CZ2002302A3 - 2-Pyrazolin-5-ones - Google Patents

Abstract

Chemical compounds having structural formula (I) and physiologically acceptable salts thereof, are inhibitors of serine/threonine and tyrosine kinase activity. Several of the tyrosine kinases, whose activity is inhibited by these chemical compounds, are involved in angiogenic processes. Thus, these chemical compounds can ameliorate disease states where angiogenesis or endothelial cell hyperproliferation is a factor. These compounds can be used to treat cancer and hyperproliferative disorders.

Description

Technical field

The present invention relates to certain 2-pyrazolin-5-ones which are inhibitors of protein kinases, particularly tyrosine kinases and serine/threonine kinases, some of which are novel compounds, to pharmaceutical compositions containing these pyrazolinones and to processes for the preparation of these pyrazolinones.

State of the art

At least 400 enzymes have been identified as protein kinases. These enzymes catalyze the phosphorylation of target protein substrates. Phosphorylation typically involves a reaction in which a phosphate group is transferred from ATP to the protein substrate. The specific structure in the target substrate to which the phosphate group is transferred is a tyrosine, serine, or threonine residue. Because these amino acid residues are the target structures for phosphoryl transfer, these protein kinase enzymes are commonly referred to as tyrosine kinases or serine/threonine kinases.

/IN

Phosphorylation reactions and counter-phosphatase reactions on tyrosine, serine, and threonine residues are involved in a myriad of cellular processes that underlie responses to various intracellular signals (typically mediated by cellular receptors), regulation of cellular functions, and activation or deactivation of cellular processes. Protein kinase cascades often participate in intracellular signal transduction, and these enzymes are essential for the execution of these cellular processes. Due to their ubiquity, protein kinases can be integral parts of the plasma membrane or cytoplasmic enzymes, or they can be localized in the nucleus, very often as components of enzyme complexes. In many cases, these protein kinases are essential elements of enzyme and structural/protein complexes that determine when and where cellular processes will occur in the cell.

Protein tyrosine kinases

Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. Posttranslational modifications of these substrate proteins, often the enzymes themselves, act as molecular switches 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 diseases, including benign and malignant proliferative disorders, as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft-versus-host disease. In addition, endothelial cell-specific PTK receptors, e.g. KDR and Tie-2, mediate angiogenic processes and thus contribute to the promotion of cancer progression and other diseases related to inappropriate vascularization (e.g. diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, psoriasis, arthritis, retinopathy of prematurity, infantile hemangiomas).

Tyrosine kinases can be of the receptor type (having extracellular, transmembrane and intracellular domains) or of the non-receptor type (being entirely intracellular).

Receptor tyrosine kinases (RTKs)

RTKs comprise a large family of transmembrane receptors with diverse biological activities. To date, at least nineteen (19) distinct subgroups of RTKs have been identified. The receptor tyrosine kinase (RTK) family includes receptors that are critical 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 function of RTKs is activated upon ligand binding, resulting in phosphorylation of receptors and multiple cellular substrates and subsequent cellular responses (Ullrich & Schlessinger, 1990, Cell 61:203-212). Thus, signal transduction mediated by receptor tyrosine kinases is initiated by extracellular interaction with a specific growth factor (ligand), typically followed by receptor dimerization, stimulation of intrinsic protein tyrosine kinase activity, and receptor transphosphorylation. This creates binding sites for intracellular signal transduction molecules and leads to the formation of complexes with a spectrum of cytoplasmic signaling molecules that promote the appropriate cellular response (e.g., cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) see Schlessinger and Ullrich, 1992, Neuron 9:120.

Proteins with SH2 (src homology-2) or phosphotyrosine binding (PTB) domains bind activated receptor tyrosine kinases and their substrates with high affinity, thereby transmitting signals into cells. Both 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., 1991, Science 252: 668-678; Shoelson, Curr. Opin. Chem. Biol. (1997), 1 (2), 227-234; Cowbum, Curr. Opin. Struct. Biol. (1997), 7 (6), 835-838). Several intracellular substrate proteins have been identified that associate with receptor tyrosine kinases (RTKs). They can be divided into two main groups: (1) substrates that have a catalytic domain; and (2) substrates that do not have this domain but serve as adaptors and associate with catalytically active molecules (Syngyang et al., 1993, Cell 72:767-778). The specificity of interactions between receptors or proteins and the SH2 or PTB domains of their substrates is determined by the amino acid residues immediately surrounding the phosphorylated tyrosine residue. For example, differences in binding affinities between SH2 domains and the amino acid sequences surrounding phosphotyrosine residues on their own receptors correlate with observed differences in their substrate phosphorylation profiles (Songyang et al., 1993, Cell 72:767-778). Observations indicate that the function of each receptor tyrosine kinase is determined not only by its expression pattern and ligand availability, but also by the set of downstream signal transduction pathways that are activated by its own receptor, as well as by the timing and duration of this stimulation. Thus, phosphorylation provides an important regulatory step that determines the selectivity of signaling pathways mediated by specific growth factor receptors, as well as differentiation factor receptors.

Several receptor tyrosine kinases, such as FGFR-1, PDGFR, and c-Met, and the growth factors that bind to them, are thought to play a role in angiogenesis, although some may stimulate angiogenesis indirectly (Mustonen and Alitalo, J. Cell. 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. Another name for human FLK-1 is "inserted domain-containing kinase receptor" (KDR) (Terman et al., Oncogene 6:1677-83, 1991). Another name for FLK-1/KDR is "vascular endothelial cell growth factor receptor 2" (VEGFR-2), because it binds VEGF with high affinity. The mouse version of FLK-1/VEGFR-2 has also been called NYK (Oelrichs et al., Oncogene 8(1):1115, 1993). DNA encoding mouse, rat, and human FLK-1 have been isolated and the nucleotide and coding amino acid sequences have been published (Matthews et al., Proc. Natl. Acad. Sci. USA, 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 72:835846, 1993). Many studies, e.g. published by Millauer et al., supra, assumes 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 the formation and growth of blood vessels, referred to as vasculogenesis and angiogenesis, respectively.

Another type III RTK subgroup, designated “fms-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). Another name for Flt-1 is “vascular endothelial cell growth factor receptor 1” (VEGFR-1). To date, members of the FLK-1/KDR/VEGFR-2 and Flt-1/VEGFR-2 subfamilies have been found to be primarily expressed on endothelial cells. Members of these subfamilies are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) ligand family (Klagsbum and D'Amore, Cytokine & Growth Factor Reviews 7:259-270, 1996). Vascular endothelial cell growth factor (VEGF) binds to Flt-1 with higher affinity than to FLK1/KDR and is mitogenic to vascular endothelial cells (Terman et al., 1992, supra·, Mustonen et al. supra·, DeVries et al., supra). Flt-1 is thought to be an essential factor in endothelial organization during vascular development. Flt1 expression is associated with early vascular development in mouse embryos and with neovascularization during wound healing (Mustonen and Alitalo, supra). Flt-1 expression in adult organs, such as renal glomerulitis, suggests an additional function of this receptor that is not related to cell growth (Mustonen and Alitalo, supra).

As noted above, recent evidence suggests that VEGF plays a role in stimulating both normal and pathological angiogenesis (Jakeman et al., Endocrinology 133: 848859, 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, et al., J. Biol. Chem. 264: 20017-20024, 1989; Brown et al., Regulation of Angiogenesis (ed. L. D. Goldberg and E. M. Rosen), 233-269, 997).

Various forms of VEGF resulting ^from alternative mRNA splicing have been reported, including four species described by Ferrar et al. (J. Cell. Biochem. 47: 211-218, 1991). Ferrar et al., supra, identified both secreted and predominantly cell-associated species of VEGF, and found that the protein exists in the form of disulfide-bonded dimers.

Several related homologues of VEGF have been identified. However, their role in normal physiological processes and diseases has not yet been elucidated. In addition, members of the VEGF family are often co-expressed with VEGF in many tissues and are generally 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 discussed below (Korpelainen and Alitalo, Curr. Opin. Cell Biol., 159-164, 1998 and references cited herein).

Placental growth factor (P1GF) has an amino acid sequence that shows significant similarity to that of VEGF (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 result from alternative splicing of mRNA and the protein exists in a dimeric form (Park et al., supra). P1GF-1 and P1GF-2 bind to Flt-1 with high affinity, and P1GF-2 also binds strongly to neuropilin-1 (Migdal et al., J. Biol. Chem. 273(35):22272-22278), but neither binds to FLK-1/KDR (Park et al., supra). It has been reported that PIGF potentiates both vascular permeability and the mitogenic effect of VEGF on endothelial cells, provided that VEGF is present at low concentrations (presumably due to heterodimer formation) (Park et al., supra).

VEGF-B is produced in two isoforms (167 and 185 residues) that are also thought to bind to Flt-1/VEGFR-1. VEGF-B may also play a role in regulating 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/FU-4, which is primarily expressed by lymphatic endothelial cells. In its fully modified form, VEGF-C can also bind KDR/VEGFF-2 and stimulate endothelial cell proliferation and migration in vitro and agniogenesis 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). Transgenic overexpression of VEGF-C causes proliferation and expansion of only lymphatic vessels, while blood vessels remain unaffected. Unlike VEGF, VEGF-C expression is not induced by hypoxia ( Ristimaki et al, J. Biol. Chem. (1998), 273(14), 8413-8418 ).

The latest to be discovered is VEGF-D, which is structurally very similar to VEGF-C.

It has been reported that VEGF-D binds to and activates at least two VEGFRs, VEGFR-3/Flt-4 and β

··· · · · · · · · · · ···

KDR/VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is prominently expressed in mesenchymal cells of the lung and skin (Achen et al., Proc. Natl. Acad. Sci. U.S.A. (1998), 95(2), 548-553 and references herein.

With respect to VEGF, VEGF-C and VEGF-D have been claimed to induce increases in vascular permeability in vivo in Miles assays when injected into cutaneous tissue (PCT/US97/14696; WO98/07832, Witzenbichler et al., supra). The physiological role and importance of these ligands in modulating vascular hyperpermeability and endothelial responses in the tissues where they are expressed remains unclear.

Recently, a virally encoded, novel type of vascular endothelial growth factor, VEGF-E (NZ-7 VEGF), has been reported that preferentially utilizes the KDF/Flk-1 receptor and has potent mitotic activity without a heparin-binding domain (Meyer et al., EMBO J. (1999), 18(2), 363-374; Ogawa et al., J. Biol. Chem. (1998), 273 (47), 31273-31282). The VEGF-E sequence has about 25% identity to mammalian VEGF and is encoded by the parapoxvirus Orf virus (OV). This parapoxvirus, which is active in sheep and goats and occasionally in humans, causes lesions with angiogenesis. VEGF-E is a dimer of approximately 20 kDa with a non-basic domain and also lacks affinity for heparin, but has the characteristic cysteine loop motif found in all mammalian VEGFs. It was also surprisingly found to be as potent and bioactive as the heparin-binding isoform of VEGF-A, VEGF165. This means that both factors stimulate tissue factor (TF) release, proliferation, chemotaxis, and growth of cultured vascular endothelial cells in vitro and angiogenesis in vivo. Like VEGF165, VEGF-E binds with high affinity to VEGF receptor-2 (KDR), leading to receptor autophosphorylation and a biphasic increase in free intracellular Ca ²⁺ , whereas, unlike VEGF165, VEGF-E did not bind to VEGF receptor-1 (Flt-1).

Based on the findings of other VEGF and VEGFR homologues and previous cases for ligands and receptor heterodimerization, the actions of such VEGF homologues may involve the formation of ligand-mediated VEGF heterodimers and/or receptor heterodimerization or binding to as yet unidentified VEGFRs (Witzenbichler et al., supra). Recent publications also suggest that neuropilin-1 (Migdal et al., supra) or VEGFR-3/Flt-4 (Witzenbichler et al., supra) or receptors other than KDR/VEGFR-2 may be involved in the induction of vascular permeability (Stacker S. A., Vítali A., Domagala T., Nice E. and Wilks A. F., “Angiogenesis and Cancer” Conference, Amer.

Ί • · ·· ···· ·· ·· ·· · · · ·*··

Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetelogia 40:S118-120 (1997)). To date, direct evidence for a significant role for KDR in VEGF-mediated vascular hyperpermeability has not been presented.

Non-receptor tyrosine kinases

Non-receptor tyrosine kinases are a group of cellular enzymes that lack extracellular and transmembrane sequences. To date, more than twenty-four individual non-receptor tyrosine kinases have been identified, comprising eleven (11) subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak, Jak, Ack, and LIMK). The Src subfamily of non-receptor tyrosine kinases is composed of the largest number of PTKs and includes Src, Yes, Fyn, Lyn, Lek, Blk, Hek, Fgr, and Yrk. The Src subfamily of enzymes is involved in oncogenesis and immune responses. A more detailed discussion of non-receptor tyrosine kinases is provided in Bolen, 1993, Oncogene 8:2025-2031, incorporated herein by reference.

Many tyrosine kinases, both RTKs and non-receptor tyrosine kinases, have been found to participate in cell signaling pathways in many pathogenic conditions, including cancer, psoriasis, and other hyperproliferative disorders or hyperimmune responses.

Development of compounds to modulate PTK

Given the presumed important role that PTKs play in the control, regulation, and modulation of cell proliferation, diseases, and disorders associated with abnormal cell proliferation, many attempts have been made to identify "inhibitors" of receptor and non-receptor tyrosine kinases by various possible means, including the use of mutant ligands (U. S. Application No. 4,966,849), soluble receptors and antibodies (Application No. WO 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: 5662; 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 No. 5,330,992 Mariani, et al., 1994, Proc. Am. Assoc. Cancer Res. 35: 2268).

Recently, attempts have been made to identify small molecules that act as tyrosine kinase inhibitors. For example, bismonocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808) have been generally described as tyrosine kinase 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 A1; Expert Opin.

Ther. Pat. (1998), 8 (4): 475-478), selenoindoles and selenides (PCT WO 94/03427), tricyclic polyhydroxy compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) have been described as tyrosine kinase inhibitors in the treatment of cancer. Anilinocinnolines (PCT WO97/34876) and quinazoline derivatives (PCT WO97/22596; PCT WO97/42187) have been described as inhibitors of angiogenesis and vascular permeability.

Additionally, attempts have been made to identify small molecules that act as serine/threonine kinase inhibitors. For example, bis(indolylmaleimide) compounds have been described as inhibitors of a particular PKC serine/threonine kinase isoform, whose signal transduction function is associated with altered vascular permeability in VEGF-related diseases (PCT WO97/40830; PCT WO97/40831).

