p. 110-112°C. 10 XXII. XXIV. Scheme IV: Synthesis of ethyl alkyloxythio or aryloxythio carbonylacetate. Example 382: Ethyl cyclopentyloxythiocarbonylacetate (XXIV) A mixture of ethyl cyclopentyloxycarbonimidoyl acetate hydrochloride (22 g 15 0.09 mol) in anhydrous pyridine (150 ml) is treated with hydrogen sulfide for 8 hours and kept at room temperature for 48 hours. The mixture reaction was acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ethereal phase was washed with water, dried and purified by distillation. Yield 15 g, (75%) b.p. 140-142°C (15 mm Hg). WO 01/09121 PCT/US0O/2O628 -146- C. Synthesis of 2-pyrazolin-5-ones. 2-Pyrazolin-5-ones were synthesized by the following four methods. h2n nh2 XXV. XXVI. 10 Scheme V: Method 1 for synthesizing 2-pyrazolin-5-ones. s 0 h2n—nh2 15 XXVII. or h xxvni. Scheme VI: Method 2 for synthesizing 2-pyrazolin-5-ones. hac, \ 20 hac h,c \ IS / O Et \ h2n—nh2 n ch3 XXIX. XXX. 25 Scheme VII: Method 3 for synthesizing 2-pyrazolin-5-ones. WO 01/09121 PCT/US00/20628 -147- nh2 HN Acetic acid 5 h XXXI. XXXII. Scheme VIII: Method 4 for synthesizing 2-pyrazoIin-5-ones. 10 Example 383: 3-(2,2,3,3-TetramethyIcyclopropyI)-2-pyrazolin-5-one. Hydrazine hydrate (1.1 g, 0.024 mol) was added to a solution of ethyl 3-(2,2,3,3-tetramethylcyclopropyl-3-oxopropionate (4.41 g, 0.020 mol) in anhydrous ethanol (60 ml). The reaction mixture refluxed for 3 h. After cooling, the solvent was evaporated, and the residue was triturated with hexane to give a white solid. 15 Example 411: 3-(4-Hydroxybenzyl)-2-pyrazolin-5-one A stirred suspension of 3-(4-methoxybenzyl)-2-pyrazolin-5-one 2.5 mmol in dichloromethane 100 ml cooled at -78°C, was treated with boron tribromide 7.5 ml (1M in dichloromethane). After 1 hour at -78°C the reaction mixture was stirred at room temperature for 12 hours. The mixture was quenched with water 50 ml. The 20 aqueous phase was separated out, and basified with 5% sodium bicarbonate solution. The formed precipitate was filtered and crystallized from methanol. Example 413: 3-(4-Carbamoylphenylethyl)-2-pyrazolin-5-one A mixture of 3-(4-methoxycarbonylphenylethyl)-2-pyrazolin-5-one (7.7 mmol) in ammonium hydroxide 25% (30 ml), was stirred at room temperature for 12 25 hours. The solvent was concentrated in vacuo and the solid product formed was filtered and dried. Example 414: 3-(2-Aminocarbonylethyl)-2-pyrazolin-5-one A mixture of 3-(ethoxycarbonylmethyl)-2-pyrazoIin-5-one (1 g, 5.8 mmol) . and NaCN (28 mg, 0.58 mmol) in 30 ml of 9M ammonia in MeOH was heated to WO 01/09121 PCT/US00/20628 -148- 45°C in sealed tube for 3 days. After cooling, the solvent was evaporated and the residue was suspended in water. The precipitated solid was collected by filtration. Example 416 : 3-(4-Methoxyphenylamino)-2-pyrazolin-5-one A mixture of 3-amino-2-pyrazolin-5-one (20 mmol), 4-methoxyaniline (25 5 mol) in 50 ml of acetic acid was refluxed for 4 hours. The solvent was evaporated, the residue was suspended in water. The solid was filtered and crystallized from methanol. Table 14: Compounds synthesized having structural formula XXVI. Example R1 % Yield M.p. (°C) Recrystallization Solvent Method 383 2,2,3,3-tetramethyl-cyclopropyl 44 195-7 NA see Example 383 384 ethoxycarbonylmethyl 44 115-6 toluene see Example 383 385 pyrrol-2-yl 30 205-8 NA see Example 383 386 indol-3-yl 69 250-3 ,NA see Example 383 387 6-methoxybenzothiazol-2-yl 40 269-70 NA see Example 383 388 2-methylcyclopropyl 70 196-7 water see Example 383 389 trans-2-phenyl-cyclopropyl 65 194-5 ethanol see Example 383 390 tetrahydrofiiran-3-yl 36 204-5 ethanol see Example 383 391 4-methoxybenzyl 73 192-5 NA see Example 383 392 4-methylbenzyl 80 212-4 ethanol: water see Example 383 393 4-chlorobenzyl 67 206-8 ethanol see Example 383 394 3-methoxybenzyl 72 163-5 NA see Example 383 395 3,4-dimethoxybenzy 1 69 193-5 NA see Example 383 WO 01/09121 PCT/USOO/20628 -149- 396 phenylethyl 72 204-7 NA see Example 383 397 2-phenylpropyl 72 215 NA see Example 383 398 3-phenylpropyl 76 200-1 ethanol see Example 383 399 4-methoxyphenylethyl 85 230 ethanol see Example 383 400 4-methylphenylethyl 90 251-2 NA see Example 383 401 4-chlorophenylethyl 63 243 NA see Example 383 402 4-nitrophenylethyl 69 247 DMF : water see Example 383 403 4-aminophenylethyl 61 220-2 NA see Example 383 404 4-methoxy-carbonylphenylethyl 77 259-60 ethanol see Example 383 405 4-phenylphenyloxy-methyl 50 250 ethanol see Example 383 406 4-methoxy-phenyloxymethyl 70 216-8 ethanol see Example 383 407 4-chloro-phenyloxymethyl 38 224-6 ethanol see Example 383 408 3-chloro-phenyloxymethyl 40 232-4 ethanol see Example 383 409 4- methylphenyloxymethyl 77 207-10 methanol see Example 383 410 cyclopentyloxy 75 180-1 toluene see Example 383 411 4-hydroxybenzyl 75 233 methanol see Example 411 412 4-hydroxyphenylethyl 70 205-6 water see Example 411 413 4-carbamoylphenylethyl 90 >270 DMF : water see Example 413 414 2-aminocarbonylethyl 66 193-6 NA see Example 414 415 2-dimethylamino-carbonylethyl 38 203-9 NA see Example 414 416 4-methoxyphenylamino 30 232-4 methanol see Example 416 WO 01/09121 PCT/US00/20628 -150- 417 4-chlorophenylamino 28 262-4 ethanol see Example 416 418 4-fluorophenylamino 35 259-60 NA see Example 416 419 cyclopropylamino 82 155-158 NA see Example 383 420 pyrazinyl 86 193(d) ethanol see Example 383 421 isopropylamino 20 123-25 ethanol see Example 383 422 2-pyrimidinyl 55 278-80 ethanol see Example 383 423 3-pyridazinyl 83 294-95 ethanol see Example 383 424 4-pyrimidiiiyl 72 290-300 ethanol see Example 383 425 4-pyrimidinyl 60 288-291 ethanol see Example 383 D. Synthesis of Aldehydes Example 426: l-(4-Acetoxybutyl)-azaindole-3-carboxaldehyde 5 A solution of 7-azaindole-3-carboxaldehyde (4.19 g, 28 mmol) in dry N,N dimehylformamide (50 ml) was added dropwise, keeping the temperature between 5-10°C, to a stirring suspension of 60% sodium hydride (oil dispersion) (1.2 g, 30 mmol) in dry DMF (65 ml) under nitrogen atmosphere. After addition was completed, stirring was continued at the same temperature for 30 min., then a 10 solution of 4-bromobutylacetate (6.16 g, 31 mmol) in dry N,N-dimethylformamide (15 ml) was added dropwise, and the mixture was allowed to warm to room temperature. The reaction mixture was stirred at room temperature for 137 h, then water (100 ml) was added, and the mixture extracted with dichloromethane (2 x 100 ml). The organic phase was washed with water (3 x 100 ml), dried over anhydrous 15 magnesium sulfate, filtered and the solvent removed under reduce pressure to give an oil (6.8 g, 93%) which was used without further purification. Example 427: l-(4-Hydroxybutyl)-7-azaindole-3-carboxaldehyde WO 01/09121 PCT/US00/20628 -151- A solution of sodium hydroxide (0.2 g, 17.5 mmol) in water (35 ml) was added to a solution of l-(4-acetoxybutyl)-7-azaindole-3-carboxaldehyde (2.3 g, 8.8 mmol) in methanol (40 ml). The mixture was heated at 60°C for 0.5 h, then the solvent was evaporated to dryness. The residue was dissolved in a mixture of ethyl 5 acetate and water (50 ml: 50 ml) and the water layer was separated out. The organic phase was washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was used without further purification. Yield 78%. m.p. 90°C. Example 428: l-(4-Hydroxybutyl)pyrrole-2-carboxaldehyde The product was obtained following the procedure in Example 51 except that 10 pyrrole-2-carboxaIdehyde was used instead of 7-azaindole-3-carboxaldehyde. The product was purified by silica gel chromatography using (5:5) ethyl acetate : hexane. Yield 67%. Example 429: 3-Isopropyl-5-methylpyrrole-2-carboxaldehyde To a solution of anhydrous DMF (2.1 ml, 27 mmol) in anhydrous 15 dichloroethane (50 ml) at 0°C under nitrogen, POCl3 (2.1 ml, 23 mmol) was added dropwise. The solution was allowed to warm at room temperature for lh. Then, the suspension was cooled at 0°C and a solution of 3-isopropyl-5-methylpyrrole (2g, 16 mmol) in dichloroethane (20 ml) was added dropwise over 20 min. After stirring at room temperature for 24 h, water followed by NaOH were added to pH:8. The 20 organic layer was extracted, dried and the solvent removed to dryness. The residue was purified by flash chromatography. Yield 67%, m.p. 90-93°C. Example 430: 3,5-Dimethyl-4-morpholinomethylpyrrole-2-carboxaldehyde 3,5-Dimethylpyrrole-2-carboxaldehyde (0.5g, 4 mmole) was added to a solution of morpholine (0.35 g, 4 mmol), formaldehyde 37% (0.32 g, 4 mmol) and 25 acetic acid (2ml). The mixture was stired overnight at room temperature under nitrogen, then the reaction was diluted with NaHC03 to pH 8. The aqueous solution was extracted with ethylacetate and the organic layer was dried over Mg S04. The ethylacetate was evaporated in vacuo to give 0.4 g of pure solid. WO 01/09121 ( PCT/US00/20628 -152- The following compounds were synthesized by a method analogous to the method described in Example 430: 3,5-Dimethyl-4-dimethylaminomethylpyrro]e-2-carboxaldehyde, 3-(4-morpholino)methyl-indole-2-carboxaldehyde, 5 3,5-dimethyl-4-diethylaminomethylpyiTole-2-carboxaldehyde, 3,5-dimethyl-4-piperidinomethylpyrro]e-2-carboxaldehyde, 3,5-dimethyl-4-[(4-methyl-l-piperazinyI)methyl]pyrrole-2-carboxaldehyde, 3,5-dimethyl-4-( 1 -pyrrolidinylmethyl)pyrrole-2-carboxaldehyde, 5-methyl-4-dimethylaminomethylpyrrole-2-carboxaldehyde, 10 3,5-dimethyl-4-p\T-methyl-N-(2-dimethylaminoethyl)aminomethyl]pyrrole-2-carboxaldehyde, 3,5-dimethyl-4-diethanolaminomethylpyrrole-2-carboxaldehyde, 4-(4-benzylpiperidinomethyl)-3,5-dimethylpyrrole-2-carboxaldehyde, 4-dimethylaminomethyl-3-isopropyl-5-methylpyrrole-2-carboxaldehyde, 15 3,5-dimethyl-4-(4-hydroxypiperidinomethyl) pyrrole-2-carboxaldehyde, and 3-dimethylaminomethyl-4,5-tetramethylenepyrrole-2-carboxaldehyde. Example 431: 3,5-Dimethyl-4-trifluoroacetamidomethylpyrrole-2-carboxaldehyde A mixture of 3,5-dimethylpyrrole-2-carboxaldehyde (2.6g, 0.02 mol) and N-(hydroxymethyl)trifluoroacetamide (3g, 0.02 mol) was added in portionwise to 20 sulfuric acid (15 ml) keeping the temperature below 10°C. The mixture of reaction was allowed to warm at room temperature for 4h. The reaction was poured into ice-water (100 ml), the precipitated solid was filtered and washed with water. The white solid (yield, 78%) was used without further purification. M.p. 200°C. Example 432: 4-Aminomethyl-3,5-dimethylpyrrole-2-carboxaldehyde 25 A mixture of 3,5-dimethyl-4-trifluoroacetamidomethylpyrrole-2- carboxaldehyde (3.9 g, 15.7 mmol), NaOH 10% (19 ml) and methanol (100 ml) was heated to reflux for lh. The solution was concentrated to half volume under reduced pressure. Water was added and the precipitated solid was filtered. Yield 72%, m.p. 210-20°C (d). WO 01/09121 PCT/US00/20628 -153- Example 433: 3-Acetyl-4-oxopentylacetate A mechanically stirred mixture of pentane-2,4-dione (60 g, 0.6 mol), 2-bromoethylacetate (100 g, 0.6 mol), anhydrous potassium carbonate (83 g, 0.6 mol), IK (99.6 g, 0.6 mol) and dry acetone (500 ml) was heated under reflux for 24 h. The 5 mixture was concentrated under reduced pressure and poured into hydrochloric acid (1.7 M, 400 ml). The product was isolated by successive extractions with ether, ethyl acetate and dichloromethane. The combined organic extracts were washed with brine, the solvent removed to dryness and the residue distilled to give 38 g of the acetate b.p. 75-80°C (0.1 mm Hg). 10 4-Acetyl-5-oxohexyl acetate [yield 60%, b.p. 110°C (0.2 mm Hg)], and 5- Acetyl-6-oxoheptyl acetate [yield 77%, b.p. 102°C (0.2 mmHg)] were prepared by the method described in Example 433. Example 434: tert-Butyl 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxylate A stirred solution of tert-butylacetoacetate (26 g, 0.165 mol) in acetic acid 15 (48 ml) was treated below 20°C by the dropwise addition of sodium nitrite (11.3 g, 0.165 mol) in water (17 ml) and left to stand overnight. A solution of 3-acetyl-4-oxopentylacetate (30 g, 0.161 mol) in acetic acid (56 ml) was heated to 80°C when a mixture of zinc dust (26.2 g, 0.40 mol), and sodium acetate (26.3 g, 0.32 mol) was added portionwise while the above hydroximino 20 derivative (97 ml, 0.165 mol) was added dropwise. The reaction mixture was stirred vigorously during the addition which was regulated so that zinc was always in excess and the temperature remained between 90-100°C. When the addition was complete the mixture was boiled gently for 15 min and stirred to room temperature overnight. The reaction mixture was poured into ice-water and allowed to stand over 25 2 hr. The solid was filtered and washed with water and recrystallized from aqueous ethanol. Yield 78%, m.p. 92°C. tert-Butyl 4-(3-acetoxypropyl)-3,5-dimethylpyrrole-2-carboxylate [yield 60%, m.p. 73°C (hexane)] and tert-Butyl 4-(4-acetoxybutyl)-3,5-dimethylpyrrole-2-carboxylate [yield 52%, m.p. 62°C (hexane)] were prepared by the method described 30 in Example 434. WO 01/09121 PCT/US00/20628 -154- Example 435: 3,5-Dimethyl-4-(2-hydroxyethyl)pyrrole-2-carboxaldehyde. tert-Butyl 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-oarboxylate (15 g, 53 mmol) was dissolved in TFA (40 ml) and the solution was stirred at 40°C under nitrogen for 10 min. The reaction mixture was then cooled to 0°C and 5 triethylorthoformate (9.6 ml, 58 mmol) was added dropwise. The mixture was allowed to warm up to 20°C and was stirred for lhr before being poured into ice water. This was extracted with dichloromethane and the extracts were washed successively with 10% aqueous ammonia and water and dried over MgS04. 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxaldehyde was purified by silica gel 10 chromatography using (7:3) ethyl acetate:hexane. Yield 45%, m.p. 125-27°C (water). To a solution of the above compound (5g, 23 mmol) in ethanol (20 ml), NaOH 10% (10 ml) was added. The mixture was stirred at room temperature for 30 min., and the final solution was concentrated, diluted with water and extracted with dichloromethane. The organic extracts were dried and the solvent was removed to 15 dryness. Yield 98%, m.p. 100°C (ethyl acetate). 3,5-Dimethyl-4-(3-hydroxypropyl)pyrrole-2-carboxaldehyde [yield 60%, m.p. 85°C (ethyl acetate/hexane)] and 3,5-Dimethyl-4-(4-hydroxybutyI)pyrrole-2-carboxaldehyde [yield 38%, m.p. 99°C (hexane)] were prepared by the method described in Example 435. 20 Example 436: 4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-carboxaldehyde. Methanesulfonyl chloride (4 ml, 51 mmol) in THF anhydrous (4 ml) was added to a stirred solution of 3,5-dimethyl-4-(2-hydroxyethyl)pyrrole-2-carboxaldehyde (4.3 g, 25.7 mmol) and triethylamine (5.2 g, 51 mmol) in THF anhydrous (60 ml) at 0-5°C and the mixture was stirred for 1 h at room temperature. 25 Water was then added to the mixture and the precipitated solid was filtered. Yield 89%, m.p. 142-44°C. A mixture of the above mesilate (23 mmol), K2C03 (23 mmol), diethylamine (90 mmol) and 2-propanol (70 ml) was heated to 100°C for 0.5 h. The solvent was removed to dryness and the residue treated with water and extracted with 30 methylenchloride. The organic extracts were dried and the solvent evaporated to dryness. Yield 70%, m.p.70°C (n-heptane). WO 01/09121 PCT/US00/20628 -155- 3,5-Dimethyl-4-[2-(l-pyrrolidinylethyl)]pyrrole-2-carboxaldehyde, 3,5-Dimethyl-4-(2-ethylaminoethy])pyrrole-2-carboxaldehyde, 4-(3-Diethylaminopropyl)-3,5-dimethylpyrrole-2-carboxaldehyde, 4-(4-Diethylaminobutyl)-3,5-dimethylpyrrole-2-carboxaldehyde, 3,5-Dimethyl-4-[3-(l-5 pyrrolidinylpropyl)]pyrrole-2-carboxaldehyde were isolated as oils and were prepared by a method analogous to the method described in Example 436. Example 437: 4-(2-Chloroacetyl)-3,5-dimethylpyrrole-2-carboxaldehyde Anhydrous aluminum chloride (42 g, 315 mmol) was added portionwise over 30 min to a room temperature solution of 3,5-dimethylpyrrol-2-carboxaldehyde (5 g, 10 40 mmol) in 1,2-dichloroethane (50 ml) under nitrogen. After stirring for 15 min, chloroacetyl chloride (17 g, 150 mmol) was added dropwise over lh. After addition was complete, the mixture was stirred at room temperature for 16 h. The mixture was poured onto crushed ice and the organic layer separated, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. Yield 57%, m.p. 15 205-09°C (toluene). Example 438: 3,5-Dimethyl-4-(2-diethylaminoacetyl)pyrrole-2-carboxaIdehyde Diethylamine (5 ml) was added to a solution of 4-(2-Chloroacetyl)-3,5-dimethylpyrrole-2-carboxaldehyde (1 g, 5 mmol) in THF (20 ml). The mixture was stirred at room temperature for 24 h. The solvent was removed under reduced 20 pressure and the residue was treated with water, NaHC03 (5%) and extracted with dichloromethane. After drying and filtering, the solvent was removed and the residue was used without further purification. 3,5-Dimethyl-4-(2-dimethylaminoacetyI)pyrrole-2-carboxaldehyde, 3,5-Dimethyl-4-[2-(l-pyrrolidinyl)acetyl]pyrrole-2-carboxaldehyde were synthesized by 25 a method analogous to the method described in Example 438. Example 439: 3,5-Dimethyl-4-ethoxyoxalylpyrrole-2-carboxaldehyde Anhydrous aluminum chloride (37 g, 277 mmol) was added portionwise over 30 min to a room temperature solution of 3,5-dimethylpyrrol-2-carboxaldehyde (7.6 g, 62 mmol) in 1,2-dichloroethane (140 ml) under nitrogen. After stirring for 30 min, 30 nitromethane (11.2 ml, 179 mmol) was added. The mixture was cooled at 0°C and ethyl chlorooxoacetate (12.8 g, 94 mmol) was added dropwise over lh. After </div>