Plk-1 kinase inhibitors

Plk-1 is a senn/threonine kinase that is an important regulator of cell cycle progression. It plays a critical role in the assembly and dynamic function of the mitotic spindle. Plk-1 and related kinases have also been shown to be closely linked to 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. They have also been found in malignant tumors of various origins. Plk-1 inhibitors are thought to block cancer cell proliferation by disrupting processes involving mitotic spindles and inappropriately activated cyclin-dependent kinases.

Cdc2/cyclin B kinase inhibitors (Cdc2 is sometimes referred to as cdkl)

Cdc2/cyclin B is another enzyme, a serine/threonine kinase, that belongs to the family of cyclin-dependent kinases (cdks). These enzymes are involved in the crucial transition between different phases of cell cycle progression. It is believed that the uncontrolled cell proliferation that is a hallmark of cancer is dependent on increased cdk activities in these cells. Inhibition of increased cdk activities in cancer cells by cdc2/cyclin B kinase inhibitors could suppress proliferation and restore normal control of cell cycle progression.

Therefore, it is important to identify effective small compounds that specifically inhibit signal transduction and cell proliferation by modulating the activity of receptor and non-receptor chromosomal kinases and serine/threonine kinases, thereby regulating and modulating abnormal or inappropriate cell proliferation, differentiation, or metabolism. In particular, it is important to identify methods and compounds that specifically inhibit tyrosine kinase function, which is essential for

angiogenic processes or the formation of vascular hyperpermeability leading to edema, ascites, effusion, exudates and macromolecular extravasation and matrix deposition, as well as related disorders, could be very beneficial.

The essence of the invention

their physiologically acceptable salts, in which the substituent R is a substituted or unsubstituted aliphatic, aromatic, heterocyclic or aralkyl group and the substituent R is a hydrogen atom, a lower alkyl group or an aryl group. The substituent R is a hydrogen atom or -AZ, where A is (CH ₂ ) _n -, -(CH ₂ ) _n NH-, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n S(O)- or -(CH ₂ ) _n S(O) ₂ -; and Z is a hydrogen atom, a lower alkyl and aralkyl group, trihalomethyl, R ³ CO-, trihalomethylcarbonyl, R ³ OC(O)-, -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , R ³ O- or a ring system selected from the group consisting of C3-C6cycloalkane, benzene, pyrrole, isoxazole, isothiazole, indole, pyridine, pyrazine, pyrimidine, thiophene, imidazole, furan. benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole, benzothiazole, tetrahydrofuran, thiazine and their useful A-oxides, which may be optionally substituted with one or more halogens, lower alkyl, R ³ O-, HO-, HOC(O)-, R ³ OC(O)-, trihalomethyl, nitro, aryl, -CN, -C(O)NR ⁴ R ⁵ or -NR ⁴ R'\ The substituent R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (Cb-Ccjcycloalkyl, heterocyclic), aralkyl, (C,-Cft)cycloalkyl-alkyl and heterocyclyl-alkyl. The substituents R ⁴ and R? in each case, each independently is a hydrogen atom or is selected from the group consisting of substituted or unsubstituted; lower alkyl groups, aromatic groups, (C1-C4)cycloalkyl groups, heterocyclic groups, aralkyl groups, (C3-C6)cycloalkyl-alkyl groups and heterocyclic-alkyl groups; optionally the substituents ^R4 and R5 together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl group, optionally each substituted with one or more moieties selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxy-lower alkyl group, an aromatic group, (C3- _C6 )cycloalkyl groups, heterocyclic groups, aralkyl groups, (C3-C6)cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; the numerical index n is an integer taking the value 0 to 3.

Suitable substituents for the R group include halogens, lower alkyl groups, R ³ O-, hydroxy, HOC(O)-, R ³ OC(O)-, R ³ OC(O)R ⁶ -, R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, nitro, -C(O)NR ⁴ R ⁵ , -NR ⁴ R ⁵ , R ³ CO-, -(CH2)nR ⁷ , -C(O)(CH2) _nR ⁷ , -C(O)NR ⁴ (CH2)nR ⁷ , -C(O)(CH2) _n -R ⁷ , -C(O)-(CH ₂ ) _n -C(O)-R ⁷ ,

-C(O)O(CH ₂ ) _n R ⁷ , -OC(O)(CH2)nR ⁷ , -NR ⁴ C(O)(CH2) _n R ⁷ , -R ⁶ NR ⁴ R ⁵ , -R ⁶ N(R ⁴ )-R ⁶ -R ⁷ , -R ⁶ C(O)O(CH2)nR , -R ⁶ OC(O)(CH2) _n R ⁷ , -R ⁶ N[R ⁶ -R ⁷ ]2, -R ⁶ C(O)NR ⁴ (CH 2 ) _n R ⁷ ,

R ^ï NR ⁴ C(O)(CH ₂ ) _; -R ⁷ , -R ⁶ CH[C(O)OR ⁴ ][NR ⁵ C(O)R ⁴ ] or a substituted aryl or aralkyl group, wherein the substituent is selected from the group consisting of halogen, trihalomethyl. hydroxy, -NR ⁴ R ⁵ , nitro, -CONR ⁴ R ⁵ , lower alkyl, R ³ O-, -C(O)OR ⁴ or -OC(O)R ³ . The substituent R ⁶ is a lower alkyl or aryl group. The substituent R is an alkoxy group, haloalkyl, lower alkyl piperazine, hydroxy, R ³ O-, R ³ C(O)- or -NR ⁴ R ⁵ .

Suitable substituents of R ³ , R ⁴ and R ⁵ include one or more moieties selected from the group consisting of halogen, lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkyl ester, trihalomethyl, preferably trifluoromethyl, nitro, phenyl, phenyl-lower alkyl, (C 3 -C ₆ )cycloalkyl, (C 1 -C 6 /cycloalkyl-alkyl, CN, amino, alkylamino, dialkylamino, -C(O)NH ₂ , -C(O)NH(alkyl) and -C(O)N(alkyl) ₂ .

Aliphatic groups include linear or branched C1-C2 hydrocarbons or cyclic C3-C3 hydrocarbons that are completely saturated or contain one or more unsaturated units. Lower alkyl groups are linear or branched C1- _C2 hydrocarbons or C1- _C2 cyclic hydrocarbons that are completely saturated.

Aromatic groups as used in the present invention include carbocyclic ring systems (e.g. benzyl or cinnamylidene) and fused polycyclic aromatic ring systems (e.g. naphthyl). Further aromatic groups include heteroaryl ring systems (e.g. pyridine, thiophene, furan, pyrrole, imidazole, oxazole, • ·· »· ··»· 0 · ·· • · · · · · «··· • ···· ·

0·· ·· · · · · · · · · · thiazole, pyrazole, triazole, pyrimidine and pyrazine) and heteroaryl ring systems in which a carbocyclic aromatic ring, a carbocyclic non-aromatic ring or a heteroaryl ring is fused to one or more other heteroaryl rings (e.g. benzimidazole, benzothiazole, indole, tetrahydroindole, azaindole, indazole, isoxazole, isothiazole, imidazole and quinone). An aryl group, as used herein, means an aromatic group having five or six atoms. An aralkyl group is an aromatic substituent which is attached to a compound by an aliphatic group having one to six carbon atoms. A heterocyclic group, as used herein, means a mono-, bi- or tri-cyclic heterocyclic group which is not aromatic or has a degree of unsaturation, wherein the unsaturation does not form an aromatic group.

Tautomers, stereoisomers, enantiomers and mixtures of these compounds are included in the present invention. Pharmaceutically acceptable addition salts of these compounds are also included in the present invention.

In one embodiment, the substituent R ² is a hydrogen atom and the substituent R is preferably substituted indole or 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, R ² is hydrogen, n is zero, and Z is cyclopropyl, 3-pyridyl, or pyrazinyl. In another preferred embodiment, R ² is hydrogen, A is -O-, n is O, and Z is ethyl, propyl, or isopropyl. In another preferred embodiment, R ² is hydrogen, A is CH ₂ , n is 2, and Z is benzene, optionally substituted with halogen, trihalomethyl, hydroxy, -NR ⁴ R ⁵ , nitro, -C(O)NR ⁴ R\ lower alkyl, R ³ 0-, -C(O)OR ⁴ , or -OC(O)R ³ .

In a preferred embodiment, the present invention is directed to a compound represented by the following general formula:

and its physiologically acceptable salts, in which the substituent 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;

the substituent R ¹ is hydrogen or -AZ;

A is -(CHX-, -(CHXNH-, -( _CH2 ) _nO- , -( _CH2 )nS-, -( _CH2 )nS(O)- or ( _CH2 ) _nS (O) _2- ;

Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC(O)-, -NR ⁴ R', -C(O)NR ⁴ R\ R ³ CO-. R ³ O- or a ring system selected from the group consisting of C3-C6cycloalkane, isoxazole, isothiazole, benzene, pyrrole. indole, pyridine, pyrazine, pyrimidine, benzothiazole. tetrahydrofuran, thiophene, imidazole, furan. triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their γ-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl. R ⁴ O-. HO-. HOC(O)-, R ³ OC(O)-, trihalomethyl. nitro groups. aromatic groups, (C1-C8)cycloalkyl groups, heterocyclic groups, aralkyl groups, (C1-C8)cycloalkyl-alkyl groups, heterocyclyl-alkyl groups. -CN, C(O)NR ⁴ R ⁵ or -NR ⁴ R ⁵ ;

The substituent R ^J in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, X-C6 cycloalkyl group, heterocyclic group, aralkyl group, (C1-C6) cycloalkyl-alkyl group and heterocyclyl-alkyl group;

The substituents R ⁴ and R ⁵ in each case are independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C ₆ )cycloalkyl, heterocyclic, aralkyl, (C ₂ -C ₆ )cycloalkyl-alkyl and heterocyclyl-alkyl;

optionally, the substituents R ⁴ and R 5 together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamortolino, azepino or perhydro-1,4-diazepin-1-yl group, each optionally substituted with one or more moieties selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxy lower alkyl group, an aromatic group, a (C 1 -C 2 ) cycloalkyl group, a heterocyclic group, an aralkyl group, a (C 1 -C 2 ) cycloalkyl 1 -alkyl group and a heterocyclyl-alkyl group and the index n is an integer taking the value 0 to 3: provided that when the substituent R is unsubstituted indol-3-yl, then the substituent R ¹ is not -NIC.

• * ·· *«*· ·· ·· ·· · ··

In another preferred embodiment, the present invention is represented by the following general structural formula:

focused on the compound

and its physiologically acceptable salts, in which the substituent 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;

the substituent R ¹ is hydrogen or -AZ;

A is -(CH ₂ ) _n -, -(CH ₂ ) n NH-, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n S(O)- or -(CH ₂ ) _n S(O) ₂ Z is a hydrogen atom, a lower alkyl group, an aralkyl group, a trihalomethyl, a trihalomethylcarbonyl, R ³ OC(O)-, -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of C 1-C 6 cycloalkane, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their A-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R ³ O-, HO-, HOC(O)-, R ³ OC(O)-, trihalomethyl, nitro, aromatic, (C3-C _Î )cycloalkyl, heterocyclic, aralkyl, (C3-C _Î )cycloalkyl-alkyl, heterocyclyl-alkyl, -CN, C(O)NR ⁴ R ⁵ or -NR ⁴ R ⁵ ;

The substituent R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C 3 _-C 4 )cycloalkyl, heterocyclic, aralkyl, (C 3 -C ₄ )cycloalkyl-alkyl and heterocyclyl-alkyl;

The substituents R ⁴ and R ⁵ in each case are independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl • * * · t * * * · ·« · 0 · * ·· 0 «·«· • β * · « · «0 ·

0··· · ··· · · • 0 ·«·· ·«*

00» ·· »0 β* * « ···· groups, aromatic groups, (CrC6)cycloalkyl groups, heterocyclic groups, aralkyl groups, (C3- _C6 )cycloalkyl-alkyl groups and heterocyclyl-alkyl groups;

optionally, the substituents R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl group, each optionally substituted with one or more moieties selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxy lower alkyl group, an aromatic group, a (C3-C6)cycloalkyl group, a heterocyclic group, an aralkyl group, a (C3- _C6 )cycloalkylalkyl group and a heterocyclyl-alkyl group; and the index n is an integer ranging from 0 to 3; provided that when the substituent R is unsubstituted indol-3-yl, then the substituent R ¹ is not -NH2; and the substituent 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 the substituent R ¹ is not a lower alkyl group, a (C 3 -C 0 )cycloalkyl group, benzene or C(O)NR ⁴ R\ wherein the substituents R ⁴ and R ⁵ are each independently a hydrogen atom, a lower alkyl group or a carbocyclic aryl group.

In another preferred embodiment, the present invention is directed to a compound represented by the following general structural formula:

and its physiologically acceptable counterparts, wherein the substituent 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-tetrabydroindole, benzoindole, azaindole, indazole, pyridine, quinoline, pyrimidine, benzene, pyrazine, pyrrole, pyrazole, oxazole and thiazole;

the substituent R ¹ is hydrogen or -AZ;

A is -(CH,),,-. -(CH ₂ ) _n NH-. -(CH _? )„O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n S(O)- or -(CH ₂ )„S(O) ₂ -; Z is a hydrogen atom, a lower alkyl group, an aralkyl group, a trihalogenmethyl, a trihalogenmethylcarbonyl, R'OC(O)-, -NR ⁴ R\ -C(O)NR ⁴ R', R ^? CO-, R O- or a ring system selected from the group consisting of Cj-Cecycloalkane, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their ΤN-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl groups. R ³ O-, HO-, HOC(O)-, R ³ OC(O)-, trihalomethyl, nitro groups, aromatic groups, (C 1 -C 6 )cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 3 -C 6 )cycloalkyl-alkyl groups, heterocyclyl-alkyl groups, -CN, C(O)NR ⁴ R ⁵ or -NR ⁴ R ⁵ ;

The substituent R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C 1 -C 6 )cycloalkyl group, heterocyclic group, aralkyl group, (C 1 -C 6 )cycloalkyl-alkyl group and heterocyclyl-alkyl group;

The substituents R ⁴ and R' in each case are independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C ₆ )cycloalkyl, heterocyclic, aralkyl, (C 3 -C 6 )cycloalkyl-alkyl and heterocyclyl-alkyl;

optionally, the substituents R ⁴ and R' together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl group, each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 1 -C 2 )cycloalkyl, heterocyclic, aralkyl, (C ₃ -C 3 )cycloalkyl-alkyl and heterocyclyl-alkyl groups; and the index n is an integer ranging from 0 to 3; provided that:

a) the substituent R is not pyrrol-3-yl or pyrrol-3-yl substituted with an alkyl or carbocyclic aryl group; and

b) the substituent R is not indol-3-yl or indol-3-yl substituted with an alkyl or carbocyclic aryl group; and

c) the substituent R is not an azaindole or an azaindole substituted in position 2 with an alkyl or carbocyclic aryl group.