Claims

<div class="application article clearfix printTableText" id="claims"> WO 01/09121 PCT/USOO/20628 -156- addition was complete, the mixture was stirred at room temperature for 4 h. The mixture was poured onto crushed ice and the organic layer separated, dried, and the evaporation afforded a white solid. Yield 45%, m.p. 125-127°C (toluene). All compounds of the foregoing Examples had NMR spectral data that were 5 consistent with the respective chemical structures. While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended 10 claims. -157- WHAT WE CLAIM IS: A use, in the manufacture of a medicament for inhibiting one or more protein kinase activities, of a compound represented by the formula: and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C$)cycloalkyI group, a heterocyclic group, an aralkyl group, a (C3-C<j)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; Rl is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cj-C^cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CH2)n-, -(CH2)ftNH-, -(CH2)bO-, -(CH2)nS-, -(CH2)nS(0)- or— (CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR4Rs, -ccojnr^5, r3o-, or a ring system selected from the group consisting of a (Ca-CcXycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxjdes thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and -NR4RS; 140979J.DOC -158- RJ for each occurrence is independently selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C(j)cycloalkyl-aJkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (CVC^cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent mdrpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1 -yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-Q)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cs-Qjcycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3, provided that the compound is not 3H-pyrazol-3-one, 2,4-_ dihydro-4-[[4-hydroxy-3,5-bis(l-methylethyl)phenyl]methylene]-5-methyl. 2. The use of claim 1 wherein the inhibition of said protein kinase is in a recipient in need thereof. 3. The use of Claim 2 wherein the compound is a mixture of stereoisomers. 4. The use of Claim 3 wherein the stereoisomers are enantiomers. 5. The use of Claim 3 wherein the stereoisomers are E and Z isomers. intellectual property office of n.z. 2 5 JUN 200V received -159- 6. The use of Claim 2 wherein the compound is a mixture of structural isomers. 7. The use of Claim 6 wherein the structural isomers are tautomers. 8. The use of Claim 2 wherein said protein kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase. 9. The use of Claim 8 wherein said tyrosine kinase is selected from the group consisting of kinase inset domain-containing receptor, fms-like tyrosine kinase-1, TIE-2, fibroblast growth factor receptor, platelet derived growth factor receptor, insulin-like growth factor-1 receptor, met proto-oncogene, lymphoid T-cell kinase, cellular homologue of Rous sarcoma virus oncoprotein, protein related to fgr and yes, present in hematopoietic tissue and brain, protein related to cellular homologue of Gardner-Rasheed sarcoma virus oncoprotein and cellular homologue of Yamaguchi 73 sarcoma virus oncoprotein, lymphoid B-cell kinase, and cellular homologue of Yamaguchi 73 sarfcoma virus oncoprotein. 10. Use for manufacturing a medicament for treating or essentially inhibiting inflammatory diseases in a recipient in need thereof of a compound represented by the formula: and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (Ca-C<s)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cj-CeXycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; INTELLECTUAL PROPERTY OFFICE OF N.Z. 1 2 MAR im >, i> n c i u e n -160- R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-Ce)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CH2V, —(CH2)nNH-, -(CH^nO-, —(CH^S-, -~<CH2)nS(0)- or -(CH2)nS(0)r; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR^R5, -C(0)NR4R5, R30-, or a ring system selected from the group consisting of a (C3-Q)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and -NR^R5; \ ■ R3 is selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (Cj-C^cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-Q)cycloaIkyl group, a heterocyclic group, an aralkyl group, a (Q-QOcycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and Rs together with the nitrogen to which they are attached represent morpholmo, pyrrolidino, pipeiidino, imidazol-l-yl, piperazino, thiamorpholino, azepino orperhydro-M-diazepm- l-yl groupseadroptionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-Cs)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C«)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3; provided that the compound is not di-phenyl-1,3 N-piperidino methylene-4-pyrazolone-5, phenyl-1 methyl-3 N-piperidino methylene-4 pyrazolone-5, phenyl-1 propyl-3-N-piperidino methylene-4 pyrazolone-5 or phenyl-1 methyl-3 N-morpholino methylene-4 pyrazolone-5. 180185 1.DOC INTELLECTUAL PROPERTY office of n.z. 2 5 JUN 20M received -161- A use, in the manufacture of a medicament for treating or inhibiting angiogenesis in a recipient in need thereof, of a compound represented by the formula: R ,R 0 N and physiologically acceptable salts thereof, wherein: r is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (c3-c6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (c3-Cfi)cycloalkyl group, a heterocyclic group, an aralkyl group, a (c3-Qs)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CHaV, -(CH2)nNH-, -{CI^O-, -(CH2)„S-, -(CH2)nS(0)- or-(CH2)nS(0)2-; z is -h, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, r3CO-, r30C(0>, -nr4r5, -ccconrV, r3o-, or a ring system selected from the group consisting of a (c3-Cc)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected INTELLECTUAL PROPERTY OFFICE OF N.Z. -162- from the group consisting of halogens, lower alkyl, R30-, HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -QCONR^5 and -NR^R5; R3 for each occurrence is each, independently is selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C<s)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C6)cycloalky] group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidine, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino orperhydro-I,4-diazepin-l-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (Q-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3. A use, in the manufacture of a medicament for inducing an anti-angiogenic effect in a recipient in need thereof, of a compound represented by the formula: and physiologically acceptable salts thereof, wherein: INTELLECTUAL property OFRCF OF N.Z. 2 0 JUL 200H -163- R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6>cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; ^ R2 is hydrogen or is selected from tHe group^consisting of arsubstkuted^or unsubstituted: lower alkyl group, an aromatic group, a (C3-C<;)cycloalkyl group, a heterocyclic group, an aralkyl group, a (c3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CHaV, -(CH2)nNH-, -(CH2)„0-, -(CH3)nS-, -(CH2)„S(0)- or -(CH2)„S(0)2-; z is -h, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, r3co-, r30C(0)-, -nr4r5, -qonr^5, r3o-, or a ring system selected from the group consisting of a (C3-Q)cycloalkyl, benzene, pyirole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionall/ substituted with one or more moieties seleaed from the group consisting of halogens, lower alkyl, r30-, ho-, hoc(o)-, r30c(0)-, trihalomethyl, nitro, aryl, -cn, -c(0)nr4r5 and -nr4r5; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (Cj-CdJcycloalkyI group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (Gj«C6)eyeloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyi-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally intellectual property OFFICE OF N.Z. 12 MAR 2004 -164- substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-aIkyl group and a heterocyclyl-alkyl group; and rr is an integer from 0 to 3. 20 13. A use in the manufacture of a medicament for treating or inhibiting the progression of a disease or condition in a recipient in need thereof, of a compound represented by the formula: and physiologically acceptable salts and biologically active 25 metabolites thereof, wherein: intellectual property office of n.z. 1 2 MAR 2004 WO 01/09121 PCT/US0O/2O628 -165- R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyI group and a heterocyclyl-alkyl group; 5 R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; 10 A is -(CH2)n-, -(CH2)nNH-, -(CH2)„0-, -(CH2)nS-, -(CH2)nS(0)- or - (CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR4R5, -C(0)NR4Rs, R30-, or a ring system selected from the group consisting of a (C3-C6)cycloalkyl, benzene, pyrrole, 15 isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, 20 HO-, HOC(O)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and - NR4RS; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a 25 heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a 30 heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to -166- which they are attached represent morpholino, pyrrolidine), piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino orperhydro-l,4-diazepin-1-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (Cj-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-aIkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3 where said disease or condition is selected from the group consisting of cancer, arthritis, atherosclerosis, restenosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, corneal disease, rubeosis, neovascular glaucoma, macular degeneration, wound healing, peptic ulcer, Helicobacter related diseases, virally induced angiogenic disorders, fractures, diabetic retinopathy, Crohn's disease, inflammatory bowel disorder, cat scratch fever, retinopathy or prematurity, ulcers, thyroid hyperplasia, burns, trauma, acute lung injury, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulatiori syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, sepsis, adult respiratory distress syndrome, multiple-organ dysfunction syndrome, ascites and tumor-associated effusions and edema. A use, in the manufacture of a medicament for affecting vascular hyperpenneability or the production of edema in a recipient in need thereof, of a compound represented by the formula: R N intellectual property office of n.z. 25 mm ocr.eiVEn WO 01/09121 PCT/us00/20628 -167- and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (C3-C6)cycloalkyI group, a heterocyclic group, an aralkyl group, a (C3-C6)cyc]oalky 1-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-Q)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Q)cycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is ~(CH2)n-, -(CKy&NH-, -(CH^O-, -(CH2)nS-, -(CH2)„S(0)- or-(CH2)nS(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NRV, -C(0)NR4R5, R30-, or a ring system selected from the group consisting of a (C3-Cfi)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, plyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxalinevpyrazole^oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, H0C(0)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR4R5 and -NR4RS; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C$)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: alower alkyl group, an aromatic group, a (C3-Q)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyl-alkyl -group and a heterocyclyl-alkyl group; intellectual property office of n.z. 1 2 MAR 2004 -168- optionally, Rd and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1 -yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an 5 aromatic group, a (C3-Q)cycloalkyI group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3. 15. The use of Claim 14, where the affect on the product of edema is antiedematous. 16. The use of Claim 2, wherein said protein kinase is a serine kinase. 17. The use of Claim 2, wherein said protein kinase is a threonine kinase. 18. A compound represented by the following structural formula; imidazole, 1,2,3-triazole, 1,2,4-triazole, benzimidazole, 4,5,6,7-tetrahydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrrole, pyrazole, oxazole and thiazole; h and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of substituted or unsubstitutedf indole, R1 is hydrogen or -A-Z; A is -(CH2)„-, -(CH2)JNH-, -(CH2)aO-, -(CH2)nS-, -(CH2)nS(0)- or - (CH2)„S(0)2-; intellectual property OFFICE OF N.Z. 12 MAR 2004 -169- Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, r30c(0)-, -nr<rs, -c(0)nr4r5, r3co-, r3o-, or a ring system selected from the group consisting of a CyCt cycloalkane, isoxazole, isothiazole, imidazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline. pyrazoIe.jsxazoIe.thiazole-andth&N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-, HO-, H0C(0)-, R3OC(0)-, trihalomethyl, nitro, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyl-alkyl group, a heterocyclyl-alkyl group, -CN, -C(0)NR4R5 or -NRV; R3 for each occurrence is, independently, selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C3-Ce)cycloalkyl group, heterocyclic group, aralkyl group, (C3-C$)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; R4 and R5 for each occurrence are each, independently, hydrogen, or are selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (C3-C6)cycloalkyl group, heterocyclic group, aralkyl group, (C3-Ctf)cycloalkyl-alkyl group, and heterocyclyl-alkyl group; ^ optionally, R4 and R5 together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted by one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group. a (C3-C6>cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3; provided that when R is an unsubstituted indol-3-yl then R1 is not -NH2; . and provided that the compound is not intellectual property office of n.z. 1 2 MAR 2004 -170- followed by page 170a 3H-pyrazol-3-one, 2,4-dihydro-4-[[4-hydroxy-3,5-bis(l-methylethyl)phenyl]methylene]-5-methyl.I p-0,N-CflH4-C oc2hs- °g oc3h6 OG og o n' h / s V.4n8v.ij ^ 1—F®h—i—if ^—r=H-ri N. A HO N' N O HO B H 0 H0 H 140979 1.DOC intellectual property office of n.z. 2 5 JUN 2004 ocrEiupn -170a- followed by page 170b C\1,(n> <^OC»H'(n) ^pOOC^fn) ocyyn) Y-r^-r-if V-r»-Y° hoY C^Hs(t) C.H9(t) COOCHj COOCHj Ti KCT? (f o ho n n o ho h COMMC.H4(n) CONHC«H,(n) M-W' XI D °ho B «/-ov h ^ ho' >j' NfCHJ, NfCHJ, NHCOCH,N NHCOCH. CH.CO. \ .Lt .'-V— vi —— >«v iNnouun "njvu I vO? W to? CH,CO ""S o HO M'" NHCONHCjH(v _ ,NHCONHC,Hs CNV . ,CN CONHC/t„(n) ccxtf vCXif {J 0 HO fj f{ "0 HO' h 0 HO H ,c0nhc,hu(n) NHCOCjH„(i), NHC0C,H„(i) £^_conh _c0nh Ij iT —o m"° W"n <f ch, 740979 l.DOC intellectual property office of n.z. 12 MAR 2004 received -170b- followed by page 171 HO OjN HO .or 20. 21. 22. 140979 1.DOC The compound of Claim 18 wherein: A is -NH-, -0-, -S-, -S(0)-or -S(0)2-; and Z is cyclopropyl, 3-pyridyl or pyrazinyl. The compound of Claim 18 wherein: A is -0-; and Z is ethyl, n-propyl or isopropyl. The compound of Claim 18 wherein: A is -CH2-; and Z is phenyl, wherein said phenyl is optionally substituted with one or more moieties selected from the group consisting of halogens, trihalomethyl, hydroxy, -NR4R5, nitro, -CONR4Rs, lower alkyl group, R30-, -C(0)0R4 and -0C(0)R4. The compound selected from the group consisting of: WO 01/09121 PCT/USOO/20628 -171- 3-Cyclopropyl-4-{[(3,5-dimethyl-4-(4-methy-l-piperazinylmethyl)pyrrol-2- yl]methylene} -2-pyrazolin-5 -one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-(l-pyrrolidinylmethylpyrTol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-Cyclopropyl-4-[(4-diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-10 pyrazolin-5-one, 3-Cyclopropyl-4- [(3 -dimethy laminomethy 1-4,5 -tetramethylenepyrrol-2- yl)methylene}-2-pyrazolin-5-one, 3- Cyclopropyl-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5 -one, 15 3- Cyclopropyl-4-[(3-diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene] -2-pyrazolin-5 -one, 3- Cyclopropyl-4-{[3-(4-methyl-1 -piperazinylmethyl)-4,5-tetramethylenepyrrol-2- yljmethylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-20 yl]methylene} -2-pyrazolin-5 -one, 3-Cyclopropyl-4-[(3-piperidinomethyI-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-2-pyrazolin-5-one, 25 3- Cyclopropyl-4-[(4-diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3- Cyclopropyl-4-(3,5-dibromo-4-hydroxybenzylidene)-2-pyrazoIin-5-one, 3- Cyclopropyl -4-[(4-oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5- one, 30 3- Cyclopropyl -4-[(4-dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 3 -Cyclopropyl-4- [(5 -trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-2-35 pyrazolin-5-one, 3-Cyclopropyl-4-[4-(2-dimethylaminoethylaminocarbonylpyrrol-2-yl)methyIene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-ethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[3-(2-dimethylaminoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-40 5-one, 3-Cyclopropyl-4-[3-(2-dimethyIaminoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 45 3-Cyclopropyl-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4a. o u> o k) n> o 3 o w -fc. 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B"SL i &3 ^ r xj B o °-3 a* ■a wa ^ o 4^ ^ 6 <d f ot 3 •S to 3 §• s fd i—^i t u> i /-*-y u> i vi 3-o- nj 1 t ¥ a a* v; §" 1 CD S* *< )—-» s &t3 a' £? y-s i m . " 3 O | r^- i" o ^ I—I 3 CD to cd | CD a C5 i to M t3* 3 CD a o u> » o 3 <1 s? "< CD c? a a1 *<_ § >3 ui i o n CD §- a § 4 •8 ! to I I s oi i u) t •s^ i k> 3" 0 3 8-| 1 vl i ^+- a> Et CD & s >3 to 3 & S CD, i w i r ia 3. o. ,<- i to n a 0 a p CD a' & 1 u § i- « 5 0 1 f i 4^ \h i p~+- CD et & cT a 1 to 3 & S CD ; I u> i IIj x) a. to b b- 3 g u, o o g S 3 CD -• 0 3 CD E? 1 on p-3' CD B *3 o oj 1 3 CD l i to i CD B M s CD oj xj oi '"w' i k) ^ U) XJ ^ 3 • 3-ui i f 1 X 8' Ui U) o ^ d ^ CD U 3 i U\ 3 o •3 §" I' § f to CD I § CD u> i ^3 a* v; i to XJ 8 o uj » o v< v<; ^ £l B | 3 CD 5 CD B o & Bid 3 • 3 CD CD •jj Oi ^ ^ S;^ B S B o O o 3' f 3' u. 3 ^ A ' oj 4i ui i i i o O I o o •-t o ■a v; to o 13 2 o o T3 v; ^ a o ■ xj B 3 o nj , u o w A &" B Z -•►2 3 XJ r «< y. t § ^ g w ch o S - § o a x ~ v; o §• o CD 0 1 o >5 a. I »—* i uj 3 & o x v; 0 1 0 3 v; ►5* 1 to "< CD S- 8-1 lj ou S 2^ e "<.-5 l¥^ §; r* to o ET^ B 9 ^ CD V- t CD w w a a << x — c& ~ ?•§ . y o V1 o xs x! g M ^ ^ ^ B >t3 p 3 M g 3 CD |-^3- lu l|s ' 7 ft ^ Ux" ' i o 3 CD 3 o >9 cj" o 3 o CD t 3 o o I. o 3 v; 3 p. o v to a »<[ S .CD. to o >-<; 3 xj 3 o •a 3* o • 8 CD B- o x v: 0 1 o 3*. 3 p. o to 3 I to xj B o o vc -j to n *3 c/2 o o o cn ki 00 WO 01/09121 PCT/US00/20628 -173- 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[4-(2-DimethyIaminoethylaminocarbonylpyrroI-2-yl)methylene]-3-(3-pyridyl)-2-5 pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaxninoethoxycarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-10 pyrazolin-5-one, 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 15 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]- 3-(3-pyridyl)- 2-pyrazolin-5-one, 20 4- {[3-(2-Acetamido-2-methoxycaibonylethyl)indol-2-yl]methylene} -3-(3 -pyridyl)-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 25 4-[(5-Chloro-4-methoxycarbonylmethyI-3-methoxycarbonylpyrrol-2-yl)methylene]- 3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3,5 -Dimethyl-4- {[(4-methyl-l -piperazinylmethyl)pyrrol-2-yl]methylene} -3-30 isopropoxy-2-pyrazolin-5-one, 4-[(3,5-DLmethyl-4-[(l-pyirolidinylmethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimetliyl-pyrrol-2-yl)methylene]-3-isopropoxy-2-pyra2olin-5-one, 35 4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3J5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-isopropoxy-2-40 pyrazolin-5-one, 3-Isopropoxy-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-f(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolm-5-one, 45 3-Is6propoxy-4-{[3-(4-methyl-l-piperazinyl)methy]-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, WO 01/09121 PCT/US0O/2O628 -174- 3-Isopropoxy-4- {[3-(l -pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 3-Isopropoxy 4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- -2-pyrazolin-5-one, 5 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-isopropoxy-2-, pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-isopropoxy-2-pyrazolin-5-one, 10 3-Isopropoxy-4-[(4-oxo-l ,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 15 4-[(5-Chloropyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin- 5-one, 20 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4- [(3 -Ethoxycarbony lindol-2-yl)methylene]-3 -isopropoxy-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 25 4-[3 -(2-Dimethylamino ethylaminocarbonylindol-2-yl)methy lene] -3 -isopropoxy- 2-pyrazolin-5-one, 3-Isopropoxy-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methyIene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-30 pyrazolin-5-one, 3-Isopropoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4- [3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene] -2-pyrazolin-5-one, 35 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-isopropoxy-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3- isopropoxy-2-pyrazolin- 5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-40 isopropoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morphoiinomethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4- {[(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3-ethoxy-2-pyrazolin-5-one, 45 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -175- 4-[(4-Diethylaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 5 4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene3-3-ethoxy-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- 2-10 pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyTTol-2-yl)methylene]-3-etlioxy-2-pyrazolin-5-one, 3-Ethoxy-4-{[3-(4-methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5 -one, 15 3-Ethoxy-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethyIenepyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-Ethoxy-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]- 2-pyrazoIin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-ethoxy-2-pyrazolin-5-20 one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-ethoxy-2-pyrazolin-5-one, 4- [(3,5 -Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene] -3 -ethoxy-2-pyrazolin-25 5-one, 3-Ethoxy-4-[(4-oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 30 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)raethylene]-3-ethoxy-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 35 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethy]aminocarbonylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[4-(4-morphoIinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 40 3-Ethoxy-4-[4-(4-morpholinoethylaminocarbonyIpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[(5-methoxyindol-2-yl)methylene]- 2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]raethylene} -3 -ethoxy -45 2-pyrazolin-5-one, 3-Ethoxy-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -176- 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-ethoxy-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-ethoxy-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)niethylene]-3-5 ethoxy -2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrroI-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazmyl-2-pyrazolin-5-one, 10 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 3-Pyrazmyl-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2-15 pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4}5,637-tetrahydroindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 20 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-(3J5-Dibromo-4-hydroxybenzylidene)-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 25 4-[(5-Chloropyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3-Pyrazinyl-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4- [(4-Ethoxycarbonylpyrrol-2 -y l)methylene] -3-pyrazinyl-2-pyrazolin-5 -one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-y])methylene]-3-pyrazinyl-2-pyrazolin- 5-one, 30 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)niethylene]-3-pyrazinyl-2-pyrazolin-5-one, 4- [(3 -Ethoxycarbonylindol-2-yl)methylene]-3 -pyrazinyl-2-pyrazolin-5 -one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 35 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-40 5-one, 4-[3-(4-Morpholiiioethoxycarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5 one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-pyrazinyI -2-pyrazolin-5-45 one, WO 01/09121 PCT/US00/20628 -177- 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3- pyrazinyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 5 3-Pyrazinyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-pyrazinyl -2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]- 3-pyrazinyl-2-pyrazolin-5-one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3 - pyrazinyl -2-pyrazoIin-5-one, 10 4- {[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene} -3- pyrazinyl -2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene] -3- pyrazinyl -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]- 3-pyrazinyl-2-pyrazolin-5-one, 15 4-[(4-Bromopyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(imidazol-2yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 4-[4-(2-DiraethylaminoethoxycarbonyIpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2- pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 25 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylarninoethylaminocarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-30 5-one, 3-(Imidazol-2-yl)-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 35 3-(Imidazol-2-yl)-4-[3-(4-morpholinoethy]aminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazo]in-5-one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl) -2-40 pyrazolin-5-one, 3-(Imidazol-2-yl) -4-[(5-methoxyindol-2-y])methylene]- 2-pyrazolin-5-one, 3-(Imidazol-2-yl) -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(imidazol-2-yl)-2-pyrazolin-5 -one, 45 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -178- 3-(Imidazol-2-yl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Imidazol-2-yl)-4-[(indoI-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)raethylene]-3-(imidazol-2-yl))- 2-pyrazolin-5-one, 5 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3- (imidazol-2-yl) 2-pyrazolin-5-one, 4- {[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene} -3-(imidazol-2-yl)-2-pyrazolin-5 one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yI)methylene]-3-10 (imidazol-2-yl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3- (imidazol-2-yl)-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(l-methyIcyclopropyl)-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 15 4-[(5-Chloropyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 3-(l-M6thylcyclopropyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 20 4- [4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3 -(1 -methylcyclopropyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(l- methylcyclopropyl)-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazoliii-5-25 one, 4- [3 -(2-Dimethylammoethoxycarbonylindol-2-yl)methylene]-3 -(1 - methylcyclopropyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 30 3-(l-Methylcyclopropyl)-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(l-Methylcyclopropyl)-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2- yl)methylene] -2-pyrazolin-5-one, 3-(l-Methylcyclopropyl)-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-35 2-pyrazolin-5-one, 3-(l-Methylcyclopropyl)-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene] -2-pyrazolin-5 -one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(l-methylcycIopropyl)-2-pyrazolin-5-one, 40 3-(1 -Methylcyclopropyl)-4- [(1 -methylindol-3-yl)methylene] -2-pyrazolin-5 -one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yI)methylene]-3-(l-methylcyclopropyl) -2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]-3-(l-methyIcyclopropyl)-2-pyrazolin-5-one, 3-(l-Methylcyclopropyl) -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-45 one, WO 01/09121 PCT/USOO/20628 -179- 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(l- methylcyclopropyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 5 4-[(Indol-3-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4- [(Pyrrol-2-yl)methylene]-3 -(1 -methyl cyclopropyl)-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(l-methylcyclopropyl))- 2-pyrazolin-5-one, 10 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-(l-methylcyclopropyl) -2-pyrazolin-5 -one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(l-methylcyclopropyl)-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-15 (1-methylcyclopropyl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyI-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(l- methylcyclopropyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 20 4-{[3,5-Dimethyl-4-(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(l -pyrrolidinylmethyl)pyrrol-2-yl]methylene} -3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-DiethyIaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-25 5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethanolaminomethy]-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 30 4-[(3-Pimethylaminomethyl-4,5-tetramethylenepyrroI-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3-Diethylaminoethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-furyl)-2-35 pyrazolin-5-one, 3-(2-Furyl)-4- {[3-(4-methyl-1 -piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-(2-Furyl)-4- {[3-(l -pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 40 3-(2-Furyl)-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-DimethyIamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-45 one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-furyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -180- 3-(2-Furyl)-4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]- 2-pyrazoIin-5-one, 3-(2-Furyl)-4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 4- [(4-Bromopyrrol-2-yl)methy lene] -3 -(2-furyl)-2-pyrazolin-5-one, 5 4- [(4-Chl oropyrrol-2-yl)methy lene] -3-(2-furyl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5- 10 one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(2-fuiyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethyiammoethoxycarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazolra-5-15 one, 4-[3-(2-Dimethylaminoetbylaminocarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-(2-Fnryl)-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Furyl)-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Furyl)-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 25 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 30 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5 -one, 4- {[3,5 -Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)niethylene]-3-(2- furyl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 35 3-(2-Furyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Furyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,4-DiethoxycarbonyIpyrrol-2-yl)methylene]-3-(3-(2-furyl))-2-pyrazolin-5-one, 4-{[3-(2-Acetaxnido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3- (2-furyl) -2- pyrazolin-5-one, 40 4- {[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene} -3-(2-furyl)-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3- (2-fiuyl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 45 4-[(3,5-Dimethyl-4-[(morpholinomethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazoIin-5-one, WO 01/09121 PCT/USQO/20628 -181- 4-[(3,5-Dimethyl-4-(4-methyl-l-piperazinyl)methylpyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methyIene]-3-(2-thienyl)-2-pyrazolin-5-one, 5 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethy]pyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5 one, 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-10 pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 15 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{[3-(l-Pyrrolidinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(2-thienyl)-2-20 pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(2-thienyl)-2-pyrazolin-5-one, 25 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methyIene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4-Oxo-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2- thienyl)-2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2- thienyl)-2-30 pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 3-(2-Thienyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 35 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin 5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 40 4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-on.e, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 45 4-[4-(4-Moipholinoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -182- 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 5 4- [3 -(4-MorpholinoethyIaxninocarbonylindol-2-y l)methylene] -3 -(2-thienyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[( 1 -Methylindol-3 -yl)methylene] -3 -(2-thi enyl)-2-pyrazolin-5 -one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-10 one, 4-[(5-Methoxyindol-2-yl)methy lene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4,5-Tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(2-thienyl) -2-pyrazolin-5-one, 15 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl]methylene}-3-(2-thienyl) -2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(Pyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(2-thienyl) -2-pyrazolin-5-one, 20 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3 -(2-thi enyl)-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4- [(5 -Ethoxy-4-methoxy carbonylmethyl-3 -methoxycarbonylpyrrol-2-yl)m ethylene] -3 -25 (2-thienyl) -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(2- thienyl)-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 30 4-[(5-Chloropyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 35 3-Cyclopropoxy-4-[4-(2-dimethylarninoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(3-ethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[3-(2-dimethylaminoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 40 3-Cyclopropoxy-4-[3-(2-dimethylaminoethylaminocaxbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[4-(4-morpholinoethylaminocarbonylpyirol-2-yl)methylene]-2-45 pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -183- 3-Cyclopropoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-Cyclopropoxy-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(5-methoxymdol-2-yl)methylene]-2-pyrazolin-5-one, 10 3-Cyclopropoxy-4- [(4,5-tetramethylenepyrrol-2-y l)methylene] -2-pyrazolin-5-one, 3-Cyclopropoxy-4-{[3,5-dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2- yl]methylene} -2-pyrazolin-5-one, 3-Cyclopropoxy-4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 15 3-Cyclopropoxy-4-[(indol-3-yl)methylene]-2-pyrazolin-5 -one, 3-Cyclopropoxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -Cyclopropoxy-4- [(Indol-2-yl)methylene] -2-pyrazolin-5 -one, 3-Cyclopropoxy-4-[(3,4-diethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-cyclopropoxy -2-20 pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-cyclopropoxy-2-pyrazolin-5-one, 3-Cyclopropoxy-4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 25 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-cyclopropoxy-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yI)methylene]-3-[2-(5-pyrimidmylethyl)]-2-pyrazolin-5-one, 30 3-[2-(5-pyrimidinylethyl)]-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-35 pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-[2-(5- pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 40 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-[2-(5- pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-45 2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -184- 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]- 3-[2-(5- pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 5 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] -2-pyrazolin- 5 -one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]- 3-[2-(5-pyrimidinyIethyl)] - 2-pyrazolin-5-one, 10 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]- 3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 3-[2-(5-pyrimidinylethyl)] -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 15 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)] -2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]- 3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 20 3-[2-(5-pyrimidinylethyl)]-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-[2-(5-25 pyrimidinylethyl)] -2-pyrazolin-5-one, 4-{[3-(2-Ammo-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5 -pyrimidinylethyl)] -2-pyrazo lin-5-one, 30 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4- [(4-Chloropyrrol-2-yl)methyl ene] -3 -(2-phenylethyl)-2-pyrazolin-5-one, 4-[(5-Chloropyrrol-2-yl)methylene3-3-(2-phenylethyl)-2-pyrazolin-5-one, 35 3-(2-phenylethyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-40 pyrazolin-5-one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]- 3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-45 pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -185- 4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)- 2-pyrazolin-5-one, 4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 5 4-[3-(4-MorpholinoethoxycarbonyIindol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]- 3-(2-phenylethyl)-2-pyrazolin-5-one, 10 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]- 3-(2-phenylethyl) -2-pyrazolin-5-one> 3-(2-phenylethyl) -4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(2-15 pheny!ethyl)-2-pyrazolin- 5 -one, 4-{[3,5-Dixnethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-(2- phenylethyl)-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one, 4- [ (3,4-Diethoxycarbonylpyrrol-2-yl)m ethylene] -3 -(2-phenylethyl)-2-pyrazolin- 5 -one, 20 4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene} -3-(2-phenylethyl)-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(2-phenylethyl)-2-pyrazolm-5-one, 4- [ (5 -Ethoxy-4-methoxycarbonyhnethyl-3 -methoxycarbonylpyrrol-2-yl)methylene] -3 -25 (2-phenylethyl)-2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]- 3- (2-phenylethyl)-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyi]-2-pyrazolin-5-one, 4-[(4-Chloropyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 30 4-[(5-Chloropyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl]-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 35 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-[2-(4- hydroxyphenyl)ethyl] -2-pyrazolin-5 -one, 4-[(3-Ethoxycarbonylindol-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-40 5-one, 4-[3-(2-DimethylammoethoxycarbonylindoI-2-yl)methylene]-3-[2-(4- hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 45 3-[2-(4-hydroxyphenyl)ethyl]-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -186- 3-[2-(4-hydroxyphenyl)ethyl]-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5 -one, 3-[2-(4-hydroxypheny])ethyl]-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-[2-(4-hydroxyphenyl)ethyl]-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 3-[2-(4-hydroxyphenyl)ethyl]-4-[(5-methoxyindol-2-yl)methylene]- 2-pyrazolin-5-one, 10 3-[2-(4-hydroxyphenyl)ethyl]-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin- 5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-[2-(4-hydroxyphenyI)ethyI]-2-pyrazolin-5-one, 4- {[3,5 -Dimethy l-4-(2-dimethylaminoethylaminocarbony l)pyrrol-2-yI)methylene] -3 - [2-15 (4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]- 3-[2-(4-hydroxyphenyl)ethyl]- 2-pyrazolin-5-one, 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 20 4- {[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yI)methylene] -3- [2-(4-hydroxyphenyl)ethyl] -2-pyrazolin-5-one, 4-[(5-Chloro-4-methoxycarbonyhnethyl-3-methoxycarbonylpyrrol-2-yl)methylene]- 3-25 [2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(4-bromopyrrol-2-yl)methylene] -2-pyrazolin-5-one, 3-[2-(4-aminophenyI)ethyl]-4-[(4-chloropyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-chloropyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-30 one, 3-[2-(4-aminophenyl)ethyl]-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-. one, 3-[2-(4-aminophenyl)ethyl]-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 35 3-[2-(4-aminophenyl)ethyl]-4-[4-(2-dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(3-ethoxycarbonylindol~2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[3-(2-dimethylaminoethoxycarbonylindol-2-40 yl)methylene]- 2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[3-(2-dimethylaminoethylaminocarbonylindol-2-yl)methyl ene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]- 4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 45 3-[2-(4-aminophenyl)ethyl]-4-[4-(4-morphoIinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -187- 3-[2-(4-aminophenyl)ethyl]-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]- 2-pyrazolin-5-one, 5 3-[2-(4-aminophenyl)ethyl]-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-{[3,5-dimethyl-4-(2-diraethylaminoethoxycarbonyl) pyrrol-2-yI]methylene}-2-pyrazolin-5-one, 10 3-[2-(4-aminophenyI)ethyl]-4- {[3,5-dimethyl-4-(2-dimethylaminoethylamino carbonyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(Indol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(3,4-diethoxycarbonyipyrrol-2-yl)methylene]-2-15 pyrazolin-5-one, 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-[2-(4-aminophenyl)ethyl]-2-pyrazolin-5-one, 4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(4-aminopheny])ethyl]-2-pyrazolin-5-one, 20 3-[2-(4-aminophenyl)ethyl]-4-[(5-ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-[2-(4-aminophenyl)ethyl]-4-[(5-chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-moipholinomethylpyiTol-2-yl)methylene]-3-(4-pyrimidinyl)-2-25 pyrazolin-5-one, 4-[(3,5-Dimethy 1-4- {[(4-methyl-1 -piperazmylmethyl)pyrrol-2-yl]methylene} -3-(4- pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 30 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-35 pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4- pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 40 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5 -one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(4- pyrimidinyl)-2-pyrazolin-5-one, 3-(4-Pyrimidinyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyTrol-2-45 yl]methylene}-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -188- 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2- pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(4-pyrimidinyl)pyrazolin-5-one, 5 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyriraidinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzyIidene)-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(4-pyrirnidmyl)-2-pyrazolin-5-one, 10 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(4-pyrimidmyl)-2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-y])methy]ene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4- {[(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(l-pyrroiidinylmethylpyixol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-diethylaminomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-20 pyrazolin-5-one, 4-[(3J5-Dimethyl-4-(piperidinomethylpyrrol-2-yI)methylene]-3-(5-pyrimidinyl)-2-pyrazoIin-5-one, 4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 25 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5.-pyrimidinyl)-30 2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4J5-tetramethylenepyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 3-(5-Pyrimidinyl)-4-{[3-(1-pyrrolidiny l)methyl-4,5-tetramethy lenepyrrol-2-y]]methylene} -2-pyrazolin-5-one, 35 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylamino-4,5,637-tetrahydroindol-2-yl)methylene] -3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-40 pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3J5-Dimethyl-4-dimethylaminomethylpyrrol-2-yI)methylene]-3-(5-pyriinidinyl)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 45 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -189- 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)niethylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4- {[(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 5 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5 -one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(piperidmomethylpyrrol-2-yI)methylene]-3-(2-pyrimidinyl)-2-10 pyrazolin-5-one, 4-[(4-Diethanolammomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 15 4-[(3-Morpholrnomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidmyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-1 -piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -3-20 (2-pyrimidinyl)-2-pyrazolin-5-one, 3-(2-Pyrimidinyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyiTol-2-yl]methylene} -2-pyrazolin-5 -one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin- 5-one, 25 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3r5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 30 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)niethylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2-pyrimidinyl)-2-p5T"azolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-35 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-{[(4-methyl-l-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 40 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethy]pyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-45 pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -190- 4- [(4-Diethanolaminomethyl-3,5 -dimethylpyrrol-2-yl)methylene] -3-(3 -pyridazinyl) 2-pyrazolin-5 -one, 4-[(3-Dimethylaminomethyl-4,5-tetramethyIenepyrrol-2-yl)methyIene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 5 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3- pyridazinyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-10 (3-pyridazinyl)-2-pyrazolin-5-one, 3-(3-Pyridazinyl)-4- {[3-( 1 -pyrrolidiny l)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl) 2-pyrazolin-5 -one, 15 4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(3-pyridazinyl)-2-pyrazolin-5-one, 20 4-[(3,5-Dimethyl-4-dimethylaminometliylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4- [(4-Dimethylaminomethyl-5-methylpyrrol-2-yl) methyl ene] -3 -(3 -pyridaziny l)-2-25 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4- [ (3,5-Dimethyl-4- {f (4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]m ethylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 30 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methyIene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-(piperidinomethylpyrTol-2-yl)methylene]-3-(4-pyridazinyl)-2-35 pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-(4- pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 40 4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4- pyridazinyl)-2-pyrazolin-5-one, 4-{[3-(4-Methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-45 (4-pyridazinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -191- 3-(4-Pyridazinyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} -2-pyrazolin-5-one, 4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5 -one, 5 4-[(4-Dimethylamino-435,6,7-tetrahydroindol-2-yI)raethylene] -3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(4-pyridazinyl)-2-pyrazolin-5-one, 10 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetrahydroindol-2-yl)methyIene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-15 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4- {[(4-methyl-1 -piperazinylmethyl)pyrrol-2-yl]methylene} -3 -(5-isoxazolyl)-2-pyrazolin-5-one, 20 4-[(3,5-Dimethyl-4-[(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-[(4-Diethanolaminomethyl-3,5-Dimethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-25 2-pyrazolin-5-one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 3 -(5 -Isoxazolyl)-4-[(3 -morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene] -2-pyrazolin-5-one, 30 4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 3-(5-Isoxazolyl)4-{[3-(4-methyl-l-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} —2-pyrazolin-5-one, 3-(5-isoxazolyl)-4-{[3-(l-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-35 yl]methylene}-2-pyrazolin-5-one, 3-(5-Isoxazolyl)-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-DimethyIamino-4,5,6,7-tetrahydroindol-2-yl)methylene] -3-(5-isoxazolyl)-2-pyrazolin-5-one, 40 4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-isoxazolyI)-2-pyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-tetraliydroindol-2-y])methylene]-3-(5-isoxazolyl)-2-pyrazoIin-5-one, 45 4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 4^ OJ U> IN? K> O O <-ri O ,— '--.oo ,, *o r^r) 7* T3 V XS ^ q-^ "3: T3 V s-'w o £• "• "oj ^ f-^i -j* *3 ^ ^ ~ g. £ o V"o ^ O o v, p> p T"1 *i 1 'II2OI2^2»{I^m» 0'*H-^ x .'. §. v* !L aF3 2. b c a E S | |j5 2 ?■ K §. K .fsS a g. n j|.§ o | |.^ o §• |S^S 8g" - s - S'W & g M 8 ^"^5" ? a § s . g> H C' (1) ■ i—► | s ' ^ » »» . Tag S^fll rav-c^ 3CSC £ H diit^ii 1 JvT^i »-'-,t^ O i H 1 i ,3 i M§ o S Lw2. k> to ^ ST* iET r+ ^ " £r* JL 3 ^ O • i 4^ I 3 I i i p '-< £Z» >—» >—* 5?* h-* 13 h. i^JaXJ *ri k gj.gf ^"3 g • 8*3 i. ■ ^ jl"* ^ i l4§lip|a|I fll llfl ll ifilv£•?!£! *M rs: V1 y*s \< cr s - 73 5 T3 ij " 1; R 1 s. 1 §*•-•« ^ s?5SB£^3 N> S* L sc1! ^ •-^>8^ i.