• · ···· ..... ·· ··

In another preferred embodiment, the present invention is directed to a compound represented by the following general structural formula:

and its physiologically acceptable salts, in which the substituent R is substituted pyrrole or 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, pyrazole, oxazole and thiazole;

the substituent R ¹ is hydrogen or -AZ;

A is -(CH ₂ ) _n -, -(CH ₂ ) _n NH-, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n S(O)- or -(CH ₂ ) _n S(O) ₂ -;

Z is a hydrogen atom, a lower alkyl group, an aralkyl group, a trihalomethyl, a trihalomethylcarbonyl, R ³ OC(O)-, -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of C 1 -C 6 cycloalkane, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their N-oxides. wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R ³ O-, HO-, HOC(O)-, R ³ OC(O)-, trihalomethyl, nitro, aromatic, (C 1 -C 1 )cycloalkyl, heterocyclic, aralkyl, (C 3 -C ₆ )cycloalkyl-alkyl, heterocyclyl-alkyl, -CN, C(O)NR ⁴ R ⁵ or NR ⁴ R\ the R ³ substituent in each case being independently selected from the group consisting of: lower alkyl, lower alkoxy lower alkyl, aromatic, (C 1 -C ₁ )cycloalkyl, heterocyclic, aralkyl, (C 1 -C 1 )cycloalkylalkyl and heterocyclyl-alkyl;

the substituents R ⁴ and R 5 in each case are independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, ((C 1 -C 3 )cycloalkyl, heterocyclic, aralkyl, ₍ C 1 -C 3 )cycloalkyl-alkyl and heterocyclyl-alkyl;

optionally, the substituents R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl group, each optionally substituted with one or more moieties selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxy lower alkyl group, an aromatic group, a (C 3 -C 6 )cycloalkyl group, a heterocyclic group, an aralkyl group, a (C ₃ -C ₆ )cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and the index n is an integer taking the value 0 to 3; provided that:

a) if the substituent R is a substituted pyrrole, then this pyrrole is substituted with a group selected from ROC(O)R ⁶ , R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, -(CH,)PR ⁷ , -O(CH2) _p R ⁷ , -C(O)N(R ⁴ )(CH2)pR ⁷ , -C(O)O(CH2) _p R ⁷ , -OC(O)(CH2)pR ⁷ , -R ⁶ N(R ⁴ )-R ^ï -R', -R ^ï N(R ⁶ -R ⁷ )2, -N(R ⁴ )C(O)(CH2)pR ⁷ , -R ^ï NR ⁴ R ⁵ , -R ⁶ OC(O)(CH2) _p R ⁷ , -R ⁶ C(O)N(R ⁴ )(CH2)pR ⁷ , -R ⁶ C(O)O(CH2) _p R ⁷ , R ⁶ N(R ⁴ )C(O)(CH ₂ ) _p R ⁷ ,

-R ^ó CH(C(O)OR ⁴ )(N(R ⁴ )C(O)R ⁴ ), substituted aryl groups or aralkyl groups, wherein:

the substituent R ⁶ at each occurrence is independently a lower alkyl group or an aryl group;

the substituent R ⁷ at each occurrence is independently alkoxy, haloalkyl, lower alkylpiperazine, hydroxy, R ³ O-, R ³ C(O)- or NR ⁴ R ⁵ ; and the index p is an integer taking the values 1-3;

b) if the substituent R is indol-3-yl, then this indol-3-yl is substituted with a group selected from R ³ OC(O)R ⁶ , R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, -O(CH2)pR ⁷ , -(CH2) _p -R ⁷ , -OC(O)(CH ₂ ) _pR ⁷ , -C(O)N(R ⁴ )(CH2)pR ⁷ , -C(O)O(CH2) _pR ⁷ , -R ⁶ N(R ⁴ )-R ^ï -R'. -R ⁶ N(R ^ď -R ⁷ ) ₂ , -N(R ⁴ )C(O)(CH2)pR ⁷ , -R ⁶ NR ⁴ R ⁵ , -R ⁶ OC(O)(CH2) _p R ⁷ , -R ^b C(O)N(R ⁴ )(CH2)pR ⁷ , -R ⁶ C(O)O(CH2) _p R ⁷ , R ⁶ N(R ⁴ )C(O)(CH ₂ ) _p R',

-R ^ï CH(C(O)OR ⁴ )(N(R ⁴ )C(O)R ⁴ ) or substituted aryl groups or aralkyl groups; and

c) if the substituent R is pyrazol-3-yl, then the pyrazol-3-yl is substituted with a group selected from R OC(O)R ^(> . R'OR ⁽ '-. trihalomethyl, trihalomethylcarbonyl,

-(CH ₂ ) _p -R ⁷ , -O(CH 2 ) p R ⁷ , -OC(O)(CH 2 ) _p R ^? , -C(O)N(R ⁴ )(CH 2 ) p R ^? , -C(O)O(CH2) _p R ⁷ , -R ^h N(R ⁴ )-R ⁽ '-R~. -R ^< 'N(R ^< '-R ⁷ )2, -N(R ^j )C(O)(CH2) _p R ⁷ , -R ^(, NR ⁴ Rg -R ⁽ 'OC(O)(CH ₂ ) _p R ⁷ , • ·

-R ⁶ C(O)N(R ⁴ )(CH2)PR ⁷ , -R ⁶ C(O)O(CH2) _P R ⁷ , R ⁶ N(R ⁴ )C(O)(CH ₂ ) _p R ⁷ ,

-R ^is CH(C(O)OR ⁴ )(N(R ⁴ )C(O)R ⁴ ) or substituted aryl or aralkyl groups.

In another preferred embodiment, the present invention is directed to a compound represented by the following general structural formula:

and physiologically acceptable salts thereof, in which the substituent 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, pyrazole, oxazole and thiazole;

the substituent R ¹ is hydrogen or -AZ;

A is -(CH ₂ ) _n -, -(CH ₂ ) _n NH-, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n S(O)- or -(CH ₂ ) _n S(O) ₂ -;

Z is a hydrogen atom, a lower alkyl group, an aralkyl group, a trihalomethyl, a trihalomethylcarbonyl, R ³ OC(O)-, -NR ⁴ R ⁵ , -C(O)NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of C 3 -C 4 cycloalkane, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their A-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, a lower alkyl group, R ³ O-, HO-, HOC(O)-, R ³ OC(O)-, trihalomethyl, nitro group, aromatic group, (C1-C6)cycloalkyl groups, heterocyclic groups, aralkyl groups, ( _C2 - _C6 )cycloalkyl-alkyl groups, heterocyclyl-alkyl ^groups , -CN, C(O) ^NR4R3 or ^{-NR4R5 ;}

the substituent R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl groups, lower alkoxy lower alkyl groups, aromatic groups, (C 1 -C _{3 )} cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 1 -C 3 )cycloalkyl-alkyl groups and heterocyclyl-alkyl groups;

the substituents R ⁴ and R' in each case are independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl • · · · • ·

groups, aromatic groups, (C 8 -C 8 cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 8 -C 8 cycloalkyl-alkyl groups and heterocyclyl-alkyl groups;

optionally, the substituents R ⁴ and R ² ' together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl group, each optionally substituted with one or more moieties selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxy lower alkyl group, an aromatic group, a (C 5 -C 6 )cycloalkyl group, a heterocyclic group, an aralkyl group, a (C ₃ C ₆ )cycloalkyl-alkyl group and a heterocyclyl-alkyl group; and the index n is an integer taking the value 0 to 3; provided that:

a) if the substituent R is unsubstituted indol-3-yl, then the substituent R ¹ is not -NH ₂ ;

b) if the substituent R is unsubstituted or substituted benzene or unsubstituted imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyrimidine, pyrazine, pyrrole, pyrazole, oxazole or thiazole; then the substituent R ¹ is not a lower alkyl group, a (C ₃ -C 6 )cycloalkyl group, benzene or -C(O)NR ⁴ R ⁵ , wherein the substituents R ⁴ and R ⁵ are each independently a hydrogen atom, a lower alkyl group or a carbocyclic aryl group;

c) the substituent R is not pyrrol-3-yl or pyrrol-3-yl substituted with an alkyl or carbocyclic aryl group;

d) the substituent R is not indol-3-yl or indol-3-yl substituted with an alkyl or carbocyclic aryl group;

e) the substituent R is not an azaindole or an azaindole substituted in position 2 with an alkyl or carbocyclic aryl group

f) if the substituent R is a substituted pyrrole, then this pyrrole is substituted with a group selected from ROC(O)R ⁶ , R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, O(CH 2 ) p R ⁷ , -(CH 2 ) _p -R ⁷ , -OC(O)(CH ₂ ) _p R ⁷ , -C(O)N(R ⁴ )(CH 2 ) p R ⁷ , -C(O)O(CH 2 ) _p R ⁷ , -R ⁶ N(R ⁴ )-R ⁶ -R'. -R ^ó N(R ⁽ '-R ⁷ ) ₂ , -N(R ⁴ )C(O)(CH2)pR ⁷ , -R ⁶ NR ⁴ R ⁵ , -R ⁶ OC(O)(CH2) _P R ⁷ , -R ⁶ C(O)N(R ⁴ )(CH2)pR ⁷ , -R ^í 'C(O)O(CH;) _p R ⁷ , R ⁶ N(R ⁴ )C(O)(CH ₂ ) _P R ⁷ ,

-R ⁶ CH(C(O)OR ⁴ )(N(R ⁴ )C(O)R ⁴ ), substituted aryl group or aralkyl group, wherein:

the substituent R ¹ at each occurrence is independently a lower alkyl group or an aryl group;

• ·

the substituent R at each occurrence is independently alkoxy, haloalkyl, lower alkylpiperazine, hydroxy, R ³ O-, R ³ C(O)- or NR ⁴ R ⁵ ; and the index p is an integer taking the values 1-3;

g) if the substituent R is indol-3-yl, then this indol-3-yl is substituted with a group selected from R ³ OC(O)R ⁶ , R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, -O(CH2)pR ⁷ , -(CH2) _p -R ⁷ , -OC(O)(CH ₂ ) _p R ⁷ , -C(O)N(R ⁴ )(CH2)pR ⁷ , -C(O)O(CH2) _p R ⁷ , -r ⁶ n(r ⁴ )-r ⁶ -r', -r ⁶ n(r ⁶ -r ⁷ ) ₂ , -n(r ⁴ )C(O)(ch ₂ ) _p r ⁷ , -r ⁶ nr ⁴ r ⁵ ,

R ⁶ C(O)N(R ⁴ )(CH2)pR ⁷ , -R ⁶ C(O)O(CH2) _p R ⁷ , -R ⁶ OC(O)(CH ₂ ) _p R ⁷ ,

-R ⁶ N(R ⁴ )C(O)(CH ₂ ) _p R ⁷ , -R ⁶ CH(C(O)OR ⁴ )(N(R ⁴ )C(O)R ⁴ ) or a substituted aryl or aralkyl group; and

h) if the substituent R is pyrazol-3-yl, then this pyrazol-3-yl is substituted with a group selected from R OC(O)R ⁶ , R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, (CH2)pR ⁷ , -O(CH2) _pR ⁷ , -C(O)N(R ⁴ )(CH2)pR ⁷ , -C(O)O(CH2) _pR ⁷ , -OC(O)(CH2)pR ⁷ , -R ⁶ N(R ⁴ )-R ^ó -R', -R ⁶ N(R ^ï -R ⁷ )2, -N(R ⁴ )C(O)(CH2)pR ⁷ , -R ^ó NR ⁴ R ⁵ , -R ⁶ OC(O)(CH2) _pR ⁷ , -R ⁶ C(O)N(R ⁴ )(CH2)pR ⁷ , -R ⁶ C(O)O(CH2) _p R ⁷ , R ⁶ N(R ⁴ )C(O)(CH ₂ ) _p R ⁷ ,

-R ^is CH(C(O)OR ⁴ )(N(R ⁴ )C(O)R ⁴ ) or substituted aryl or aralkyl groups.

In a more preferred embodiment, the present invention provides any of the above compounds wherein A is -NH, -O-, -S-, -S(O)- or -S(O) ₂ ; and Z is cyclopropyl,

3-pyridyl or pyrazinyl.

In a more preferred embodiment, the present invention provides any of the above compounds wherein A is -O-; and Z is ethyl, α-propyl or isopropyl.

In a more preferred embodiment, the present invention provides any of the above compounds wherein A is -CH ₂ -; and Z is phenyl, said phenyl being optionally substituted with one or more moieties selected from the group consisting of halogen, trihalomethyl, hydroxy, -NR ⁴ R ³ , nitro, -CONR ⁴ R\ lower alkyl, R ³ O-, -C(O)OR ⁴ and OC(O)R'.

In another preferred embodiment, the present invention describes any of the above compounds, wherein the substituent R is substituted with one or more substituents, each independently selected from the group consisting of halogen, lower alkyl. R ³ O~, hydroxy, HOC'(O)-, ROC(O)-, R OC(O)R ⁽ '-, R ³ OR ^h -, trihalomethyl. trihalomethylcarbonyl, nitro, -C(O)NR ⁴ R\ -NR ⁴ R\ R'CO-, -(CH2)„-R\ ΑΧΟΙ').!/.. -C(O)NR ⁴ (CH2) _n R', -C(O)(CH ₂ ) _n -R ⁷ , -C'(O)-(CH ₂ )„··· · · · · · · ·

C(O)-R ⁷ , -C(O)O(CH ₂ ) _n R ⁷ , -OC(O)(CH2)nR ⁷ , -NR ⁴ C(O)(CH2) _n R ⁷ , -R ⁶ NR ⁴ R ⁵ , -R ⁶ N(R ⁴ )R ⁶ -R ⁷ , -R ⁶ C(O)O(CH ₂ ) _n R ⁷ , -R ⁶ OC(O)(CH2)nR ⁷ , -R ⁶ N(R ⁶ -R ⁷ )2, -R ⁶ C(O)NR ⁴ (CH2)nR ⁷ , R ⁶ NR ⁴ C(O)(CH2) _n R ⁷ , -R ⁶ CH(C(O)OR ⁴ )(NR ⁵ C(O)R ⁴ ), optionally substituted aryl groups and optionally substituted aralkyl groups. The optionally substituted aryl group and the optionally substituted aralkyl group are optionally substituted with one or more substituents selected from the group consisting of halogen, trihalomethyl, hydroxy, -NR ⁴ R ⁵ , nitro, -CONR ⁴ R ⁵ , lower alkyl, R ³ O-, C(O)OR ⁴ , and -OC(O)R ³ . The substituent R ⁶ is a lower alkyl group or an aryl group. The substituent R ⁷ is an alkoxy group, haloalkyl, lower alkyl piperazine, hydroxy, R ³ O-, R ³ C(O)-, or -NR ⁴ R ⁵ . In one aspect of this embodiment, the substituent R is pyrrolyl, indolyl, azaindolyl, phenyl, pyrazolyl, imidazolyl, thienyl, 4,5,6,7tetrahydroindolyl, or quinolinyl. In another aspect of this embodiment, the substituent 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, thien-2-yl or quinolin-5-yl.

In another preferred embodiment, the present invention describes any of the above compounds, in which the substituent R ¹ is trifluoromethyl, amino, cyclopropylamino, methyl, ethyl, propyl, isopropyl, cyclopropyl,

2-methylcyclopropyl, 2,2,3,3-tetramethylcyclopropyl, 2-phenylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -(CH ₂ ) _p -O-phenyl, -(CH ₂ ) _p -O-(4-methylphenyl), -(CH ₂ ) _P methoxyphenyl), -(CH 2 ) p -O-(4-chlorophenyl), -(CH ₂ ) _p -O-(4-hydroxyphenyl), -(CH ₂ ) _p -O-(4-hydroxyphenyl) _{2 ) p -O- ( 3methylphenyl ) ​ ​ ​ ​} -NH-(4-chlorophenyl), -NH-(4-fluorophenyl), -NH-(4isopropylphenyl), isopropoxy, ethoxy, cyclopentyloxy, -(CH ₂ ) _P indolyl, -(CH ₂ )p-pyridyl, -(CH ₂ ) _p -benzothiazolyl, -(CH ₂ ) _p -pyrrolyl, -(CH ₂ ) _P tetrahydrofuryl, -(CH ₂ ) _p pyrazinyl, -(CH ₂ ) _p -furyl, -(CH ₂ ) _p -thienyl, -(CH ₂ ) _p -phenyl, -(CH ₂ ) _P (5-methylisoxazolyl), -(CH ₂ ) _p -isoxazolyl, -(CH ₂ ) _p -pyridazinyl, -(CH ₂ ) _p -pyrimidinyl, (CH ₂ ) _n -C(O)-OMe, -(CH 2 ) ₂ ) _n -C(O)-OEt or benzyl optionally substituted with one or more chlorine, fluorine, OMe, methyl or amino groups. The index p is an integer taking values from 1 to 3. Within an aspect of this embodiment, the substituent R is optionally substituted with one or more moieties selected from the group consisting of Br, Cl, F, aminomethyl, N,N-dimethylaminomethyl, carboxy, carboxymethyl, carboxyethyl, carbonylmethyl, carbonylethyl, methoxycarbonyl, ethoxycarbonyl.

• · • ·

phenyl, 4-morpholinomethyl, -C(O)-O-(CH ₂ ) 2 -N(Me) 2 , -C(O)-O-(CH ₂ ) ₂ -N(Et) ₂ , -C(0)-OCH ₂ -N(Me) ₂ , -C(O)-O-(CH ₂ ) ₂ -N(Me) 2 , -C(O)-O-(CH 2 ) 2 -N(Me) ₂ , -C(O)-NH-(CH ₂ ) ₂ -N(Me) ₂ , -CH ₂ -NH-C(O)-CF ₃ and an optionally substituted moiety selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and phenyl, wherein the optionally substituted moiety is optionally substituted with one or more groups selected from Br, Cl, F, hydroxy, nitro, amino or lower alkyl.

In another aspect, the present invention provides a pharmaceutical composition comprising any one or more compounds of the present invention, as also defined in the present invention, and a pharmaceutically acceptable carrier or diluent.

In another aspect, the present invention provides a method of inhibiting the activity of one or more protein kinases, comprising administering a compound of the general formula:

and its physiologically acceptable salts and biologically active metabolites, in which the substituent R is selected from the group consisting of substituted or unsubstituted: aliphatic group, aromatic group, (C ₃ -C 6 )cycloalkyl group, heterocyclic group, aralkyl group, (C 3 -C 6 )cycloalkyl-alkyl group and heterocyclyl-alkyl group;

the substituent R ¹ is hydrogen or -AZ;

the substituent R ² is a hydrogen atom or is selected from the group consisting of a substituted or unsubstituted: lower alkyl group, aromatic group, (C ₃ -C 6 ) cycloalkyl group, heterocyclic group, aralkyl group, (C ₃ -C ₍ , ) cycloalkylalkyl group and heterocyclyl-alkyl group;

A is -(CH ₂ ) _n , -(CH ₂ ) _n NH-, -(CH ₂ ) _n O-, -(CH ₂ ) _n S-, -(CH ₂ ) _n S(O)- or -(CH ₂ ) _n S(O) ₂ -;

Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC(O)-, -NR ⁴ R\ -C(O)NR ⁴ R\ R ³ CO-, R ³ O- or a ring system selected from the group consisting of C ₃ -C _Î cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, • · • · · · • · - Λ · · · * ix-uj-ux thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their V-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl groups. R ³ O-, HO-, HOC(O)-, R ³ OC(O)-, trihalomethyl, nitro, aryl, -CN, -C(O)NR ⁴ R ⁵ or -NR ⁴ R ⁵ ;

The substituent R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl group, lower alkoxy lower alkyl group, aromatic group, (C 1 -C 6 cycloalkyl group, heterocyclic group, aralkyl group); (C 1 -C 6 cycloalkyl-alkyl group and heterocyclyl-alkyl group; the substituents R ⁴ and R ⁵ in each case are independently hydrogen atom or are selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (C 1 -C 6 cycloalkyl group, heterocyclic group, aralkyl group, (C 1 -C 6 ) cycloalkyl-alkyl group and heterocyclyl-alkyl group;

optionally, the substituents R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent a morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl group, each optionally substituted with one or more moieties selected from the group consisting of a lower alkyl group, a hydroxy group, a lower alkoxy 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; and the index n is an integer taking the value 0 to 3.

A preferred embodiment of the above method is one wherein the inhibition of the protein kinase is in a recipient in need thereof.

A preferred method of any of the above methods is one where the compound is a mixture of stereoisomers.

A preferred method of any of the above methods is one where the stereoisomers are enantiomers.

A preferred method of any of the above methods is one where the stereoisomers are E and Z isomers.

A preferred method of any of the above is one where the compound is a mixture of structural isomers.

A preferred method of any of the above methods is one where the structural isomers are tautomers.

• Φ φφφ • ·

A preferred method of any of the above methods is one wherein said protein kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase.

A preferred method of any of the above methods is one wherein said tyrosine kinase is selected from the group consisting of KDR, Fit-1, ΊΊΕ-2, FGFR, PDGFR, IFG1-R, c-Met, Lek, Src, fyn, Lyn, Blk and yes.

In another aspect, the present invention is directed to a method of treating or significantly inhibiting hyperproliferative disorders or inflammatory diseases in a recipient in need of such treatment comprising administering to said recipient any compound of the present invention as defined herein.

In another aspect, the present invention is directed to a method of treating or inhibiting angiogenesis in a recipient in need of such treatment comprising administering to said recipient any compound of the present invention as defined herein.

In another aspect, the present invention provides a method of inducing an anti-angiogenic effect in a recipient in need of such treatment comprising administering to said recipient any compound of the present invention as defined herein.

In another aspect, the present invention provides a method of treating or inhibiting the progression of a disease or condition in a recipient in need of such treatment comprising administering to said recipient any compound of the present invention as defined herein, wherein 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, coma, rubeosis, neovascular glaucoma, macular degeneration, wound healing, peptic ulcer, Helicobacter-related diseases, virally induced angiogenic disorders, fractures, diabetic retinopathy, Crohn's disease, inflammatory bowel disorders, cat scratch fever, retinopathy of prematurity, ulcers, thyroid hyperplasia, burns, trauma, acute lung injury, chronic lung disease, stroke, polyps, cysts, synovitis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, sepsis, adult respiratory distress syndrome, multiple organ dysfunction syndrome, ascites and tumor-related effusions and edema.

In another aspect, the present invention is directed to a method of affecting vascular hyperpermeability or edema formation in a recipient in need of such treatment comprising administering to said recipient any of the compounds of the present invention as defined herein. A preferred method of the above-mentioned method is one in which the effect on edema formation is anti-edematous.

A preferred method according to any of the above methods is one in which the protein kinase is a serine kinase.

A preferred method according to any of the above methods is one in which the protein kinase is a threonine kinase.

Particularly preferred compounds of the present invention are:

3-Cyclopropyl-4-{[(3,5-dimethyl-4-(4-methyl-1-piperazylmethyl)pyrrol-2-yl]methylene}2-pyrazolin-5-one,

3- Cyclopropyl-4-[(3,5-dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-[(4-diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin5-one,

3-Cyclopropyl-4-[(3,5-dimethyl-4-piperidinomethylphenyl-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropyl-4-[(4-diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-[(3-dimethylaminomethyl-4, 5-tetramethylenepyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-[(3-diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-{[3-(4-methyl-1-piperazinylmethyl)-4,5-tetramethylenepyrrol-2ylmethylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-[ {3-(1-PynOlidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

3-Cyclopropyl-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-[(4-dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-2-pyrazolin5-one,

3-Cyclopropyl-4-[(4-diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5one, • ·

44··

3-Cyclopropyl-4-(3,5-dibromo-4-hydroxybenzylidene)-2-pyrazolin-5-one,

3- Cyclopropyl-4-[(4-oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-2-pyrazolin-5-one,

-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-pyrazolin-5-one,

3-Cyclopropyl-4-[4-(2-dimethylaminoethylaminocarbonylpynOl-2-yl)methylene]-2pyrazolin-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]-2pyrazolin-5-one,

3-Cyclopropyl-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropyl-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

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,

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-2yl)methylene]-2-pyrazolin-5-one,

3- Cyclopropyl-4-[(5-chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2yl)methylene]-2-pyrazolin-5-one,

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-[(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin5-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)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(4-Diethanolaminornethyl-3,5-dimethyl-pyrrol-2-yl)rnethylene]-3-(3-pyridyl)-2pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2pyrazolin-5-one,

4-{[3-(4-Methyl-1-piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(3pyridyl)-2-pyrazolin-5-one,

3-(3-Pyridyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin5-one,

4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(4-Bromopyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(4-Chloropyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(5-Chloropyrrol-2-yl)methylene]-3-(3-pyridyl-2-pyrazolin-5-one,

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-Dimethylaminoethoxycarbonylphenyl-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one, • · • 0 « 0 · ·

4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2pyrazolin-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)-2pyrazolin-5-one,

4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylenej-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[4-(4-Morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[3-(4-Morphblinoethylaminocarbonylindol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

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)methylene]-3-(3pyridyl)-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(3pyridyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-morpholinomethylpynOl-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-{[(4-methyl-1-piperazinylmethyl)pyrrol-2-yl]methylene}-3-isopropoxy2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-[(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-isopropoxy-2pyrazolin-5-one, φφ ·φ* *

4-[(3-Dimethylaminomethyl-4, 5-tetramethylenepyrrol-2-yl)methylene]-3-isopropoxy-2pyrazolin-5-one,

3- Isopropoxy-4-[(3-morpholinomethyl-4, 5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-isopropoxy-2pyrazolin-5-one,

3-Isopropoxy-4-{[3-(4-methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2ylmethylene}-2-pyrazolin-5-one,

3-Isopropoxy-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

3- Isopropoxy-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin5-one,

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,

3- Isopropoxy-4-[(4-oxo-1,5,6,7-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,

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,

4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-isopropoxy-2pyrazolin-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, *« ··

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-isopropoxy-2pyrazolin-5-one,

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,

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,

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-isopropoxy-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-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,

4-[(3,5-Dimethyl-4-[(1-PynOlidinylmethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one,

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,

4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-ethoxy-2pyrazolin-5-one,

3- Ethoxy-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin5-one,

3-Ethoxy-4-{[3-(4-methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}2-pyrazolin-5-one,

3- Ethoxy-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-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-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-5-one,

3- Ethoxy-4-[(4-oxo-1,5,6,7-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,

4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-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,

4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-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-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)pyriOl-2-yl]rnethylene}-3-ethoxy-2pyrazolin-5-one,

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-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3ethoxy-2-pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one.

• · · ·

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2pyrazolin-5-one,

4-{[3-(4-Methyl-1-piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

3- Pyrazinyl-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepynol-2-yl]methylene}-2pyrazolin-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,

4-[(4-Diethylaminoethyl-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,

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-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-pyrazolin5-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,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin5-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,

4-[3-(4-Morpholinoethoxycarbonylindol-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-pyrazinyl-2-pyrazolin-5-one,

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-[(1-Methylindol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

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-pyrazolin-5-one,

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,

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-2-yl)-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)-2pyrazolin-5-one,

4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)'2pyrazolin-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)-2pyrazolin-5-one,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(imidazol-2-yl)-2pyrazolin-5-one,

3-(Imidazol-2-yl)-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-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,

3-(Imidazol-2-yl)-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)inethylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one, • · • ·

3-(Imidazol-2-yl)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one,

3-(Imidazol-2-yl)-4-[(5-methoxyindol-2-yl)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-(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-[(indol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl))-2-pyrazolin-5-one, 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-(iniidazol-2-yl)-2-pyrazolin-5-one,

4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpynOl-2-yl)methylene]-3-(imidazol-2-yl)-2-pyrazolin-5-one,

4-[(4-Bromopyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-[(4-Chloropyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-[(5-Chloropyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

3-(1-Methylcyclopropyl)-4-[(5-trifluoromethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(4-Ethoxycarbonylpyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one, 4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(1methylcyclopropyl)-2-pyrazolin-5-one,

4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one, • ·

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(1-methylcyclopropyl)2-pyrazolin-5-one,

3-(1-Methylcyclopropyl)-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-(1-Methylcyclopropyl)-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-(1-Methylcyclopropyl)-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2pyrazolin-5-one,

3-(1-methylcyclopropyl)-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

3-(1-Methylcyclopropyl)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2pyrazolin-5-one,

4-[(5-Methoxyindol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

3-(1-Methylcyclopropyl)-4-[(4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4- {[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-(1methylcyclopropyl)-2-pyrazolin-5-one,

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-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(1-methylcyclopropyl))-2-pyrazolin-5-one,

4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-(1methylcyclopropyl)-2-pyrazolin-5-one,

4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(1methylcyclopropyl)-2-pyrazolin-5-one,

4-[(5-Chloro-4-rnethoxycarbonylrnethyl-3-rnethoxycarbonylpyrrol-2-yl)methylene]-3-(1-methylcyclopropyl)-2-pyrazolin-5-one,