-e p &&i1sb> ' f ||t r-- O gv 3 tS CB -\ i cz» Ct> i •" t-> 1 ^ ^ w 5 IeT y ^ — W&S3 tl §■•" 2 N Q WO 01/09121 PCT/US00/20628 -193- 4-(l-3-[(dimethylamino)methyl]-4,5,6,7-tetrahydro-l/f-2-indolylmethylidene)-3-(2- pyrazinyl)-4,5 -dihydro- IH-5 -pyrazolone, 4-(l-4-[(dimethylamino)methyl]-3,5-dimethyl-li/-2-pyrrolylmethylidene)-3-(5-methyl-3-isoxazolyl)-4,5-dihydro-l//-5-pyrazolone, 5 3-Cyclopropyl-4-[(4,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -B enzyl-4- [(pyrrol-2-yl)methylene] -2-pyrazolin-5 -one, 3-(4-Methoxyphenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Phenyloxymethyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenyloxymethyl)-4-[(pyrrol-2-yI)methylene]-2-pyrazolin-5-one, 10 3-(4-Methoxybenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Benzyl-4-{[4-(2-carboxyethyl)-3-methylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-Benzyl-4-{[3-(2-carboxyethyl)-4-methylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 15 3-(4-Methylphenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 2-Amino-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Phenylethyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Phenylamino-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-(4-Methylbenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methylphenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methoxyphenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -(4-Chlorobenzyl)-4- [(pyrrol-2-yl)methylene] -2-pyrazolin-5 -one, 3-(4-Chlorophenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 25 3-(3-Chlorophenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(Indol-3-yl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Methoxybenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3,4-Dimethoxybenzyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Methoxyphenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 30 3-(4-Phenylphenyloxymethy])-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Phenylpropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Phenylpropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-phenylethyl-2-pyrazolin-5-OTie, 35 3-(4-Methylphenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Nitrophenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Fluorophenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 40 3-(4-Chlorophenylethyl)-4-[(pyrrol-2-yl)methyIene]-2-pyrazolin-5-one, 4-[(4,5-Dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one, 4- {[ 1 -(4-Hydroxybutyl)pyrrol-2-yl]methylene} -3-isopropoxy-2-pyrazolin-5-one, 45 3-Cyclopentyloxy-4- [(pyrrol-2-yl)methylene] -2-pyrazoIin-5-one, 3-Tert-butylureido-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -194- 3-Isopropoxy-4-[(4-methylpyrrol-2-yI)methylene]-2-pyrazolin-5-one, 3 -(4- Aminopheny lethyl)-4- [(4-raethylpyrrol-2-yl)methylene] -2-pyrazolin-5 -one, 3-Isopropoxy-4-[(l-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 5 3-(4-AminophenyIethyl)-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[(5-methylpyrrol-2-yI)methylene]2-pyrazolin-5-one, 3-(4-Carbamoylphenylethyl)-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 10 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(4-methoxycarbonylphenylethyl- 2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-15 2-pyrazolin-5-one, 4-[(5-Ethylpyrrol-2-yl)methylene]-3-isopropoxy-2~pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one, 3-(Ethoxycarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 20 3-(4-Methoxyphenylaminocarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin- 5-one, 4- {(3-(2-Carboxyethyl)-4-methylpyrrol-2-yl]methylene} -3-i sopropyl-2-pyrazolin-5 -one, 3-Cyclopropyl-4-[(pyrrol-2-yl)methylene]-2-ppyrazolin-5-one, 25 3-Cyclobutyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Pyridil)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[[l-(3,5-dichlorophenyl)pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Pyrrol-2-yl)methylene]-3-(2,2,3,3-tetramethylcyclopropyl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 30 3-Cyclopentyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Methylcyclopropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-(Benzothiazol-2-yl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4,5-Dimethylpyrrol-2-yl)methylene]-4-(3-pyridyl)]-2-pyrazoIin-5-one, 3-Cyclopropyl-4[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 35 3-(Pyrrol-2-yl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3 -Cyclopropyl-4- [(4-methylpyrrol-2-yl)methylene] -2-pyrazolin-5 -one, 3-(Benzothiazol-2-y])-4-[(4-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5 -Dimethy lpyrrol-2-yl)methylene]-3-(3 -pyridyl)-2-pyrazolin-5-one, 4-[3,5-Dimetyl-4-ethylpyirol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 40 3-Cyclopropyl-4-[(5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(5-Methylpyrrol-2-yl)methylene]-3-(-3-pyridyl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-ethylpyrrol-2-yl)methyIene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 45 3-Isopropoxy-4-[(5-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Propyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -195- 3-Methyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Isopropylphenylamino)-4-[(pyrrol-2-yI)methylene]-2-pyrazolin-5-one, 3-(3-Phenylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5 -one, 3-Cyclopropyl-4-{[l-(4-hydroxybutyl)pyrrol-2-yl]methylene]-2-pyrazolin-5-one, 5 4- {[4-(2-Carboxyethyl)-3-methylpyrrol-2-yl]methyIene} -3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-10 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Acetyl-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimetylaminoethyloxycaibonyl)pyrrol-2-yl]methylene}-3-15 isopropoxy-2-pyrazolin-5-one, 4- {[3,5 -Dimethy l-4-(2-dimetylaminoethylaminocarbony l)pyrrol-2-yl]methylene} -3 -isopropoxy-2-pyrazolin-5-one, 4-[(5-Ethoxycarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(5-Carboxypyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 20 3-(4-Chlorophenylaminocarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one, 25 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 4-[(3,5-dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazoIin- 5-one, 3 -Cyclopropyl-4-[(3,5 -dim ethy 1-4-morpholinomethylpyrro l-2-yl)methylene] -2-30 pyrazolin-5-one, 4-[(3,4-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3-methylpyrrol-2-yl]methylene}-3-cyclopropyl-2-pyrazolin- 5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-2-35 pyrazolin-5-one, 3-Cyclopropyl-4-[(5-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(2-Methoxycarbonylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxycarbonyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 40 3 -Isopropyl-4- [(pyrrol-2-y l)methylene]-2-pyrazolin-5 -one, 3-(trans-2-phenylcyclopropyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclohexyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropylamino-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 45 3-Cyclopropyl-4-[(5-morpholinomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(5-Carboxypyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -196- 4-[(4-Chloropyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(4-Bromopyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4- [(5 -Chloropyrrol-2 -yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4[(4-Chloropyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 5 4-[(4-Bromopyrrol-2-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 3-Pyrazinyl-4-[(4J5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Pyridyl)-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3 -Cyclopropyl-4- {[3,5-dimethyl-4-(2-dimethylaminoethyloxycarbonyl)pyrrol-2- 10 yl]methyIene}-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4(2-dimethylaminoethyloxycarbonyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one maleate, 4-{[3,5-Dimethyl-4-(2-morpholinoethylaminocarbonyl)pyrrol-2-yl]methylene-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 20 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 4-[(3,5-dimethylpyrrol-2-yl)methyIene]-3-(2-furyl)-2-pyrazolin-5-one, 4-[(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-pyrazinyI-2-pyrazolin-5-one, 25 4-[(3,5-dimethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazoIin-5-one, 3-Cyclopropyl-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-trifluoroacetamidomethylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 3-Cyclopropyl-4-[(4-aminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-30 5-one, 3-(Benzothiazol-2-yl)-4-[(3,5-dimethylpyrrol-2-yI)methylene]-2-pyrazolin-5-one, 3-(Benzothiazol-2-yl)-4-[(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]- 2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyirol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 35 4-[(4-Ethoxycarbonylpyirol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Carboxypyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-diethanolaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2- pyrazolin-5-one, 4-[(3,5-Dimethyl-4-trifluoroacetamidomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-40 pyrazolin-5-one, 3-Cyclopropyl-4-[(4-ethoxycarbonyl-3-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(l-pyrrolidinylmethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -197- 4-[(3,5-Dimethyl-4-dimethylaminomethylpyiTol-2-yl)methylene]-3-(2-thieiiyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminornethylpyirol-2-yl)methy]ene]-3-(3-pyridyl)-2-pyrazolin-5-one, 5 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 4-[(3,4-Di(ethoxycarbonyl)pyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 3-Ethoxy-4-[(4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 10 4-[(3,5-Dimethyl-4-ethoxycarbonyIpyrrol-2-yl)methyIene]-3-(2-pyridylethyl)-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(l-methyl-2-phenylethyl)-2-pyrazolin-5-one, 4-[(4-Carboxy-355-dimethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 15 3-Ethoxy-4-[(5-nitropyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-[(4-nitropyrrol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(4-Carboxypyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene}-3-ethoxy-2-pyrazolin-5-one, 20 4-[(5-Chloro-3-methoxycarbonyl-4-methoxycarbonylmethylpyrrol-2-yI)methylene]- 3-ethoxy-2-pyrazolin-5-one, 4-{[3-(2-Carboxyethyl)-4-methylpyrrol-2-yl]methylene}-3-ethoxy-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-25 one, 3-Ethoxy-4-[(4,5-tetramethylenepynoI-2-yl)methylene]-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-trifluoromethyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-30 pyrazolin-5-one, 3-(3-Aminophenyl)-4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-{[2-(4-morpholinoethyl)aminocarbonylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 35 4-[(4-Ethoxycarbonyl-3-phenylpyirol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(4-Methyl-l-pyperazinyLmethyl)-3,5-diraethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-40 pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-pyTazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, 45 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -198- 4-[(5-Methyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3,5-Dimethyl-4-[N-(2-dimethylaminoethyl)-N-methylaminomethylpyrrol-2-yl} methylene} -3 -pyrazinyl-2-pyrazolin-5 -one, 5 3-Cyclopropyl-4-[(3-dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene] -2-pyrazolin-5 -one, 4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl- 2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3,5-dimethyl-4-dimethylaminomethylpyTrol-2-yl)methylene]-2-10 pyrazolin-5-one maleate, 4-{[4-(3-Chloropropionyl)-3,5-dimethylpyrrol-2-ylJmethylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethy]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(4-hydroxypiperidinomethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Aminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-20 one maleate, 4- {[4-(4-Benzylpiperidino)methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin- 5-one, 4-{[3,5-Dimethyl-4-(2-hydroxyethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4- { {3,5-Dimethyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-{{3,5-Dimethyl-4-[2-(l-pyrrolidinylethyl)]pyixoI-2-yl} methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3,5-Dimethyl-4-(2-hydroxyethyl)pyrrol-2-yl]methylene}-2-30 pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(3-Diethylaminopropyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4- {[3,5 -Dimethyl-4-(3-hydroxypropyl)p5rrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-[(3,5-Dimethyl-4-dimethylaminoacetylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazo!in-5-one hydrochloride, 4-[(3,5-Dimethyl-4-dimethylaminoacetylpyrrol-2-yl)methylene]-3-ethoxy-2-40 pyrazolin-5-one, 3-Cyclopropyl-4-{[(2-diethylaminoethyl)-3,5-dimethyl-4-pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-dimethylaminoethyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 45 4- {[3,5-Dimethyl-4-(4-hydroxybutyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazoIin-5-one, WO 01/09121 PCT/US00/20628 -199- 4-{[4-(4-Diethylaminobutyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl-N-oxide)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4-{[3,5-dimethyl-4-(l-pyrrolidinylacetyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Diethylammoacetyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-Isopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 10 4-{[3,5-Dimethyl-4-[3-(l-pyrrolidinylpropyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(Dimethylaminomethyl-3-isopropyl-5-methylpyrTol-2-yl)methylene]-3-pyrazinyl- 2-pyrazolin-5-one, 3-Cyclopropyl-4-[(dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-15 yl)methylene]-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethoxyoxalyl)pyrroI-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 3-Benzyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Benzyl-4- {[ 1 -(4-hydroxybutyl)indol-3 -yl]methylene} -2-pyrazolin-5 -one, 20 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenyloxymethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-phenyloxymethyl-2-pyrazoIin-5-one, 3-(4-Chlorophenyloxymethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxybenzyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methylphenyloxymethyl)-2-pyrazolin-5-one, 25 4-[(Indol-3-yl)rnethylene]-3-phenylethyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene] -3-(4-methylbenzyl)-2-pyrazolin-5-one, 4-[(Indol-3-yI)methylene]-3-phenylamino-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methylphenylamino)-2-pyrazolin-5-one, 30 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylamino)-2-pyrazolin-5-one, 3-(4-Chlorobenzyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-{[l-(4-hydroxybutyl)indol-3-yl]methylene}-3-(4-methoxybenzyl)-2-pyrazolin-5-one, 3-(4-Chlorophenylamino)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 35 4- [(Indol-3 -yl)methylene] -3 -(3 -methoxybenzyl)-2-pyrazolin-5-one, 3-(3,4-dimethoxybenzyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-hydroxybenzyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(3-Chlorophenyloxymethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(Indol-3-yI)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 40 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yI)methylene]-3-(4-phenylphenyloxymethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-phenylpropyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(3-phenylpropyl)-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 45 4-[(Indol-3-yl)methylene]-3-(4-methylphenylethyl)-2-pyrazolin-5-one, 3-Ethoxy-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -200- 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-isopropoxy-2-pyrazolin-5-one, 4- {[ 1 -(4-Hydroxybutyl)indol-3 -yljmethylene} -3-phenylethyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-nitrophenylethyl)-2-pyrazolin-5-one, 4- [(Indol-3 -yl)methylene]-3-propoxy-2-pyrazolin-5-one, 5 3-(4-Fluorophenylamino)4-[(indol-3-yl)methylene]- -2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(2-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-[(7-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4- [(7-Methylindo 1-3 -y l)methylene] -3-phenylethyl-2-pyrazolin-5 -one, 10 3-Cyclopentyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3 -Isopropoxy-4- [(1 -methylindol-3-yl)methylene] -2-pyrazolin-5 -one, 4-[(Indol-3-yl)methylene]-3-(4-methoxycarbonylphenylethyl)-2-pyrazolin-5-one, 3-Isopropoxy-4-[(l-isopropylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 15 3-Isopropyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenylaminocarbonylmethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxycarbonylmethyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylaminocarbonylmethyl)-2-pyrazolin-20 5-one, 3-Cyclopropyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 3-(2-Aminocarbonylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Cyclobutyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 25 3-(2-Dimethylaminocarbonylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4- {[ 1 -(4-hydroxybutyl)indol-3 -yl]methylene} -2-pyrazolin- 5-one, 4-[(Indol-3-yl)methylene]-3-(4-pyridyl)-2-pyrazolin-5-one, 3-Cyclopentyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2,2,3,3-tetramethylcyclopropyl)-2-pyrazolin-5-one, 30 4-[(Indol-3-yl)methylene]-3-(2-methylcyclopropyl)-2-pyrazolin-5-one, 3-Cyclohexyl-4-{[l-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one, 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-(4-pyridyl)-2-pyrazolin-5-one, 3-(Benzothiazol-2-yl)-4-[(indol-3-yl)methylene]-2-pyrazoIin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 35 3-Dimethylamino-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4- [(Indol-3 -yl)methylene] -3 -(pyrrol-2-yl)-2-pyrazolin-5 -one, 4-[(Indol-3-yl)methylene]-3-(6-methoxybenzothiazol-2-yl)-2-pyrazolin-5-one, 3 -Cyclopropyl-4- [(1 -methy lindo 1-3 -yl)methylene] -2-pyrazolin-5-one, 3 -Cyclopropyl-4- [(7-methylindol-3 -yl)methylene]-2-pyrazolin-5 -one, 40 4-[(l-Methylindol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-propyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-methyl-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-trifluoromethyl-2-pyrazolin-5-one, 4- {[ 1 -(4-Hydroxybutyl)indol-3-yl]methylene} -2-pyrazolin-5-one, 45 4- {[1 -(4-Hydroxybutyl)indol-3-yl]methylene} -3-methyl-2-pyrazolin-5-one, 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-trifluoromethyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -201- 4-{[l-(4-Hydroxybutyl)indol-3-yl]methylene}-3-(tert-butyl)-2-pyrazolin-5-one, 3-Ethoxycarbonyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(2-methoxycarbonylethyl)-2-pyrazolin-5-one, 4-[(Indol-3-yl)methylene]-3-(trans-2-phenyl-l-cycIopropyl)-2-pyrazolin-5-one, 5 3-Cyclobutyl-4- {[ 1 -(4-hydroxybutyl)indol-3-yl]methylene} -2-pyrazolin-5-one, 4-[(6-Carboxy-l-methylindol-3-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-methoxy-l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(l,7-dimethylindol-3-yl)methylene]-2-pyrazolin-5-one, 10 4-[(l-Methylindol-3-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one, 3-Cyclopropylamino-4-[(l-methylindol-3-y])methylene]-2-pyrazo]in-5-one, 4- [(6-Carboxy-1 -methylindol-3 -yl)methylene] -3 -isopropoxy-2-pyrazoIin-5-one, 4-[( 1,7-Dimethylindol-3 -yl)methylene]-3 -isopropoxy-2-pyrazolin-5 -one, 3-Isopropoxy-4-[(5-methoxy-l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 15 3-(4-FluorophenyIamino)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(l-MethyIindol-3-yl)methylene]-3-trifluoroacetamido-2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(l-methylindoI-3-yl)methyIene]-2-pyrazoIin-5-one, 3-Amino-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Chlorophenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one, 20 3-Ethoxy-4-[( 1 -methylindol-3 -yl)methylene]-2-pyrazolin-5 -one, 3-(5-Isoxazolyl)-4-[(l-methylindol-3-yl)methylene]-2-pyrazolin-5-one, 4-[(l-Methylindol-3-yl)methylene]-3-tert-butyl-2-pyrazolin-5-one, 4-[(6-Carboxy-1 -methylindol-3 -yl)methylene] -3 -pyrazinyl-2-pyrazolin-5-one, 4- {{1 -Methyl-6-[2-(4-morpholino)ethyl]aminocarbonylindol-3-yl}methylene} -3-25 pyrazinyl-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-Aminophenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3-(4-MethoxycarbonylphenylethyI)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 30 3-(4-Carbamoylphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3 -Cyclopropyl-4- [(indol-2-y l)methylene] -2-pyrazolin-5 -one, 3-Cyclopropyl-4-[(3-dimethylaminomethylindol-2-yl)methylene]-2-pyrazolin-5-one 4-[(Indol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 3-Isopropoxy-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazoiin-5-one, 35 3-Isopropoxy-4-[(l-methylindol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-(tetrahydrofdran-3-yl)-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(5-methoxyindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4- [(5 -nitroindol-2-yl)methylene] -2-pyrazolin-5 -one, 4- [(Indol-2-yl)methylene] -3 -isopropylamino-2-pyrazolin-5 -one, 40 3-(4-Carboxyphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 4-[(Indol-2-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 3-Isopropoxy-4-[(3-methylindol-2-yl)methylene]-2-pyrazolin-5-one, 3-Isopropoxy-4-{[3-(2-methoxycarbonyl-2-acetamidoethyl)indol-2-yl]methylene}- 2-pyrazolin-5-one, 45 3-Ethoxy-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one, 3-Ethoxy-4-{[3-(4-morpholinomethyl)indol-2-yl]methylene}-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -202- 3-Cyclopropyl-4-{[3-(4-morpholinomethyl)indol-2-yl]methylene}-2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(5-Methoxyindol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one, 5 4-[(4-Chloro-6,7-dihydroindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(4-Chloro-6,7-dihydroindol-2-yl)methylene]-3-pyrazinyl-2Tpyrazolin-5-one, 4-[(4-Oxo-l,5,6,7-dihydroindol-2-yl)methyIene]-3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-DimethylaininomethylindoI-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-benzyl-2-pyrazolin-5-one, 10 3-Benzyl-4-{[l-(4-hydroxybutyl)-7-azaindol-3-yl]methylene}-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-methoxyphenyloxymethyl)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Amino-4-[(7-azaindol-3-yl)methylene]-2-pyrazoIin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-methoxybenzyl)-2-pyrazolin-5-one, 15 4-[(7-Azaindol-3-yl)methylene]-3-phenylamino-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-methylbenzyl)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-hydroxyphenylethyl)-2-pyrazoIin-5-one, 4-{[l-(4-Hydroxybutyl)-7-azaindol-3-yl]methylene}-3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one, 20 4-[(7-Azaindol-3-yl)methylene]-3-isopropyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3 -yl)methylene]-3 -cyclopropyl-2-pyrazolin-5 -one, 4-[(7-Azaindol-3-yl)methylene]-3-cyclobutyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-phenyl-2-pyrazolin-5-one, 25 4-[(7-Azaindol-3-yl)methylene]-3-(4-fluorophenylamiiio)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-propyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-methyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-trifluoromethyl-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(tert-butyl)-2-pyrazolin-5-one, 30 4-{[l-(4-Hydroxybutyl)-7-azaindol-3-yl]methylene}-3-trifluoromethyl-2-pyrazolin- 5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(4-isopropylphenylammo)-2-pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-(3-methylphenylamino)-2-pyrazolin-5-one, 4-{[l-(4-Hydroxybutyl)-7-azaindol-3-yl]methylene}-3-(3-methylphenylamino)-2-35 pyrazolin-5-one, 4-[(7-Azaindol-3-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one, 3 -B enzyl-4- [(4-dimethylaminopheny l)methy lene] -2-pyrazolin-5 -one, 4-[(4-Dimethylaminophenyl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4- [(4-Dimethylaminophenyl)methylene] -3 -phenylethy l-2-pyrazolin-5 -one, 40 3-Cyclopropyl-4- [(4-dimethylaminopheny l)methylene]-2-pyrazolin- 5-one, 3-Isopropoxy-4-[(3-methylpyrazol-4-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(3-methylpyrazol-4-yl)methylene]-2-pyrazolin-5-one, 4-[(Imidazol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3 -Cyclopropyl-4-[(imidazol-2-yl)methylene]-2-pyrazolin-5 -one, 45 4-[(Imidazol-4-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(thien-2-yl)methylene]-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -203- 4[(Indol-3-yl)methylene]-3-isopropyl-l-methyl-2-pyrazolin-5-one, 3-Isopropoxy-4-[(pyrrol-3-yl)methylene]-2-pyrazoliii-5-one, 4-[(8-Hydroxyquinolin-5-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one, 4- {[4-(2-Diethy]aminoethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-(2-pyrimidinyl) 5 2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 10 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4- {[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-(4-pyrimidinyl) 2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl) 15 2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)- 2-pyrazolin-5-one, 3-Cyclop'ropyl-4-[(3,5-dimethyl-4-(l -pyrrolidinylmethylpyrrol-2-yl)raethylene]-2-pyrazolin-5-on.e, 20 3-Cyclopropyl-4-[(4-diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methy]ene]-2-pyrazolin-5-one, 3-CycIopropyl-4-{[4-(2-cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3,5-dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-2-25 pyrazolin-5-one, 3 -Cyclopropyl-4- {{3,5-dimethyl -4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl} methylene}-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-cyclopropyl-2-pyrazolin-5-one, 30 3-Cyclopropyl-4-[(4-diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[4-(l-pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yljmethylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4- { {3-isopropyl-5-methyl-4-[2-(1 -pyrrolidinylethyl)]pyrrol-2-35 yl} methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4- {[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -2-pyrazo lin- 5 -one, 3-Cyclopropyl-4- {{4-[3-(l -pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 40 3-Cyclopropyl-4-{[3-isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{{4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methyIene}-2-pyrazolin-5-one, 3-Cyclopropyl-4-{[4-(4-dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-45 yljmethylene} -2-pyrazolin-5 -one, WO 01/09121 PCT/US00/20628 -204- 3-Cyclopropyl-4-[(3-cyclopropyl-4-diethylaminomethyl-5-raethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclopropyl-4- {[3-cyclopropyl-4-( 1 -pirrolidinylmethyl)-5-methylpyirol-2-yl]methylene} -2-pyrazolin-5-one, 5 3-Cyclopropyl-4- { {3-cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl} methylene}-2 pyrazolin-5-one, 3-Cyclopropyl-4-{{3-cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one, 10 3-Cyclopropyl-4-{[3-cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yljmethylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-{{3-cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrro 1-2-yl} methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4-{[3-cyclopropyl-5-methyl-4-(3-phenyLmethylarnmopropyI)pyrroI-15 2-yl]methylene}-2-pyra2olin-5-one, 3-Cyclopropyl-4- {{3-cyclopropyl-5-methyl-4-[4-(l -pyrrolidinyl)butyl]pyirol-2-yl} methylene} -2-pyrazolin-5 -one, 3-Cyclopropyl-4-{[3-cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 20 4- {[4-(2-Cyclopropylaminoethyl)-3,5-dimethyIpyrrol-2-yl]methylene} -3-pyrazinyl- 2-pyrazolin- 5 -one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyI-2-pyrazoIin-5-one, 4- { {3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene} -3-25 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazoliri-5-one, 30 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-35 pyrazinyl-2-pyrazolin-5-one, 3-Pyrazinyl-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 40 3-Pyrazinyl-4- { {4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5 -one, 4- {[4-(4-Dimethylammobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-45 pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -205- 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-2-pyrazinyl-2-pyrazolin-5-one, 5 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {[3 -Cyclopropyl-5-methy l-4-(3 -phenylmethylaminopropyl)pyrrol-2-10 yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {3-Cyclopropyl-5-methyl-4-[4-(l -pyrrolidinyl)butyl]pyiTol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-( 1 -pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-fuxyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methyIene}-3-(2-furyl)-20 2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene} -3-(2-furyl)-2-pyrazolin-5-one, 25 4-{{3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(2-furyl)- 2-pyrazolin-5-one, 4- {[4-( 1 -Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yI]methylene} -3-(2-30 fuiyl)-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, 35 4- {[4-(2-Cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-(2-fiiryl)-2-pyrazolin-5-one, 3-(2-Furyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene}-2-pyrazolin-5-one, 3-(2-Furyl)-4- {[3 -isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene} -40 2-pyrazolin-5-one, 3-(2-Furyl)-4-{{4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene} -2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 45 4- [(3 -Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-fuiyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -206- 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene} -3 -(2-fiiryl)-2-pyrazoIin-5 -one, 5 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3-(2-fuiyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidiiiyl)propyl]-5-methylpyrrol-2-yl} methylene} -3 -(2-furyl)-2-pyrazolin-5 -one, 4- {[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-10 yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(2-furyl)-2-pyrazolin-5 -one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5 -one, 15 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrroI-2-yl)methylene]-3-(2- thienyl)-2-pyrazolin-5-one, 4- {[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-(2-20 thienyl)-2-pyrazolin-5-one, 4- {[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene} -3-(2- thienyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 25 4-{{3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(2-thienyl)-2-pyrazolin-5 -one, 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrroI-2-yl)methylene]-3-(2-30 thienyl)-2-pyrazolin-5-one, 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4- {{3-Isopropyl-5-methyl-4-[2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl} methylene} -3 -(2-thienyl)-2-pyrazolin-5-one, 35 4-{[4-(2-CycIopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazo lin-5 -one, 4-{{4-[3-(l-Pyrrolidmyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(2-thienyl)-2-pyrazolin-5 -one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(2-40 thienyl)-2-pyrazolin-5-one, 4-{{4-[3-(4-PyridylmethyIamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -3-(2- thienyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -207- 4-{{3-Cyclopropyl-5-methyl-4-[2-( 1-pyrrolidinyl)ethyl]pyrrol-2-yl} methylene}-3 -(2- thienyl)-2-pyrazolin-5-one, 4- {{3 -Cyclopropyl-4- [2-di(methoxyethyl)aminoethy 1] -5-methylpyrrol-2 -yl}methylene} -3-(2- thienyl)-2-pyrazolin-5-one, 5 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl} methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4- {[3 -Cyclopropyl-5-methyl-4-(3 -phenylmethylaminopropyl)pyiTol-2-10 yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(2- thienyl)-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-20 pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)- 2-pyrazolin-5-one, 25 4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-(2-Carboxy ethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3 -(4-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3 -isopropyl-5-methylpyrrol-2-yl)methylene]-3-(4-30 pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4- {{3 -Isopropyl-5-methyl-4- [2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl} methylene} -3 -(4-pyrimidinyl)-2-pyrazolin-5-one, 35 4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 3-(4-Pyrimidinyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrroI-2-yl}methylene} -2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(4-40 pyrimidinyl)-2-pyrazolin-5-one, 4-{{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-(4-Dimethylaminobutyl)-3-isopropyl-5 -methy lpyrrol-2-yl]methylene} -3-(4-pyrimidinyl)-2-pyrazolin-5-one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US0O/2O628 -208- 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyI]-5-methylpyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 5 4- {[3 -Cyclopropyl-4-(3 -diethylaminopropyl)-5 -methy lpyrrol-2-y l]methylene} -3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene} -3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-10 yl]methylene} -3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one, 4- {[3 -Cyclopropyl-5 -methy I-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methy lene} -3-(4-pyrirnidinyl)-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyirol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrTol-2-yl)methylene]-3-(5-pyrimidmyl)-2-pyrazolin-5-one, 4- {[4-(2-Cyclopropylaminoethyl)-3,5 -dimethylpyrrol-2-yl]methylene} -3-(5 -20 pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazo lin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)- 2-pyrazo lin- 5-one, 25 4-{ {3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazol in-5 -one, 4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3 -(5 -pyrimidinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(5-30 pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-( 1 -Pirrolidinylmethyl)-3 -isopropyl-5-methylpyrrol-2-yl]methylene} -3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4- {{3-Isopropyl-5-methyl-4-[2-( l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5 -one, 35 4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 3-(5-Pyrimidinyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(5-40 pyrimidinyl)-2-pyrazolin-5-one, 4-{{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -209- 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrroI-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 5 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidmyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-10 yl]methylene}-3-(5-pyrimidinyl)-2-pyraz;olin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one, 15 4- [(3,5 -Dimethy l-4-( 1 -pyrrolidinylmethylpyxrol-2-yl)methylene] -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- [(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3 -(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-20 pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-DimethyI-4-(2-ethylaininoetliyl)-pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethy])p}TTol-2-yl]methylene}-3-(2-pyrimidinyl)- 2-pyrazolin-5-one, 25 4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yI}methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, ■ 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methyIene]-3-(2-30 pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-( 1 -Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 35 4- {[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 3-(2-Pyrimidinyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyxrol-2-yl} methylene} -2-pyrazolin-5 -one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(2-40 pyrimidinyl)-2-pyrazolin-5-one, 4-{{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methyIene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- {[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3 -(2-pyrimidinyl)-2-pyrazolin-5-one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -210- 4- { {3-Cyclopropyl-5 -methy l-4-[2-( 1 -pyrrolidinyl)ethyl]pyrrol-2-yl} methylene} -3 -(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 5 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methyIene} -3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl}methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-10 yl]methylene}-3-(2-pyrimidinyl)-2-pyrazo]in-5-one, 4-{{3-Cyclopropyl-5-methyI-4-[4-(l-pyirolidinyl)butyl]pyrrol-2-yl}methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, 4- {[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene} -3 -(2-pyrimidinyl)-2-pyrazo'lin-5 -one, 15 4-[(3,5-Dimethyl-4-(l -pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3 -pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5 -one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(3-20 pyridazinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yI]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5 -one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(3-pyridazinyl)- 2-pyrazolin- 5 -one, 25 4- {{3,5-dimethyl-4-[2-(4-pyridylmethylammo)ethyl]pyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one,. 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(3-30 pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrro]-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 35 4- {[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene} -3-(3-pyrida2inyl)-2-pyrazolin-5-one, 3-(3-Pyridazinyl)-4-{{4-[3-(l-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(3-40 pyridazinyI)-2-pyrazolin-5-one, 4- {{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -3 -(3 -pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropy]-5-methylpyrrol-2-yl]methylene}-3-(3-pyridaziny I)-2-pyrazolin-5-one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -211- 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(3 -pyridazinyl)-2-pyrazolin-5-one, 4- { {3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene} -3-(3-pyridazinyl)-2-pyrazolin-5-one, 5 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4- { {3 -Cyclopropyl-4-[3 -(2,5-dimethyl-1 -pyrrolidinyl)propyl]-5-methylpyrrol-2-yl} methylene} -3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenyImethylaminopropyl)pyrrol-2-10 yl]methylene} -3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(3 -pyridazinyl)-2-pyrazolin-5 -one, 15 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4- [(4-Diethylaminomethyl-3,5 -dimethylpyrrol-2-yl)methylene]-3 -(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-20 pyridazinyl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5 -one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl) 2-pyrazolin-5-one, 25 4- {{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-30 pyridazinyl)-2-pyrazolin-5-one, 4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Isopropyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 35 4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4 pyridazinyl)-2-pyrazolin-5-one, 3-(4-Pyridazinyl)-4-{{4-[3-(l-pyirolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methy]-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(4-40 pyridazinyl)-2-pyrazolin-5-one, 4-{{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyridaziny l)-2-pyrazolin- 5 -one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -212- 4-{{3-Cyclopropyl-5-methyl-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene} -3-(4-pyridazinyl)-2-pyrazolin-5-one, 5 4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4- {{3-Cyclopropyl-4-[3-(2,5-dimethyl-1 -pyrrolidinyl)propyl]-5-methylpyrrol-2-yl} methylene} -3 -(4-pyridazinyl) -2-pyrazolin-5 -one, 4- {[3 -Cyclopropyl-5 -methy l-4-(3 -phenylmethylaminopropyl)pyrrol-2 -10 yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one, 15 4-[(3,5-Dimethyl-4-(l-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5 -one, 4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(l,2,4-20 triazin-3-yl)-2-pyrazolin-5-one, 4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)-pyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5 -one, 4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 25 4- {{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(l,2,4-30 triazin-3-yl)-2-pyrazolin-5-one, 4-{[4-(l-Pirrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{{ 3-Isopropyl-5-methyl-4-[2-( 1-pyrrolidinylethyl)]pyrrol-2-yl} methylene}-3-(1,2,4-triazin-3-yl)-2-pyrazolin-5-one, 35 4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{{4-[3-(l-PyiTolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(1,2,4-triazin-3 -yl)-2-pyrazolin-5-one, 4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(l,2,4-40 triazin-3-yl)-2-pyrazolin-5-one, 4-{{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yI}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4- {[4-(4-Dimethylaminobutyl)-3 -isopropyl-5 -methylpyrrol-2-yl]methylene } -3 -(1,2,4-triazin-3 -yl)-2-pyrazolin- 5 -one, 45 4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, WO 01/09121 PCT/US0O/2O628 -213- 4- { {3-Cyclopropyl-5-methyI-4-[2-(l-pyrrolidinyl)ethyl]pyrrol-2-yl} methylene} -3-(1,2,4-tri azin- 3 -y 1)-2-pyr azo lin-5-one, 4- { {3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 5 4- {[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene} -3-(1,2,4-triazin-3 -yl)-2-pyrazolm-5 -one, 4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-l-pyrrolidinyl)propyl]-5-methylpyrrol-2-yl} methylene} -3-(l ,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-10 yl]methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{{3-Cyclopropyl-5-methyl-4-[4-(l-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(l,2,4-triazin-3-yl)-2-pyrazolin-5-one, 4-{[3-Cyelopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(1,2,4-triazin-3 -yl)-2-pyrazolin-5 -one, 15 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(l-pyrrolidinylethyl)]-3-trifluoromethylpyrrol-2-yl}methylene}-3 -pyrazinyl-2-pyrazolin-5 -one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-20 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(4-pyridiylmethylaminoethyl)]-3-trifluoromethylpyrrol-2-yljmethylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-( 1 -Imidazoyl)ethyl]-5-methyl-3 -trifluoromethylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 25 4- {[4-(2-Aminoethyl)-5 -methyl-3 -trifluoromethylpyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazoIin-5-one, 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(l-pyrrolidinylethyl)]-3-tert-butylpyrrol-2-yl}methyIene}-3-30 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-4-[2-(4-pyridiylmethylaminoethyl)]-3-tert-butylpyrrol-2-y ljmethyl ene) -3 -pyraziny 1-2 -pyrazolin-5 -on e, 35 4- {{4-[2-(l -Imidazoyl)ethyI]-5-methyl-3-tert-butylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-tert-butylylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethy]aminoethyl)-3-ethyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-40 pyrazolin-5-one, 4-{{3-Ethyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Ethyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- { {3-Ethyl-5-methyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, WO 01/09121 PCT/US00/20628 -214- 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-ethylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyr azo 1 in-5 -one, 4- {[4-(2-Aminoethyl)-5-methyl-3 -ethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 5 4-{[3-Cyclobutyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{{3-CyclobutyI-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclobutyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-10 pyrazinyl-2-pyrazolin-5-one, 4- { {3 -Cyclobutyl-5-methyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-cyclobutylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4- {[4-(2-Aminoethyl)-5-methyl-3-cyclobutylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-CycIopentyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yI]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{{3-Cyclopentyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-20 pyrazinyl-2-pyrazolin-5-one, 4- {[3-Cyclopentyl-4-(2-ethylaminoethyI)-5-methylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopentyl-5-methyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-cyclopentylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-cyclopentylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one 4-{[3-Cyc]ohexyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-30 pyrazinyl-2-pyrazoIin-5-one, 4-{{3-Cyclohexyl-5-methyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazo Iin-5 -one, 4-{[3-CycIohexyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4- { {3-CyclohexyI-5-methyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-cyclohexylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-cyclohexylpyrrol-2-yl]methylene}-3-pyrazinyl-2-40 pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin- 5 -one, 4- {{5-Methyl-3-phenyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene} -3-pyraziny 1-2-pyrazolin- 5 -one, 45 4- {[4-(2-EthylaminoethyI)-5-methyl-3-phenylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -215- 4-{{5-Methyl-3-phenyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyI-3-phenylpyrroI-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- {[4-(2-Aminoethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene} -3-pyrazinyI-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-(4-methoxyphenyl)-4-[2-(l -pyrrolidinylethyl)]pyrrol-2-10 yl} methylene} -3 -pyrazinyI-2-pyrazolin-5 -one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3 pyrazinyl -2-pyrazolin-5 -one, 4-{{5-Methyl-3-(4-methoxyphenyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4- {{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene} -3-20 pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3-(2-pyridyl)-4-[2-(l -pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminoethyl)-5-methy 1-3 -(2-pyridyl)pyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 25 4- {{5-Methyl-3-(2-pyridyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl }methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4- {-{4- [2-(l -Imidazoyl)ethyl]-5-methyl-3-(2-pyridyl)pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-30 pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-pyrazinyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyI-2-pyrazolin-5-one, 4- {{5-Methyl-3 -pyrazinyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-pyrazinylpyrrol-2-yl}methylene}-3-40 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoetliyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 45 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5 -one, WO 01/09121 PCT/US00/20628 -216- 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- {{4-[2-( 1 -Imidazoyl)ethyl]-5-methyl-3-(2-imidazoyl)pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}- 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Diethylaminoethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene} -3-10 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2- pyrimidinyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl} methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminoethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 15 4- { {5-Methyl-3-(2- pyrimidinyl)-4-[2-(4-pyridiylmethylammoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl}methylene}-3 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-20 yljmethylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazo 1 in-5 -one, 4-{{5-Methyl-3-(3-isoxazolyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3 pyrazinyl-2-pyrazolin-5-one, 25 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(3-isoxazolyl)-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)ethyl]-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl}methylene}-3-30 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene} 3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{{5-Methyl-3-(2-furyl)-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl 2-pyrazolin-5-one, 4- { {5-Methyl-3-(2-furyl)-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-40 yl} methylene} -3 -pyrazinyl-2-pyrazolin- 5 -one, 4- { {4- [2-(l -Imidazoyl)ethyl]-5-methyl-3-(2-furyl)pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {[4-(2-Diethylaminoethyl)-5 -hydroxymethyl-3-isopropylpyrrol-2-yl]methylene} - 3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -217- 4- {{5-Hydroxymethyl-3-isopropyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yI]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 5 4- {{5-Hydroxymethyl-3-isopropyl-4-[2-(4-pyridiylmethylaminoethyl)]pyrrol-2-yI}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-( 1 -Imidazoyl)ethyl]-5 -hydro xymethyl-3-isopropylpyrro 1-2-yl} methylene} -3 -pyraziny l-2-pyrazolin-5 -one, 4-{[4-(2-Cyclopropylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-10 yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl- 2-pyrazolin-5-one, 4-{{3,5-Dicyclopropyl-4-[2-(l-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 15 4- {[4-(2-EthyIaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- { { 3,5-Dicyclopropyl-4- [2-(4-pyridiylmethylamino ethyl)]pyrrol-2-yl} methylene} - 3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-( 1 -Imidazoyl)ethyl]-3,5-dicyclopropylpyrrol-2-yl}methylene}-3-pyrazinyl 20 2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3 pyrazinyl-2-pyrazolin-5-one, 25 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene} 3'pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(l-pyrrolidinylmethyl)]-3-trifluoromethylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-30 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-4-[2-(4-pyridiylmethylaminomethyl)]-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { (4-[2-(l -Imidazoyl)methyl]-5-methyl-3-trifluoromethylpyrrol-2-yl}methylene}- 3-pyraziny l-2-pyrazolin-5-one, 35 4- {[4-(2-Aminomethyl)-5-methyl-3 -trifluoromethylpyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Dimethylaminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene} -3-40 pyrazinyl-2-pyrazolin-5-one, 4-{ {5-Methyl-4-[2-(l-pyrrolidinylmethyl)]-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- { { 5 -Methyl-4- [2-(4-pyridiylmethylaminomethyl)] ^-3 -tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/US00/20628 -218- 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-tert-butylylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- {[4-(2-Diethylaminomethyl)-3-ethyl-5-methylpyrrol-2-yl]rnethylene} -3-pyrazinyl 2-pyrazolin-5-one, 4-{[4-(2-Dimethy]aminomethyl)-3-ethyl-5-methylpyTrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{3 -Ethy]-5-methyl-4-[2-( 1 -pyrrolidinylmethyl)]pyrrol-2-yl} methylene} -3 -10 pyrazinyl-2-pyrazolin-5-one, 4- {[3 -Ethyl-4-(2-ethylaminomethyl)- 5 -methylpyrrol-2-yl]methylene} -3 -pyrazinyl-2 pyrazolin-5-one, 