4 • 4

4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)rnethylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(4-methyl'1-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(2-furyl)-2pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(1-pyrrolidinylmethyl)pyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-[(4-Diethanolaminornethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-furyl)-2pyrazolin-5-one,

3-(2-Furyl)-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(3-Diethylaminoethyl-4,5-tetramethylenepynOl-2-yl)methylene]-3-(2-furyl)-2-pyrazolin5-one,

3-(2-Furyl)-4-{[3-(4-methyl-1-piperazinylmethyl)-4,5-tetramethylenepyrrol-2yl]methylene}-2-pyrazolin-5-one,

3-(2-Furyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

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-dimethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-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,

4-[(4-Bromopyrrol-2-yl)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,

4-[4-(2-Dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin5-one,

4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazobn-5-one,

4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

3-(2-Furyl)-4-[4-(4-morpholinoethoxycarbonylpyrroI-2-yl)methylene]-2-pyrazolin-5-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-one,

4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

3-(2-Furyl)-4-[(1-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-tetramethylenepyriOl-2-yl)methylene]-2-pyrazolin-5-one,

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)pyriOl-2-yl)methylene]-3-(2furyl)-2-pyrazolin-5-one,

3-(2-Furyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one,

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-Diethoxycarbonylpyrrol-2-yl)methylene]-3-(3-(2-furyl))-2-pyrazolin-5-one, 4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-(2-furyl)-2-pyrazolin-5-one,

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-(2furyl)-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylcn-3-(2furyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-[(morpholinomethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5one, • ·

4-[(3,5-Dimethyl-4-(4-methyl-1-piperazinyl)methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrcl-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-piperidinomethylpynol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2pyrazolin-5-one,

4- {[3-(4-Methyl-1-piperazinylmethyl)-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{[3-(1-Pyrrolidinylmethyl)-4,5-tetramethylenephenyl-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin5-one,

4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-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,

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-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-trifluoromethylpyriTol-2-yl)methylene]-2-pyrazolin-5-one, • · • · · · · • · · · · • · • · ··

4-[(4-EthoxycarbonylpyriTol-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)-2pyrazolin-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-pyrazolin5-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,

4-[3-(4-Morphblinoethoxycarbonylindol-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,

4-[(1-Methylindol-3-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[3,5-Dimethyl-4-ethoxycarbonylpyrrol-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,

4-{[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-[(Indol-3-yl)methyl]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(Pyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(Indol-2-yl)methyl]-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,

4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(2thienyl)-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,

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-pyrazolin5-one,

3-Cyclopropoxy-4-[4-(2-dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

-Cyclopropoxy-4-[(3-ethoxycarbonylindol-2-yl)methyl en]-2-pyrazolin-5-one,

3-Cyclopropoxy-4-[3-(2-dimethylaminoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin5-one,

3-Cyclopropoxy-4-[3-(2-dimethylaminoethylaminocarbonylindol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropoxy-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropoxy-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2-pyrazolin5-one,

-Cyclopropoxy-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropoxy-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2-pyrazolin5-one,

3-Cyclopropoxy-4-[(3,5-dimethyl-4-ethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropoxy-4-[(1-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-methoxyindol-2-yl)methylene]-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-2yl]methylene}-2-pyrazolin-5-one,

3-Cyclopropoxy-4-[[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2yl)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-[(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-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-2yl)methylene]-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-rnethoxycarbonylpyrrol-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-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one,

3-[2-(5-pyrimidinylethyl)]-4-[(5-trifluoromethylpynol-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-pyrimidinylethyl)]-2-pyrazolin-5-one,

4-[4-(2-Dimethylaminoethylaminocarbonylpyrrol-2-yl)methylene]-3-[2-(5pyrimidinylethyl)]-2-pyrazolin-5-one,

4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidmylethyl)]-2-pyrazolin-5-one,

4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2pyrazolin-5-one,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-[2-(5pyrimidinylethyl)]-2-pyrazolin-5-one,

4-[4-(4-Morpholinoethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2pyrazolin-5-one,

4-[4-(4-Morpholinoethylaminocarbonylpynol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2pyrazolin-5-one,

4-[3-(4-Morpholinoethoxycarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2pyrazolin-5-one,

4-[3-(4-Morpholinoethylaminocarbonylindol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one,

4-[(1-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)]-2pyrazolin-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,

4- {[3,5-Dimethyl-4-(2-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-3-[2-(5pyrimidinylethyl)]-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-[2-(5pyrimidinylethyl))-2-pyrazolin-5-one,

4-[(Indol-3-yl)methylene]-3-[2-(5-pyrimidinylethyl)]-2-pyrazolin-5-one,

3-[2-(5-pyrimidinylethyl)]-4-[(pynOl-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-pyrimidinylethyl)]-2-pyrazolin-5-one,

4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(5-pyrimidinylethyl)]-2pyrazolin-5-one,

4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3[2-(5pyrimidinylethyl)]-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2-(5pyrimidinylethyl)]-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-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one,

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-pyrazolin5-one,

4-[4-(2-DimethylaminoethylaminocarbonylpynOl-2-yl)methylene]-3-(2-phenylethyl)-2pyrazolin-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-pyrazolin5-one,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-(2-phenylethyl)-2pyrazolin-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-phenylethyl)-2-pyrazolin5-one,

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-[(1-Methylindo 1-3-yl)methylene]-3-(2-phenylethyl)-2-pyrazolin-5-one,

4-[3,5-Dimethyl-4-ethoxycarbonylpynOl-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-phenylethyl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pynol-2-yl)methylene]-3-(2phenylethyl)-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,

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-pyrazolin-5-one,

4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(2phenylethyl)-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-(2phenylethyl)-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,

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,

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-(4hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

4-[(3-Ethoxycarbonylindol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

4-[3-(2-Dimethylaminoethoxycarbonylindol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]2-pyrazolin-5-one,

4-[3-(2-Dimethylaminoethylaminocarbonylindol-2-yl)methylene]-3-[2-(4hydroxyphenyl)ethyl]-2-pyrazobn-5-one,

3-[2-(4-hydroxyphenyl)ethyl]-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-Hydroxyphenyl)ethyl]-4-[4-(4-morphobnoethylaminocarbonylpynOl-2-yl)methylene]2-pyrazolin-5-one,

3-[2-(4-hydroxyphenyl)ethyl]-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-hydroxyphenyl)ethyl]-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2pyrazolin-5-one,

4-[3,5-Dimethyl-4-ethoxycarbonylpynOl-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2pyrazolin-5-one,

3-[2-(4-hydroxyphenyl)ethyl]-4-[(5-methoxyindol-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-(4hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-yl)methylene]-3-[2-(4hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

4-[(3,4-Diethoxycarbonylpyrrol-2-yl)methylene]-3-[2-(4-hydroxyphenyl)ethyl]-2-pyrazolin5-one,

4-{[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-[2-(4hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(4-hydroxyphenyl)ethyl]-2pyrazolin-5-one, « *

4-[(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2(4-hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

4-[(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl)methylene]-3-[2-(4hydroxyphenyl)ethyl]-2-pyrazolin-5-one,

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)methylene]-2-pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[(4-ethoxycarbonylpyrrol-2-yl)rethylene]-2-pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[4-(2-dimethylaminoethoxycarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[4-(2-dimethylaminoethylaminocarbonylpyrrol-2yl)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-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[3-(2-dimethylaminoethylaminocarbonylindol-2yl)methylene]-2-pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[4-(4-morpholinoethoxycarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[4-(4-morpholinoethylaminocarbonylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[3-(4-morpholinoethoxycarbonylindol-2-yl)methylene]-2pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[3-(4-morpholinoethylaminocarbonylindol-2-yl)methylene]-2pyrazolin-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-dimethylaminoethoxycarbonyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one,

3-[2-(4-amino phenyl )ethyl]-4-{ [3,5-dimethyl-4-(2dimethylaminoethyl\'aminocarbonyl)pyrrol-2-yl]methylene}-2-pyrazolin-5-one, 3-[2-(4-amino phenyl )ethyl]-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

I» ·4·· ·· ··

3-[2-(4-aminophenyl)ethyl]-4-[(Indol-2-yl)methylene]-2-pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[(3,4-diethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4- {[3-(2-Acetamido-2-methoxycarbonylethyl)indol-2-yl]methylene}-3-[2-(4aminophenyl)ethyl]-2-pyrazolin-5-one,

4-{[3-(2-Amino-2-carboxyethyl)indol-2-yl]methylene}-3-[2-(4-aminophenyl)ethyl]-2pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[(5-ethoxy-4-methoxycarbonylmethyl-3methoxycarbonyl[beta]tol-2-yl)methylene]-2-pyrazolin-5-one,

3-[2-(4-aminophenyl)ethyl]-4-[(5-chloro-4-methoxycarbonylmethyl-3methoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-{[(4-methyl-1-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethanolaminomethyl-3,5-dimethylpynOl-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)

2-pyrazolin-5-one,

4-{[3-(4-Methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

3-(4-Pyrimidinyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one, • » · · • ·

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(4-pyrimidinyl)pyrazolin5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-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)-2pyrazolin-5-one,

4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-((3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolone,

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-(1-pyrrolidinylmethylpyrrol-2-yl)methylene)-3-(5-pyriniidinyl)-2pyrazobn-5-one,

4-((3,5-Dimethyl-4-diethylaminomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-((3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene)-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-{[3-(4-Methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(5pyrimidinyl)-2-pyrazolin-5-one, φ φ · ·

t ·

3-(5-Pyrimidinyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Dirnethylarnino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(5-pyrimidinyl)-2-pyrazolin-5-one,

4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-{[(4-methyl-1-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one, • * • · * · · ·

4- {[3-(4-Methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

3-(2-Pyrimidinyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene} 2-pyrazolin-5-one,

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrroI-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-{[(4-methyl-1-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)

2-pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin5-one,

4-[(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin-5-one.

tt · * ♦··· • * * ·

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-{{3-(4-Methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one,

3-(3-Pyridazinyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2-pyrazolin5-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)-2pyrazolin-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-pyrazolin5-one,

4-((3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin5-one,

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-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyriOl-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(piperidinomethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin5-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)-2pyrazolin-5-one,

4-[(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-{[3-(4-Methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

3-(4-Pyridazinyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

4-[(3-Piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-[(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2-pyrazolin5-one,

4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(4-pyridazinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

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-pyrazolin5-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,

4-[(3,5-Dimethyl-4-[(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2pyrazolin-5-one,

4-[(4-Diethanolaminomethyl-3,5-Dimethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2pyrazolin-5-one, » · *»»♦

3-(5-Isoxazolyl)-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2pyrazolin-5-one,

3-(5-Isoxazolyl)-4-{[3-(4-methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol-2ylmethylene}-2-pyrazolin-5-one,

3-(5-isoxazolyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2-yl]methylene}-2pyrazolin-5-one,

3-(5-Isoxazolyl)-4-[(3-piperidinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-2pyrazolin-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)methylene]-3-(5-isoxazolyl)-2-pyrazolin5-one,

4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-isoxazolyl)-2-pyrazolin-5-one,

4-[(4-Oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin-5-one,

4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-{[(4-methyl-1-piperazinylmethyl)pyrrol-2-yl]methylene}-3-(5-methyl3-isoxazolyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-[(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(5-methyl-3isoxazolyl)-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,

4-[(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl)methylene]-3-(5-methyl-3isoxazolyl)-2-pyrazolin-5-one,

4-[(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-methyl-3isoxazolyl)-2-pyrazolin-5-one,

II ·· « +

3-(5-Methyl-3-isoxazolyl)-4-[(3-morpholinomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]2-pyrazolin-5-one,

4-[(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-(5-methyl-3isoxazolyl)-2-pyrazolin-5-one,

3-(5-Methyl-3-isoxazolyl)-4-{[3-(4-methyl-1-piperazinyl)methyl-4,5-tetramethylenepyrrol2-yl]methylene}-2-pyrazolin-5-one,

3-(5-Methyl-3-isoxazolyl)-4-{[3-(1-pyrrolidinyl)methyl-4,5-tetramethylenepyrrol-2ylmethylene}-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-isoxazolyl)-2-pyrazolin-5-one,

4-[(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2pyrazolin-5-one,

4-(3,5-Dibromo-4-hydroxybenzylidene)-3-(5-methyl-3-isoxazolyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-methyl-3isoxazolyl)-2-pyrazoin-5-one,

3-(5-Methyl-3-isoxazolyl)-4-[(4-oxo-1,5,6,7-tetrahydroindol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(4-Dimethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5-methyl-3-isoxazolyl)-2pyrazolin-5-one,

3-cyclopropyl-4-(1-3-[(dimethylamino)methyl]-4,5,6,7-tetrahydro-1/7-2indolylmethylidene)-4,5-dihydro-1/7-5-pyrazolone, maleate salt of 3-cyclopropyl-4-(1-4-[(1,1-dimethylammonio)methyl]-3,5-dimethyl-1/7-2pyrrolylmethylidene)-4,5-dihydro-1/7-5-pyrazolone,

4-[1-(4-[[2-(dimethylamino)ethyl](methyl)amino]methyl-3,5-dimethyl-1//-2pyrrolyl)methylidene]-3-(2-pyrazinyl)-4,5-dihydro-1//-5-pyrazolone,

4-(1-4-[2-(diethylamino)ethyl]-3,5-dimethyl-1H-2-pyrrolylmethylidene)-3-(2-pyrazinyl)4,5-dihydro-1H-5-pyrazolone,

4-1-[4-(3-Chloropropanoyl)-3,5-dimethyl-1H-2-pyrrolyl]methylidene-3-(2-pyrazinyl)-4,5dihydro-1H-5-pyrazolone,

4-(1-3-[(dimethylamino)methyl]-4,5,6,7-tetrahydro-1//-2-indolylmethylidene)-3-(2-pyrazinyl)-4,5-dihydro-1//-5-pyrazolone, ·*· ·· • ·· r ι >·· *·

4-(1-4-[(dimethylamino)methyl]-3,5-dimethyl-177-2-pyrrolylmethylidene)-3-(5-methyl-3-isoxazolyl)-4,5-dihydro-1H-5-pyrazolone,

3-Cyclopropyl-4-[(4,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-Benzyl-4-[(pynol-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-[(pynOl-2-yl)methylene]-2-pyrazolin-5-one,

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,

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-[(p\Trol-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,

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,

3-(3-Chlorophenyloxymethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-(Indol-3-yl)-4-[(pyrcol-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-pyrazoliri-5-one,

3-(4-Methoxyphenylethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-(4-Phenylphenyloxymethyl)-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-DiTiethylpyrrol-2-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one,

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-[(pynOl-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,

3-(4-Chlorophenylethyl)-4-[(pyrrol-2-yl)methylene]-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, 3-Cyclopentyloxy-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

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-[(1-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-Isopropoxy-4-[(5-methylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

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,

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]-2pyrazolin-5-one,

4-[(5-Ethylpyrrol-2-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-ethylpynOl-2-yl)methylene]-3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one,

3-(Ethoxycarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-(4-Methoxyphenylaminocarbonylmethyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4- {(3-(2-Carboxyethyl)-4-methylpyrrol-2-yl]methylene}-3-isopropyl-2-pyrazolin-5-one, 3-Cyclopropyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-Cyclobutyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one, 3-(3-Pyridyl)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3- Cyclopropyl-4-[[1-(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,

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-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-pyrazolin-5-one,

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-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

-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)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)methylenej-2-pyrazolin-5-one,

3-Propyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

-Methyl-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

-(4-Isopropylphenylamino)-4-[(pyrrol-2-yl)methylenej-2-pyrazolin-5-one,

-(3-Penylamino)-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3- Cyclopropyl-4-{[1-(4-hydroxybutyl)pyrrol-2-yl]methylene]-2-pyrazolin-5-one,

4-{[4-(2-Carboxyethyl)-3-methylpyrrol-2-yl]methylene}-3-isopropoxy-2-pyrazolin-5-one, 4-[(4-Carboxy-3,5-dimethylpynOl-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-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)niethylene]-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-dimethylaminoethyloxycarbonyl)phenyl-2-yl]methylene}-3isopropoxy-2-pyrazolin-5-one,

4-{f3,5-Dimethyl-4-(2-dimethylaminoethylaminocarbonyl)pyrrol-2-y]]methylene}3isopropoxy-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,

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, 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-pyrazolin-5-one,

-Cyclopropyl-4-[(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-2-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]-2pyrazolin-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,

3-Isopropyl-4-[(pyrrol-2-yl)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,

3- Cyclopropyl-4-[(5-morpholinomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

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-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,

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-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-2yl]methylene}-2-pyrazolin-5-one, • · · · · ·

4-{[3,5-Dimethyl-4-(2-dimethylaminoethyloxycarbonyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolm-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, maleate salt of 4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-morpholinoylaminocarbonyl)pyrrol-2-yl]methylene-3-pyrazinyl-2-pyrazolin-5-one,

4-[(3,5-Dimethylpyrrol-2-yl)methylene]-3-(2-pyridyl)-2-pyrazolin-5-one,

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)methylene]-3-(2-furyl)-2-pyrazolin-5-one,

4-[(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

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,

3-Cyclopropyl-4-[(3,5-dimethyl-4-trifluoroacetamidomethylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-[(4-aminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-(Benzothiazol-2-yl)-4-[(3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

3-(Benzothiazol-2-yl)-4-[(3,5-dimethyl-4-morphoblinomethylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

4-[(3,5-Dimethyl-4-ethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

4-[(4-Ethoxycarbonylpyrrol-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-pyrazolin5-one,

4-[(3,5-Dimethyl-4-trifluoroacetamidomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

3- Cyclopropyl-4-[(4-ethoxycarbonyl-3-phenylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4- {[3,5-Dimethyl-4-(1-pyrrolidinylmethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(2-furyl)-2-pyrazolin-5-one.

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethyl- pynOl-2-yl)methylene]-3-(3-pyridyl)-2-pyrazolin5-one,

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,

4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(2-pyridylethyl)-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-3-(1-methyl-2-phenylethyl)-2-pyrazolin-5-one,

4-[(4-Carboxy-3,5-dimethylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one,

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}-3ethoxy-2-pyrazolin-5-one,

4-[(5-Chloro-3-methoxycarbonyl-4-methoxycarbonylmethylpyrrol-2-yl)methylene]-3ethoxy-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-one

3- Ethoxy-4-[(4,5-tetramethylenepyrrol-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-isoxazoyl)-2-pyrazolin-5-one,

3-(3-Aminophenyl)-4-[(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl)methylene]-2-pyrazolin5-one,

3- Ethoxy-4-{[2-(4-morpholinoethyl)aminocarbonylpyrrol-2-yl]methylene}-2-pyrazolin-5-one,

4- [(4-Ethoxycarbonyl-3-phenylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4-{[4-(4-Methyl-1-piperazinylmethyl)-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,

4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2-pyrazolin5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-isoxazolyl)-2pyrazolin-5-one,

4-[(5-Methyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one, 4- {{3,5-Dimethyl-4-[N-(2-dimethylaminoethyl)-7V-methylaminomethylpyrrol-2-yl}methylene}-3-pyrazmyl-2-pyrazolin-5-one,

3- Cyclopropyl-4-[(3-dimethylaminomethyl-4,5-tetramethylenepynOl-2-yl)methylene]-2pyrazolin-5-one,

4-[(3-Dimethylammomethyl-4,5-tetramethylenepyrrol-2-yl)methylene]-3-pyrazinyl-2pyrazolin-5-one, maleate salt of 3-Cyclopropyl-4-[(3,5-dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-2-pyrazolin-5-one,

4-{[4-(3-Chloropropionyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl)methylene]-3-(5-methyl-3isoxazolyl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(4-hydroxypiperidinomethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2pyrazolin-5-one, maleate salt of 4-[(4-Aminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-pyrazinyl-2pyrazolin-5-one,

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,

4-{{3,5-Dimethyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

3-Cyclopropyl-4- {{3,5-Dimethyl-4-[2-( 1 -pyrrolidinylethyl)]pyrrol-2-yl}methylene}-2pyrazolin-5-one, • · c · • · · · ······ · !

• ····· · ··· · • · ···· ·· ·· ·· ·· ·· ·· ·· ·· ··

3- Cyclopropyl-4-{[3,5-Dimethyl-4-(2-hydroxyethyl)pyrrol-2-yl]methylene}-2-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,

4-{[3,5-Dimethyl-4-(3-hydroxypropyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-[(3,5-dimethyl-4-dimethylaminoacetylpyrrol-2-yl)methylene]-3-pyrazinyl2-pyrazolin-5-one hydrochloride,

4-[(3,5-Dimethyl-4-dimethylaminoacetylpyrrol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one,

3- Cyclopropyl-4-{[(2-diethylaminoethyl)-3,5-dimethyl-4-pyrrol-2-yl]methylene}-2pyrazolin-5-one,

4- {[3,5-Dimethyl-4-(2-dimethylaminoethyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(4-hydroxybutyl)pynOl-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(4-Diethylaminobutyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin5-one,

4-{[4-(2-Diethylaminoethyl-α-oxide)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3,5-dimethyl-4-(1-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-Isopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-[3-(1-pyrrolidinylpropyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-[(Dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

3- Cyclopropyl-4-[(dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-2pyrazolin-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)methylene]-2-pyrazolin-5-one,

3- Benzyl-4-{[ 1-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one,

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,

4-[(Indol-3-yl)methylene]-3-phenylethyl-2-pyrazolin-5-one,

4-[(Indol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

4-[(Indol-3-yl)methylene]-3-(4-rnethylbenzyl)-2-pyrazolin-5-one,

4-[(Indol-3-yl)methylene]-3-phenylamino-2-pyrazolin-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,

3-(4-Chlorobenzyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one,

4-{[1-(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, 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-yl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one,

4-[(Indol-3-yl)methylene]-3-(4-methoxyphenylethyl)-2-pyrazolin-5-one,

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-yl)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,

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-pyrazolin-5-one,

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)methylene]-3-phenylethyl-2-pyrazolin-5-one,

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-[(1-isopropylindol-3-yl)methylene]-2-pyrazolin-5-one, 3-(4-Hydroxyphenylethyl)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

-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-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,

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,

-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-pyrazolin-5-one,

3- Cyclohexyl-4-{[1-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one,

4- {[1-(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- 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-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

3- Cyclopropyl-4-[(7-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[(1-Methylindol-3-yl)methylene]-3-(3-pyridyl)-2-pyrazolin-5-one,

4-[(indol-3-yl)methyl]-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,

4-{[1-(4-Hydroxybutyl)indol-3-yl]methylene}-3-methyl-2-pyrazolin-5-one,

4-{[1-(4-Hydroxybutyl)indol-3-yl]methylene}-3-trifluoromethyl-2-pyrazolin-5-one,

4-{[1-(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-1-cyclopropyl)-2-pyrazolin-5-one,

3- Cyclobutyl-4-{[1-(4-hydroxybutyl)indol-3-yl]methylene}-2-pyrazolin-5-one,

4-[(6-carboxy-1-methylindol-3-yl)methylene]-3-cyclopropyl-2-pyrazolin-5-one,

3- Cyclopropyl-4-((5-methoxy-1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[(1-Methylindol-3-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

3- Cyclopropyl-4-((1,7-dimethylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-((1-Methylindol-3-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one,

3- Cyclopropylamino-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[(6-Carboxy-1-methylindol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

4-((1,7-Dimethylindol-3-yl)methylene]-3-isopropoxy-2-pyrazolin-5-one,

3-Isopropoxy-4-[(5-methoxy-1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

3-(4-Fluorophenylamino)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[(1-Methylindol-3-yl)methylene]-3-trifluoroacetamido-2-pyrazolin-5-one,

3-(4-Aminophenylethyl)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

- Amino-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

3-(4-Chlorophenylethyl)-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one,

3-Ethoxy-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

3-(5-Isoxazolyl)-4-[(1-methylindol-3-yl)methylene]-2-pyrazolin-5-one,

4-[(1-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-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-Methoxycarbonylphenylethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one,

3-(4-Carbamoylphenethyl)-4-[(indol-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropyl-4-[(indol-2-yl)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-pyrazolin-5-one,

3- Isopropoxy-4-[(1-methylindol-2-yl)methylene]-2-pyrazolin-5-one,

4-[(bidol-2-yl)methylene]-3-(tetrahydrofuran-3-yl)-2-pyrazolin-5-one,

-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,

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}-2pyrazolin-5-one,

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,

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,

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-1,5,6,7-dihydroindol-2-yl)methylene]-3-pyrazinyl-2-pyrazolin-5-one,

4-[(3-Dimethylaminomethylindol-2-yl)methylene]-3-ethoxy-2-pyrazolin-5-one,

4-[(7-Azaindol-3-yl)methylene]-3-benzyl-2-pyrazolin-5-one,

3- Benzyl-4-{[1-(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,

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-pyrazolin-5-one,

4- {[1-(4-Hydroxybutyl)-7-azaindol-3-yl]methylene}-3-(4-hydroxyphenylethyl)-2-pyrazolin-5-one,

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,

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,

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,

4-{[1-(4-Hydroxybutyl)-7-azaindol-3-yl]methylene}-3-trifluoromethyl-2-pyrazolin5-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,

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,

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,

3- Cyclopropyl-4-[(thien-2-yl)methylene]-2-pyrazolin-5-one,

4-[(Indol-3-yl)methyl]-3-isopropyl-1-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)-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,

4- {[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin5-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)-2-pyrazolin-5-one,

4- {[4-(2-Diethylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2pyrazolin-5-one,

3-Cyclopropyl-4-[(3,5-dimethyl-4-(1-pyrrolidinylmethylpynol-2-yl)methylene]-2-pyrazolin-5-one,

3-Cyclopropyl-4-[(4-diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-2-pyrazolin5-one,

3-Cyclopropyl-4-{[4-(2-cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-2pyrazolin-5-one,

3-Cyclopropyl-4-{[3,5-dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-2-pyrazolin5-one,

3- Cyclopropyl-4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2yl}methylene}-2-pyrazolin-5-one,

4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-cyclopropyl-2-pyrazolin-5-one,

3-Cyclopropyl-4-[(4-diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-{[4-(1-pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-2pyrazolin-5-one,

3-Cyclopropyl-4- {{3-isopropyl-5-methyl-4-[2-(1 -pyrrolidinylethyl)]pyrrol-2yl}methylene}-2-pyrazolin-5-one, • · · · • ·

3-Cyclopropyl-4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2ylmethylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{ {4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

-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-2yl}methylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{[4-(4-dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}2-pyrazolin-5-one,

3- Cyclopropyl-4-[(3-cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-2pyrazolin-5-one,

3-Cyclopropyl-4-{[3-cyclopropyl-4-(1-pyrrolidinylmethyl)-5-methylpyrrol-2ylmethylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{{3-cyclopropyl-5-methyl-4-[2-(1-pyrrolidinyl)ethyl]pyrrol-2yl}methylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4- {{3-cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5 methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{[3-cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2yl]methylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{{3-cyclopropyl-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5methylpyrrol-2-yl}methylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{[3-cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2yljmethylene}-2-pyrazolin-5-one,

3-Cyclopropyl-4-{{3-cyclopropyl-5-methyl-4-[4-(1-pyrrolidinyl)butyl]pyrrol-2yl}methylene}-2-pyrazolin-5-one,

3- Cyclopropyl-4-{[3-cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2yl]methylene}-2-pyrazolin-5-one,

4- {[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-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-pyrazinyl2-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-pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3 pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

3- Pyrazinyl-4-{ {4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}2-pyrazolin-5-one,

4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pynol-2-yl]methylene}-3-pyrazinyl-2pyrazolin-5-one,

-Pyrazinyl-4- {{4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-pyrazinyl-2pyrazolin-5-one,

4-{ {3-Cyclopropyl-5-methyl-4-[2-(1-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,

4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[ 3 -Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl] mehylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[4-( 1 -pyrrolidinyl)butyl]pyrrol-2-yl[methylene[-3-pyrazinyl-2-pyrazolin-5-one, • · · ·

4-{[3-Cyclopropyl-5-niethyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazobn-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidmylmethylpyrrol-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)-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,

4-{{3,5-Dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(2-furyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(2-furyl)-2pyrazolin-5-one,

4-{[4-(1-Pyrrobdinylmethyl)-3-isopropyl-5-methylphenyl-2-yl]methylene}-3-(2-furyl)-2-pyrazobn-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-(1-pynolidinylethyl)]pyrrol-2-yl}methylene}-3-(2-furyl)-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-furyl)2-pyrazolin-5-one,

3-(2-Furyl)-4-{{4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpynOl-2-yl}methylene}2-pyrazolin-5-one,

3-(2-Furyl)-4-{[3-isopropyl-5-methyl-4-(4-piperidinobutyl)pynol-2-yl]methylene}2pyrazolin-5-one,

3-(2-Furyl)-4-{{4-[3-(4-pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-furyl)-2-pyrazobn-5-one,

4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(2-furyl)-2pyrazolin-5-one, • « · « · ι

4-{{3-Cyclopropyl-5-methyl-4-[2-(1-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-furyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-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-2yl}methylene}-3-(2-furyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)phenyl-2-yl]methylene}-3-(2furyl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[4-(1-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(2furyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(2furyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin5-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-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-pyrazolin5-one,