4- { {3-Ethyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl]methylene} ■ 3-pyrazinyl-2-pyrazolin-5-one, 15 4- {{4-[2-(l -Imidazoyl)methyl]-5-methyl-3-ethylpyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazoIin-5-one, ' 4-{[4-(2-Aminomethyl)-5-methyl-3-ethyIpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclobutyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-20 pyrazinyI-2-pyrazolin-5-one, 4-{[3-Cyclobutyl-4-(2-dimethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 4-{{3-Cyclobutyl-5-methyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4-{[3-Cyclobutyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclobutyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yljmethylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-cyclobutylpyrrol-2-yl}methylene}-3-30 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-cyclobutylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-CyclopentyI-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{[3-Cyclopentyl-4-(2-dimethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclopentyl-5-methyl-4-[2-(l-pyrrolidinyImethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopentyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-40 pyrazinyl-2-pyrazolin-5-one, 4- {{3 -Cyclopentyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{4-[2-(l -Imidazoyl)methyl]-5-methyl-3-cyclopentylpyrrol-2-yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 45 4-{[4-(2-Aminomethyl)-5-methyl-3-cyclopentylpyrrol-2-yl]methylene}-3-pyrazinyl 2-pyrazolin-5-one WO 01/09121 PCT/US00/20628 -219- 4-{[3-Cyclohexyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin- 5 -one, 4-{[3-Cyclohexyl-4-(2-dimethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4-{{3-Cyclohexyl-5-methyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclohexyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3-Cyclohexyl-5-methyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-10 yl}methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-cyclohexylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-cyclohexylpyrrol-2-yl]methyIene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3-phenyl-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl} methylene} -3-20 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-phenyI-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one, 25 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-phenylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-30 yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene } -3 -pyrazinyl-2-pyrazolin-5 -one, 4- { {5-Methyl-3 -(4-methoxypheny l)-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(4-methoxyphenyI)pyrrol-2-yl]methylene}-3 -pyrazinyl-2 -pyrazolin-5-one, 4-{{5-Methyl-3-(4-methoxyphenyl)-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl} methylene} -3 -pyrazinyl-2-pyrazolin-5 -one, 4- {{4-[2-( 1 -Imidazoyl)methyI]-5-methyl-3-(4-methoxyphenyl)pyrrol-2-40 yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Aminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-pyridyI)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5 -one, WO 01/09121 PCT/US00/20628 -220- 4- {{5-MethyI-3-(2-pyridyl)-4-[2-(l -pyrrolidinylmethyl)]pyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 5 4- { {5-Methyl-3-(2-pyridyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(2-pyridyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Aminomethyl)-5-methyl-3 -(2-pyridyl)pyrrol-2-yl]methylene} -3-pyrazinyl 10 2-pyrazolin-5-one, 4- {[4-(2-Diethylaminomethy l)-5-methyl-3 -pyrazinylpyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-pyrazinylpyirol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4-{{5-Methyl-3-pyrazinyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-pyrazinyl-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-20 yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-( 1 -Imidazoyl)methyl]-5-methyl-3-pyrazinylpyrrol-2-yl}methylene} -3-pyraziny l-2-pyrazolin-5 -one, 4-{[4-(2-Cyclopropylaminomethyl)-5-methyI-3-pyrazinylpyrrol-2-yl]methylene}-3 pyrazinyl-2-pyrazolin-5-one, 25 4- {[4-(2-Diethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}- 3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene} 30 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminomethyl)-5-methyl-3 -(2-imidazoyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(2-imidazoyl)pyrrol-2-yl}methylene}-3 pyrazinyl-2-pyrazoliii-5-one, 4- {[4-(2-Cyclopropylaminomethyl)-5-methyl-3 -(2-imidazoyl)pyrrol-2-yl]methylene} -3 -pyrazinyl-2-pyra2olin-5-one, 4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene}-40 3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Dimethylaminomethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {5-Methyl-3-(2- pyrimidinyl)-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {[4-(2-Ethylaminomethyl)-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5-one, WO 01/09121 PCT/USOO/20628 -221- 4- {{5-Methyl-3-(2- pyrimidinyl)-4-[2-(4-pyridiylmethylaminomethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-(l -Imidazoyl)methyl]-5-methyl-3-(2- pyrimidinyl)pyrrol-2-yl}methylene} 3-pyrazinyl-2-pyrazolin-5 -one, 5 4- {[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2- yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminoethyl)-5-methyl-3-(3-isoxazoly])pyrrol-2-yl]methylene}-3- 10 pyrazinyl-2-pyrazolin-5-one, 4-{{5-Methyl-3-(3-isoxazolyI)-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene} 3 -pyrazinyl-2-pyrazolin- 5 -one, 4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 15 4- { {5-Methyl-3-(3-isoxazolyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl}methylene}-3 pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyelopropylammomethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-20 yl]methylene} -3 -pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Diethylaminomethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene} -3-pyrazinyl-2-pyrazolin-5 -one, 4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5 -one, 25 4-{{5-Methyl-3-(2-furyl)-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {[4-(2-Ethylaminomethyl)-5 -methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4- {{5-Methyl-3-(2-fiiryl)-4- [2-(4-pyridiylmethylaminomethyl)]pyrrol-2-30 yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{4-[2-(l-Imidazoyl)methyl]-5-methyl-3-(2-furyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(2-furyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 35 4-{[4-(2-Diethylaminomethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{5-Hydroxymethyl-3-isopropyl-4-[2-(l-pyrrolidinylmethyl)]pyrrol-2-40 yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Ethylaminomethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3 -pyrazinyl-2-pyrazolin-5 -one, 4-{{5-Hydroxymethyl-3-isopropyl-4-[2-(4-pyridiylmethylaminomethyI)]pyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one, 45 4- {{4-[2-(l-Imidazoyl)methyl]-5-hydroxymethyl-3-isopropylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one, -222- 4-{[4-(2-Cyclopropylaminomethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-ylJmethylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Diethylaminomethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(2-Dimethylaminomethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{{3,5-Dicyclopropyl-4-[2-(l-pyrrolidinylmethyl)]pyrroI-2-yl}methylene}-3-pyrazinyl-2=pyrazolin-5ione5 4- {[4-(2-Ethylaminomethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene} -3-pyrazinyl-10 2-pyr azolin-5 -one, 4-{ {3,5-Dicyclopropyl-4-[2-(4-pyridiylmethylaniinomethyl)]pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- { {4-[2-( 1 -Imidazoyl)methyl]-3,5-dicyclopropylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 15 4-[(4-Cyclopropylaminomethyl-3,5-dicyclopropylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopropylaminomethyl-5-methyl-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-Cyclopropylaminomethyl-5-methyl-4-(2-hydroxyethyl)pyrrol-2-20 yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, 4-{[3-dimethylaxninomethyl-5-methyl-4-(2-diethylaminoethyI)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one, and 4-{[3-hydroxymethyl-5-methyl-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one. 25 30 35 ' 23T The compoimd of Claim l £ wherein the compound is a mixture of stereoisomers. 24: The compound of Claim 23 wherein the stereoisomers are enantiomers. 25. The compound of Claim 24 wherein the stereoisomers iare E and Z isomers. 26. The compound of Claim 18wherein the compound is a mixture of structural isomers. 27The compoimd of Claim 26 wherein the structural isomers are tautomers. 28. A use of a compound of claim 18 in the manufacture of a medicament for inhibiting one or more protein kinase activities. INTELLECTUAL PROPERTY OFFICE OF N.Z. 12 MAR 2004 -223- 29. A use of a compound of claim 18 in the manufacture of a medicament for treating a recipient in need of having one or more protein kinases inhibited. 5 30. The use of Claim 29 wherein the compound is a mixture of stereoisomers. 31. The use J of Claim 30 wherein the stereoisomers are enantiomers. 10 32. The use of Claim 30 wherein the stereoisomers are E and Z isomers. 33. The use of Claim .29 wherein the compound is a mixture of structural isomers. 15 34. The use of Claim 29 wherein the structural isomers are tautomers. 35. The use of Claim 29 wherein said protein kinase is a tyrosine kinase. 36. The use according to Claim 35 wherein said tyrosine kinase is selected 20 from the group consisting of KDR, Flt-1, TIE-2, Lck, Src, fyn, Lyn, Blk, and yes. 37. A use of a compound of claim 18 in the manufacture of a medicament for affecting hyperproliferative disorders in a recipient. 25 38. Auseof a compound of claim 18 in the manufactureof a medicament for affecting angiogenesis in a recipient. 39 r a pharmaceutical composition comprising a compound of Claim 18 and a 30 pharmaceutically acceptable carrier or diluent. intellectual property office of n.z. 25 mm RECEIVED WO 01/09121 PCT/USOO/20628 -224- 40. A pharmaceutical composition comprising a compound of Claim 22 and a pharmaceutically acceptable carrier or diluent. 41V A compound according to Claim 18 wherein R is substituted with one or 5 more substituents, each independently selected from the group consisting of halogens, lower alkyl groups, R30-, hydroxy, H0C(0)-, R30C(0)-, R30C(0)R6-, R3OR6-, trihalomethyl, trihalomethylcarbonyl, nitro, -C(0)NR4R5, -NR4R5, R3CO-, -(CH2)n-R7, -C(0)(CH2)„-R7, -C(0)-(CH2)n-C(0)-R7, -OCCH^R7, -C(0)NR4(CH2)nR7, -CCOOCCH^R7, -10 0C(O)(CH2)nR7,-NR4C(O)(CH2)nR7,-R6NR4R5,-R6N(R4)-R6-R7,-R6N(R6- R7)2)-R6C(0)NR4(CH2)nR7,-R6C(0)0(CH2)nR7, -R^CCOXCH,)^7, -R6NR4C(0)(CH2)nR7, -R6CH(C(0)0R4)(NR5C(0)R4), an optionally substituted aryl and an optionally substituted aralkyl group; wherein the optionally substituted aryl and optionally substituted 15 aralkyl groups are optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, -NR4RS, nitro, -CONR.4R5, lower alkyl group, R30-, -C(0)0R4 and -OC(0)R3; R6 is a lower alkyl group or an aryl group; and R7 is alkoxy, haloalkyl, lower alkyl piperazine, hydroxy, R30-, 20 R3C(0)- or -NR4RS. 42. A compound of Claim At, wherein R is pyrrolyl, indolyl, azaindolyl, pyrazolyl, imidazolyl, 4,5,6,7-tetrahydroindolyl, or quinolinyl. 25 43. A compound of Claim 42/wherein R is pyrrol-2-yl, pyrrol-3-yl, indol-2-yl, indol-3-yl, azaindol-3-yl, pyrazol-4-yl, imidazol-2-yl, imidazol-4-yl, or quinolin-5-yl. 1-7 < 44. A compound of Claim J.S or 43, wherein R1 is trifluoromethyl, amino, 30 cyclopropylamino, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2- methylcyclopropyl, 2,2,3,3-tetramethylcyclopropyl, 2-phenylcyclopropyl, intellectual property office of n.z. 2 5 JUN 2004 ftlCEIVID -225- cyclobutyl, cyclopentyl, cyclohexyl, -(CH^p-O-phenyl, -(CH2)p-0-(4-methoxyphenyl), -(CH2)p-0-(4-chlorophenyl), -(CH2)p-0-(4-methylphenyl), -(CH2)p-0<3-methylphenyl), -(CH2)p-0-(4-phenylphenyl), -(CH2)p-0-(4-hydroxyphenyl), -(CH2)p-0-(4-nitrophenyl), -(CH2)p-0-(4-aminophenyl), -(CH2)p-0-(4-carbamoylphenyl)) -<CH2)p-0-(4-methoxycarbonylphenyl), -NH-phenyl, -NH-(4-methoxyphenyl), -NH-(4-chlorophenLyl), -NH-(4-fluorophenyl), -NH-(4-isopropylphenyl), isopropoxy, ethoxy, cyclopentyloxy, -(CH^p-indolyl, -(CH^p-pyridyl, -(CH^p-benzothiazoiyi, -(CH^p-pyrrolyl, -(CH2)p-tetrahydrofuryl, -(CRJp-pyrazinyl, -(CH2)p-furyl, -(CH2)p-thienyl, -(CH2)p-phenyl, -(CH2)p-isoxazolyl, -(CH^"^-methylisoxazolyl), -(CH^p-pyrimidinyl, -(CHj)p-pyridazinyl, -(CH2)n-C(0)-OMe, -(CH^-CCO-OEt and benzyl optionally substituted with one or more of CI, F, OMe, methyl or amino where p is an integer from 1 to 3. A compound of Claim 44, wherein R is optionally substituted with one or more moieties selected from the group consisting of Br, CI, F, aminomethyl, N,N-dimethyIaminomethyl, carboyxl, carboxymethyl, carboxyethyl, carbonylmethyl, carbonylethyl, methoxycaibonyl, ethoxycaibonyl, phenyl, 4-morpholinomethyl, -C(0)-0-(CH2)2-N-<Me)2, -C(0)-0-(CH2)2-N(Et)2, -C(0)-0-CH2-N(Me)2, -C(0)-NH-(CH2)2-N(Me)2, -CH2-NH-C(0)-CF3 and an optionally substituted moiety selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and phenyl, wherein said optionally substituted moiety is optionally substituted with one or more of Br, CI, F, hydroxy, nitro, amino or Ci-Q alkyl. Use for manufacturing a medicament for treating or essentially inhibiting hyperproliferative disorders in a recipient in need thereof of a compound represented by the formula: intellectual property office of n.z. 1 2 MAR 2004 -226- R R O \ n n and physiologically acceptable salts thereof, wherein: R is selected from the group consisting of a substituted or unsubstituted: aliphatic group, aromatic group, a (Ca-C^cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Ce)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R1 is hydrogen or -A-Z; R2 is hydrogen or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, an aromatic group, a (C3-C6)cycloa]kyl group, a heterocyclic group, an aralkyl group, a (C3-C6)eycloalkyl-alkyl group, and a heterocyclyl-alkyl group; A is -(CKbV, -"(CH2)»NH-t -(CH2)nO-, -(CH2)„S-, -(CH2)„S(0)- or-(CH2)„S(0)2-; Z is -H, a lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R3CO-, R30C(0)-, -NR^R5, -C^NR^5, R30-, or a ring system selected from the group consisting of a (C3-Q)cycloalkyl, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, triazine, imidazole, furan, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and the N-oxides thereof wherein said ring system can be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R30-,H0-, H0C(0)-, R30C(0)-, trihalomethyl, nitro, aryl, -CN, -C(0)NR,tRs and -NR^5; R3 is seleaed from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a intellectual property office of n.z. RECEIVED 1.DOC -227- heterocyclic group, an aralkyl group, a (C3-C6)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; R* and Rs for each occurrence axe each, independently, hydrogen or are selected from the group consisting of substituted or unsubstituted: a lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-Q)cycloalkyl-alkyl group and a heterocyclyl-alkyl group; optionally, R4 and R5 together with the nitrogen to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-l-yl, piperazino, thiamorpholino, azepino or perhydro-l,4-diazepin-l-yl groups each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3-C6>cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and n is an integer from 0 to 3. 47. Use as defined in claim 1 substantially as herein described with refea-ence to any example thereof. 48. Use as defined in claim 10 substantially as herein described with reference to any example thereof. 49. Use as defined in claim 11 substantially as herein described with reference to any example thereof. 50. Use as defined in claim 12 or claim 13 substantially as herein described with reference to any example thereof. 51. Use as defined in claim 14 substantially as herein described with reference to any example thereof. 52. A compound as defined in claim 18 substantially as herein described with reference to any example thereof. 140979 I.DOC intellectual property office of n.z. 1Z MAR 2004 -228- 53. A compound as claimed in claim 22 substantially as herein described with reference to any example thereof. 54. A use as defined in claim 22 substantially as herein described with reference to any example thereof. A use as claimed in claim 37 or claim 38 substantially as herein described with reference to any example thereof. A pharmaceutical composition as claimed in claim 39 or claim 40 substantially as herein described with reference to any example thereof. Use as claimed in claim 46 substantially as herein described with reference to any example thereof. 56. 57. END OF CLAIMS 140979 1.DOC intellectual property office of n.z. 1 2 MAR 2004 </div>