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-methylpyrrol-2-yl)methylene]-3-(2-thienyl)-2pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-thienyl)-2pyrazolin-5-one, • * • 9 · *

4- {{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(2-thienyl)2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3-isopropyl-5-methylpynOl-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{{4-[3-(1-Pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(2-thienyl)-2-pyrazolin-5-one,

4- {{4-[ 3 -(4-Pyridylmethylamino)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-methylpynOl-2-yl)methylene]-3-(2-thienyl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[2-(1-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3(2-thienyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-(2-thienyl)-2-pyrazolin-5-one,

4- {[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[4-(1-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(2thienyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)-2pyrazolin-5-one, «4 ··»·

4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-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)-2pyrazolin-5-one,

4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin5-one,

4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyrimidinyl)2-pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

3-(4-Pyrimidinyl)-4- {{4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

4- {[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(4-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-methylpyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-5-methyl-4-[2-(1-pyrrolidmyl)ethyl]pyrrol-2-yl}methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3(4-pyrimidinyl)-2-p\Tazolin-5-one, «« «·»· • ·· • · 4 * • · · • · · « «·· ·· »· «

• » ·· ·» »· • · · « • · · • « · • · » ·· »9 9 ·

4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl]methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-5-methyl-4-[4-(1-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(4pyrimidinyl)-2-pyrazolin-5-one,

4-[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(4-pyrimidinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(5-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)-2pyrazolin-5-one,

4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one,

4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(5-pyrimidine])-2-pyrazolin5-one,

4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(5-pyrimidinyl)2-pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(5pyrimidinyl)-2-pyrazolin-5-one,

4- {{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl (methylene}-3-(5pyrimidinyl)-2-pyrazolin-5-one,

4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(5pyrimidinyl)-2-pyrazolin-5-one, • · • · · · • * · · · · ··· ·· ·· · ·

3-(5-Pyrimidinyl)-4-{{4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-prazolin-5-one,

4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(5-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-p\Tazolin-5-one,

4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(5pyrimidinyl)-2-p\Tazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[2-(1-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(5pyrimidinyl)-2-p\Tazolin-5-one,

4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3(5-pyrimidinyl)-2-pyrazolin-5-one,

4-{[3-cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(5pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Cycloprop[1-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-(5-pyrimidinyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl]methylene}-3-(5pyrimidinyl)-2-pyrazolin-5-one,

4-{ {3-Cyclopropyl-5-methyl-4-[4-(1-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,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)pyritol-2-yl]methylene}-3-(2-pyrimidinyl)-2pyrazolin-5-one, • · • · · ·

• · · ·

4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(2pyrimidinyl)-2-p\Tazolin-5-one,

4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin5-one,

4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(2-pyrimidinyl)2-pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2pyrimidinyl)-2-pyrazolin-5-one,

4- {{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(2pyrimidinyl)-2-pyrazolin-5-one,

4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

3-(2-Pyrimidinyl)-4-{{4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)2-pyrazolin-5-one,

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-(2pyrimidinyl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[2-(1-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(2pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}methylene}-3(2-pyrimidinyl)-2-pyrazolin-5-one,

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-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one, • · • · · ♦ · · · ··· · · • « · · · · · · · · · · · · · · · ·

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl]methylene}-3-(2-pyrimidinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-5-methyl-4-[4-(1-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,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpynol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(3-pyridazinyl)-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)"3,5-dimethylpyrrol-2-yl]methylene}-3-(3-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-pyridazmyl)-2-pyrazolin-5-one,

4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(3pyridazinyl)-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-pyridazinyl)2-pyrazolin-5-one,

4-{[4-(1-Pyrrolidin-1-methyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)2-pyrazolin-5-one,

4- {{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pynOl-2-yl}methylene}-3-(3pyridazinyl)-2-pyrazolin-5-one,

4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one,

3-(3-Pyridazinyl)-4-{ {4-[3-(1-pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

4- {[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(3-pyridazinyl)-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-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-pyridazinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-5-methyl-4-[2-(1-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,

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-2yl}methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol'2-yl]methylene}-3-(3-pyridazinyl)-2-pyrazolin-5-one,

4-{{3-Cycloprop[i]-5-methyl-4-[4-(1-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,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpynOl-2-yl)methylene]-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2pyrazolin-5-one,

4- {[3,5-Dimethyl-4-(2-ethylaminoethyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one,

4-{}3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl(methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one, • · · ·

• 9

4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(4-pyridazinyl)2-pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

4- {[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin5-one,

4-{{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

3-(4-Pyridazinyl)-4-{ {4-(3-(1 -pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2yl}methylene}-2-pyrazolin-5-one,

4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(4-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-pyridazinyl)-2-pyrazolin-5-one,

4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(4pyridazinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-5-methyl-4-[2-(1-pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl}rnethylene}-3(4-pyridazinyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl]methylene}-3-(4-pyridazinyl)-2-pyrazolin-5-one,

4-{ {3-Cyclopropyl-5-methyl-4-[4-(1-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]rnethylene}-3-(4pyridazinyl)-2-pyrazolin-5-one,

4-[(3,5-Dimethyl-4-(1-pyrrolidinylmethylpynOl-2-yl)methylene]-3-(1,2,4-triazin-3-yl)-2pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl)methylene]-3-(1,2,4-triazin-3-yl)-2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(1,2,4-triazin-3yl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-ethylaminoethyl)pyrrol-2-yl]methylene}-3-(1,2,4-triazm-3-yl)-2-pyrazolin-5-one,

4-{[3,5-Dimethyl-4-(2-phenylaminoethyl)pyrrol-2-yl]methylene}-3-(1,2,4-triazin-3-yl)-2pyrazolin-5-one,

4-{{3,5-dimethyl-4-[2-(4-pyridylmethylamino)ethyl]pyrrol-2-yl}methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{[4-(2-Carboxyethyl)-3,5-dimethylpyrrol-2-yl]methylene}-3-(1,2,4-triazin-3-yl)-2-pyrazolin-5-one,

4-[(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl)methylene]-3-(1,2,4-triazin-3yl)-2-pyrazolin-5-one,

4-{[4-(1-Pyrrolidinylmethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(1,2,4-triazin3-yl)-2-pyrazolin-5-one,

4-{{3-Isopropyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{[4-(2-cyclopropylaminoethyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{{4-[3-(1-Pyrrolidinyl)propyl]-3-isopropyl-5-methylpyrrol-2-yl}methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{[3-Isopropyl-5-methyl-4-(4-piperidinobutyl)pyrrol-2-yl]methylene}-3-(1,2,4-triazin-3yl)-2-pyrazolin-5-one,

4-{{4-[3-(4-Pyridylmethylamino)propyl]-3-isopropyl-5-methylpyrrol-2-yl} methylene}-3(1,2,4-triazin-3-yl)-2-pyrazolin-5-one,

4-{[4-(4-Dimethylaminobutyl)-3-isopropyl-5-methylpyrrol-2-yl]methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-[(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl)methylene]-3-(1,2,4-triazin3-yl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[2-( 1 -pyrrolidinyl)ethyl]pyrrol-2-yl}methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[2-di(methoxyethyl)aminoethyl]-5-methylpyrrol-2-yl} methylene}-3(1,2,4-triazin-3-yl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-4-(3-diethylaminopropyl)-5-methylpyrrol-2-yl]methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{{3-Cyclopropyl-4-[3-(2,5-dimethyl-1-pyrrolidinyl)propyl]-5-methylpyrrol-2yl}methylene}-3-(1,2,4-triazin-3-yl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(3-phenylmethylaminopropyl)pyrrol-2-yl]methylene}-3(1,2,4-triazin-3-yl)-2-pyrazolin-5-one,

4- {{3-Cyclopropyl-5-methyl-4-[4-(1-pyrrolidinyl)butyl]pyrrol-2-yl}methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{[3-Cyclopropyl-5-methyl-4-(4-cyclobutylaminobutyl)pyrrol-2-yl]methylene}-3-(1,2,4triazin-3-yl)-2-pyrazolin-5-one,

4-{[4-(2-Diethylaminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{{5-Methyl-4-[2-(1-pyrrolidinylethyl)]-3-trifluoromethylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{5-Methyl-4-[2-(4-pyridylmethylaminoethyl)]-3-trifluoromethylpyrrol-2-yl]methylene}3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-trifluoromethylpyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Aminoethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-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-( 1 -pyrrolidinylethyl)]-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-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-pyridylmethylaminoethyl)]-3-tert-butylpynOl-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[4-(2-Aminoethyl)-5-methyl-3-tert-butylpyrrol-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,

4-{{3-Ethyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[3-Ethyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{3-Ethyl-5-methyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-ethylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Aminoethyl)-5-methyl-3-ethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3-Cyclobutyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{3-Cyclobutyl-5-methyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[3-Cyclobutyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{3-Cyclobutyl-5-methyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-cyclobutylpyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Aminoethyl)-5-methyl-3-cyclobutylpyrrol-2-yl]methylene}-3-pyrazinyl-2' pyrazolin-5-one,

4-{[3-Cyclopentyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{{3-Cyclopentyl-5-methyl-4-[2-(1-pyrrolidinylethyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3-Cyclopentyl-4-(2-ethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {3-Cyclopentyl-5-methyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-cyclopentylpyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Aminoethyl)-5-methyl-3-cyclopentylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3-Cyclohexyl-4-(2-diethylaminoethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

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-Cyclohexyl-5-methyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-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,

4-{[4-(2-Diethylaminoethyl)-5-methyl-3-phenylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-} {5-Methyl-3-phenyl-4-[2-(1-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-pyrazolin-5-one,

4-{ {5-Methyl-3-phenyl-4-[2-(4-pyridylinethylaminoethyl)]pyrrol-2-yl} methylene}-3pyrazinyl-2-pyrazolin-5-one, • ·

Λ Λ Λ and

4-{(4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-phenylpyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one,

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-pyrazolin-5-one,

4- {{5-Methyl-3-(4-methoxyphenyl)-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-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-pyridylmethylaminoethyl)]pyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-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-pyrazinyl-2-pyrazolin-5-one,

4-{{5-Methyl-3-(2-pyridyl)-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{5-Methyl-3-(2-pyridyl)-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-(2-pyridyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[4-(2-Aminoethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-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-(1-pyrrolidinylethyl)]pyrrol-2-yl} methylene}-3-pyrazinyl-2pyrazolin-5-one, • ·

4-{[4-(2-Ethylaminoethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{5-Methyl-3-pyrazinyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{j 4-[2-(1-Imidazoyl)ethyl]~5-methyl-3-pyrazinylpyriTol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-1[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-(1-pyriOlidinylethyl)]pyrrol-2-yl}methylene-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-pyndylmethylaminoethyl)]pyrrol-2-yl}methylene}3-pyrazinyl-2-pyrazolin-5-one,

4- {{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-(2-imidazoyl)pyrrol-2-yl}methylene}-3pyrazinyl-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)pynOl-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{ {5-Methyl-3-(2-pyrimidinyl)-4-[2-(1-pyridolidinylethyl)]phenyl-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-([4-(2-Ethylaminoethyl)-5-methyl-3-(2-pyrimidinyl)pyriOl-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{{5-Methyl-3-(2-pyrimidinyl)-4-[2-(4-β-ylmethylaminoethyl)]phenyl-2-yl methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl}methylene}-3pyrazinyl-2-piazolin-5-one,

4-{[4-(2-Cyclopropylaniinoyl)-5-methyl-3-(2-p>THImidinyl)pyriOl-2-yl]inethylene}-3pyrazinyl-2-pyrazolin-5-one, «· · 9 · · · • · · · ·

4-([4-(2-Diethylininoethyl)-5-methyl-3-(3-isoxazolyl)pynOl-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{}5-Methyl-3-(3-isoxazolyl)-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl! methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2pyrazolin-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-(1-Imidazoyl)ethyl]-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl}methylene}-3-pyrazinyl2-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,

4-{{5-Methyl-3-(2-furyl)-4-[2-(1-pyrrolidinylethyl)pyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-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-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{ {4-[2-(1-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-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Diethylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {5-Hydroxymethyl-3-isopropyl-4-[2-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{ {5-Hydroxymethyl-3-isopropyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one, • · • ····· · » * · · · • · ···· ··· ··· ·· ·· ·· ·· ····

4-{{4-[2-(1-Irnidazoyl)ethyl]-5-hydroxymethyl-3-isopropylpyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminoethyl)-5-hydroxymethyl-3-isopropylpyrrol-2-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-(1-pyrrolidinylethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminoethyl)-3,5-dicyclopropylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{3,5-Dicyclopropyl-4-[2-(4-pyridylmethylaminoethyl)]pyrrol-2-yl}methylene}3pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)ethyl]-3,5-dicyclopropylpyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-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,

4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{5-Methyl-4-[2-(1-pyrrolidinylrnethyl)]-3-trifluoromethylpyrrol-2-yl}rnethylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-5-methyl-3-trifluoromethylpyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{{5-Methyl-4-[2-(4-pyridylmethylaminornethyl)]-3-trifluoromethylpyrrol-2yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-trifluoromethylpyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

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-2pyrazolin-5-one, • · · · • · · · • · ·

9 9

9 9 •9 9999

4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{{5-Methyl-4-[2-(1-pyrrolidinylmethyl)]-3-tert-butylpyrrol-2-yl}methylene}-3-pyrazinyl2-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-pyridylmethylaminomethyl)]-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{4-(2-(1 -Imidazoyl)methyl]-5-rnethyl-3-tert-butylpynOl-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[4-(2-Aminomethyl)-5-methyl-3-tert-butylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

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-(1-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazmyl-2pyrazolin-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-pyridylmethylaminomethyl)]pyrrol-2-yl]methylene}3pyrazinyl-2-pyrazolin-5-one,

4- {(4-(2-(1 -Imidazoyl)methyl]-5-methyl-3-ethylpyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[4-(2-Aminomethyl)-5-methyl-3-ethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin5-one,

4-{(3-Cyclobutyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl2-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-( 1 -pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one, • · · · , ·« ·· ·»·· · * «··· ·* · · · • ····* · ·· · • · · · · ·· • » · · · · ·· · ·

4-{[3-Cyclobutyl-4-(2-ethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazobn-5-one,

4-{ {3-Cyclobutyl-5-methyl-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-cyclobutylpyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

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-dimethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {3-Cyclopentyl-5-methyl-4-[2-(1-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2-pyrazobn-5-one,

4-{[3-Cyclopentyl-4-(2-ethylaminomethyl)-5-methylpynol-2-yl]methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{{3-Cyclopentyl-5-methyl-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2-yl]methylene}3-pyrazinyl-2-pyrazolin-5-one,

4-{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-cyclopentylpyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Aminomethyl)-5-methyl-3-cyclopentylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one

4-{[3-Cyclohexyl-4-(2-diethylaminomethyl)-5-methylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[3-Cyclohexyl-4-(2-dimethylaminomethyl)-5-methylpynOl-2-yl]rnethylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {3-Cyclohexyl-5-methyl-4-[2-(1-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-pyridylmethylaminomethyl)]pynol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one, .· ·· ···· ·· *· ...... · * · ♦ ’

4-{ {4-[2-(1-Imidazoyl)methyl]-5-methyl-3-cyclohexylpyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Aminomethyl)-5-methyl-3-cyclohexylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

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-(1-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-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-pyridylmethylaminomethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-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-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{{5-Methyl-3-(4-methoxyphenyl)-4-[2-(1-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{ {5-Methyl-3-(4-methoxyphenyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {4-[2-(1-Imidazoyl)methyl]-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl} methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Aminomethyl)-5-methyl-3-(4-methoxyphenyl)pyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one, • · * · · · » • ·« · *

4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{5-Methyl-3-(2-pyridyl-4-[2-(1-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {5-Methyl-3-(2-pyridyl)-4-[2-(4-pyridylmethylaminomethyl)]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-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Aminomethyl)-5-methyl-3-(2-pyridyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-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-pyrazmylpyrrol-2-yl]methylene}-3-pyrazyn]2-pyrazolin-5-one,

4- {{5-Methyl-3-pyrazinyl-4-[2-(1-pyrrolidinylmethyl)pyrrol-2-yl}methylene}-3-pyrazinyl2-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-pyridylmethylaminomethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{ {4-[2-(1-Imidazoyl)methyl]-5-methyl-3-pyrazinylpynol-2-yl}methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-pyrazinylpyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrroI-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one, • « 4 » · ·

4-{ }5-Methyl-3-(2-imidazoyl)-4-[2-(1-pyrrolidinylmethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{{5-Methyl-3-(2-imidazoyl)-4-[2-(4-pyridylmethylaminomethyl))pyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-(2-imidazoyl)pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(2-imidazoyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Diethylaminomethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Dimethylaminomethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{{5-Methyl-3-(2-pyrimidinyl)-4-[2-(1-pyrrolidinylmethyl)}pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{{5-Methyl-3-(2-pyrimidinyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(2-pyrimidinyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Diethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl2-pyrazolin-5-one,

4-{[4-(2-Dimethylaminoethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4- {{5-Methyl-3-(3-isoxazolyl)-4-[2-(1-pyrrolidinylmethyl)}pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl}methylene}-3-pyrazinyl2-pyrazolin-5-one, • 4 * *» · • · • « · · · · ··* >·· 4 » 4 4 · · * * ·»·

4-{ {5-Methyl-3-(3-isoxazolyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{[4-(2-Cyclopropylaminomethyl)-5-methyl-3-(3-isoxazolyl)pyrrol-2-yl]methylene}-3pyrazinyl-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-pyrazinyl2-pyrazolin-5-one,

4-{ {5-Methyl-3-(2-furyl)-4-[2-(1-pyrrolidinylmethyl)]pynol-2-yl}methylene}-3-pyrazinyl2-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-furyl)-4-[2-(4-pyridylmethylaminomethyl)]pyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

4-{{4-[2-(1-Imidazoyl)methyl]-5-methyl-3-(2-furyl)phenyl-2-yl}methylene}-3-pyrazinyl-2pyrazolin-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-(1-pyrrolidinylmethyl)]pynOl-2-yl}methylene}-3pyrazinyl-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-pyridylmethylaminomethyl)]pyrrol-2yl}methylene}-3-pyrazinyl-2-pyrazolin-5-one,

4-{ {4-[2-(1-Imidazoyl)methyl]-5-hydroxymethyl-3-isopropylpyrrol-2-yl}methylene}-3pyrazinyl-2-pyrazolin-5-one,

Φ· ···*

Φ· » * φ φ* • φ · φ φ · ·

Φ » · Ο ·· »* φφ φ* • φ φ φ • * · φ φ * · • 9 *

ΦΦ ·»··

5-{[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-2pyrazolin-5-one,

4-{[4-(2-Ethylaminomethyl)-3,5-dicyclopropylpynOl-2-yl]methylene}-3-pyrazinyl-2pyrazolin-5-one,

4-{{3,5-Dicyclopropyl-4-[2-(4-pyridylmethylaminomethyl)]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,

4-[(4-Cyclopropylaminomethyl-3,5-dicyclopropylpyrrol-2-yl)methylene]-3-pyrazinyl-2pyrazolin-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-pyrazinyl-2-pyrazolin-5-one,

4-{[3-dimethylaminomethyl-5-methyl-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one, and 4-{[3-hydroxymethyl-5-methyl-4-(2-diethylaminoethyl)pyrrol-2-yl]methylene}-3pyrazinyl-2-pyrazolin-5-one.

The compounds of formula (I) may exist as salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [e.g., (+)-tartrates, (-)-tartrates, or mixtures thereof, including racemic mixtures], succinates, benzoates, and salts with amino acids such as glutamic acid. These salts may be prepared by standard methods.

Certain compounds of formula (I) having acidic substituents may exist as salts with pharmaceutically acceptable bases. The present invention includes such salts. Examples of such salts include sodium, potassium, lysine and arginine salts. These salts may be prepared by standard methods.

Certain compounds of formula (I) and their salts may exist in more than one crystalline form, and the present invention includes each of these crystalline forms and mixtures thereof.

Certain compounds of formula (I) and their salts may also exist in the form of solvates, e.g. hydrates, and the present invention includes each such solvate and mixtures thereof.

Certain compounds of formula (I) may contain one or more chiral centers and therefore exist in different optically active forms. When compounds of formula (I) contain one chiral center, then the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. Enantiomers may be separated by standard methods, e.g. by the formation of diastereomeric salts which can be separated, e.g. by crystallization; by the formation of diastereomeric derivatives or complexes which can be separated, e.g. by crystallization, GLC or LC; by the selective reaction of one of the enantiomers with an enantiomerically selective agent, e.g. by enzymatic esterification; or by GLC or LC in a chiral environment, e.g. on a chiral auxiliary medium, e.g. silica gel with a bound chiral ligand or in the presence of a chiral solvent. Where the desired enantiomer is converted to another chemical entity by one of the above methods, a further step is required to release the desired enantiomeric form.

Alternatively, specific enantiomers can be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts, or solvents, or by converting one enantiomer to the other by asymmetric transformation.

If a compound of formula (I) contains more than one chiral center, it may exist in diastereoisomeric forms. Diastereoisomeric pairs may be separated by standard methods, e.g., chromatography or crystallization, and the individual enantiomers in each pair may be separated by the methods described above. The present invention includes each diastereoisomer of the compounds of formula (I) and mixtures thereof.

Certain compounds of formula (I) may exist in different tautomeric forms or as different geometric isomers, and the present invention includes each such 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 its limited rotation about an asymmetric single bond, e.g. due to steric hindrance or ring strain, may allow the separation of different conformers. The present invention includes each of these conformational isomers of compounds of formula (I) and mixtures thereof.

Certain compounds of formula (I) may exist in the form of a zwitterion of a compound of formula (I) and mixtures thereof.

The compounds of the present invention are effective as inhibitors of serine/threonine kinases and tyrosine kinases. In particular, the compounds of the present invention are effective as inhibitors of tyrosine kinases, which are important in hyperproliferative diseases, especially in the process of angiogenesis. For example, certain of these compounds are inhibitors of receptor kinases, e.g. KDR, Flt-1, FGFR, PDGFR, c-Met or IGF-1-R. Since these compounds are antiangiogenic, they are important agents for inhibiting the progression of disease states in which angiogenesis plays an important role. Certain of the compounds of the present invention are effective as inhibitors of serine/threonine kinases, e.g. erk, MAP kinases, cdks, Plk-1 or Raf-1. These compounds are effective in the treatment of cancer and hyperproliferative disorders. Furthermore, certain of the compounds are effective inhibitors of non-receptor kinases, e.g. src, lyn, lek, fyn, blk, hek. These compounds are effective in the treatment of cancer, hyperproliferative disorders and immunological diseases.

The present invention provides a method of inhibiting the kinase activity of tyrosine kinases and serine/threonine kinases comprising administering a compound represented by general formula (I) to said kinase at a concentration sufficient to inhibit the enzymatic activity of said kinase.

The present invention further includes the use of these compounds in pharmaceutical compositions comprising a pharmaceutically effective amount of the above compounds and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions can be administered to recipients to slow or stop the process of angiogenesis in diseases that promote angiogenesis or to treat edema, effusions, exudates or ascites and other conditions associated with vascular hyperpermeability. Certain pharmaceutical compositions can be administered to recipients to treat cancer and hyperproliferative disorders by inhibiting serine/threonine kinases. e.g. cdk, Plk-1, erk, etc.

Detailed description of the invention

The compounds of the present invention have antiangiogenic properties. These antiangiogenic properties are due at least in part to the inhibition of protein tyrosine kinases essential for the angiogenic process. Therefore, these compounds can be used as active agents against disease states, e.g., arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral collaterals, ischemic limb angiogenesis, wound healing, Helicobacter-associated peptic ulcer, virus-induced angiogenic disorders, fractures, CrowFukas syndrome (POEMS), preeclampsia, menometrorrhagia, cat scratch fever, rubeosis, neovascular glaucoma, and retinopathy, e.g., that associated with diabetic retinopathy, retinopathy of prematurity, or age-related macular degeneration. Furthermore, some of these compounds may be used as active agents against solid tumors, malignant ascites, hematopoietic cancers and hyperproliferative disorders, e.g., thyroid hyperplasia (especially Graves' disease), and cysts (e.g., hypervascular ovarian stroma characteristic of polycystic ovary syndrome (Stein-Leventhal syndrome), since such diseases require proliferation of blood vessel cells for growth and/or metastasis.

Furthermore, some of these compounds may be used as active agents against burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, delayed-type hypersensitivity, ovarian hyperstimulation syndrome, cerebral edema associated with brain tumors, altitude sickness, trauma or hypoxia-induced cerebral or pulmonary edema, ocular or macular edema, ascites and other diseases in which vascular hyperpermeability, effusion, exudate, protein extravasation or edema is a manifestation of the disease. The compounds will also be effective 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 production of VEGF potentiates inflammatory processes, e.g., monocyte recruitment and activation. The compounds of the present invention will also be effective in the treatment of inflammatory disorders, e.g., inflammatory bowel disease (IBD) and Crohn's disease.

VEGFs are unique in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and edema formation. It appears that vascular hyperpermeability and edema, which are associated with the expression or application of many other growth factors, may be mediated through VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia leads to significant upregulation of VEGF in many tissues, and thus situations involving infarction, occlusion, ischemia, anemia, or circulatory failure typically • · · · .:. ..· ·.. · .· .....

use VEGF/VPF-mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange, and macromolecular extravasation, often accompanied by diapedesis, can result in excess matrix deposition, aberrant stromal proliferation, fibrosis, etc. Thus, VEGF-mediated hyperpermeability may contribute significantly to disorders with the aforementioned etiological features.

The above disorders are believed to be mediated to a significant extent by the activity of protein tyrosine kinases including KDR/VEGFR-2 and/or Flt-1/VEGFR-1 tyrosine kinases. By inhibiting the activity of these tyrosine kinases, the progression of the disorders is inhibited because the angiogenic or vascular component of the hyperpermeability of the disease states is critically reduced. The efficacy of certain compounds of the present invention, due to their selectivity for specific tyrosine kinases, results in minimizing the side effects that would occur if tyrosine kinase inhibitors with less selectivity were used. Certain compounds of the present invention are also potent inhibitors of FGFR, PDGFR, c-Met and IGF-1-R. These receptor kinases can directly or indirectly potentiate angiogenic and hyperproliferative responses in various disorders, and therefore their inhibition can prevent disease progression.

The compounds of the present invention have inhibitory activity against protein kinases, which means that these compounds modulate the signal transduction of protein kinases. The compounds of the present invention inhibit protein kinases of the serine/threonine kinase and tyrosine kinase families. In particular, these compounds selectively inhibit the activity of KDR/FLK-1/VEGFR-2 tyrosine kinases. Certain compounds of the present invention also inhibit the activity of other tyrosine kinases, e.g. Flt-1/VEGFR-1, FGFR, PDGFR, IGF-IR, c-Met, Src-subfamily kinases, e.g. Lek, Src, fyn, yes, etc. Furthermore, some compounds of the present invention significantly inhibit serine/threonine kinases, e.g. PKC, MAP kinases, erk, CDKs. Plk-1 or Raf-1, which play an important role in cell proliferation and cell cycle progression. The potency and specificity of the generic compounds of the invention towards an individual protein kinase can often be altered and optimized by variations in the nature, number and arrangement of substituents (i.e. R1, _R2 , R3, R4, R5, R6 and _R7 ) and conformational constraints. In addition, metabolites of certain compounds may also have significant inhibitory activity against protein kinases.

The compounds of the present invention, when administered to recipients in need thereof, inhibit vascular hyperpermeability and edema formation in such recipients. It is believed that these compounds act by inhibiting the activity of the KDR tyrosine kinase, which is involved in the process of vascular hyperpermeability and edema formation. KDR tyrosine kinase may also be referred to as FLK-1 tyrosine kinase, NYK tyrosine kinase, or VEGFR-2 tyrosine kinase. KDR tyrosine kinase is activated when vascular endothelial cell growth factor (VEGFR) or another activating ligand (e.g., VEGF-C, YEGF-D, VEGF-E, or HIV Tat protein) binds to the KDR tyrosine kinase receptor, which is located on the surface of vascular endothelial cells. Upon activation of KDR tyrosine kinase, hyperpermeability of blood vessels occurs and fluid migrates from the bloodstream through the blood vessel walls into the interstitial spaces, thereby creating an area of edema. This form of response is also often accompanied by diapedesis. Similarly, excessive vascular hyperpermeability can disrupt normal molecular exchange across the endothelium in critical tissues and organs (e.g., lung and kidney), causing macromolecules to extravasate and deposit. Following this acute response to KDR stimulation, which is thought to promote the subsequent angiogenic process, prolonged stimulation of the KDR tyrosine kinase leads to proliferation and chemotaxis of vascular endothelial cells and the formation of new vessels. Inhibition of KDR tyrosine kinase activity, either by blocking the production of activated ligand, blocking the binding of activated ligand to the KDR tyrosine kinase receptor, preventing receptor dimerization and transphosphorylation, inhibiting the enzymatic activity of KDR tyrosine kinase (inhibiting the phosphorylation function of the enzyme), or by some other mechanism that interrupts the downstream signaling pathway (D. Mukhopedhyay et al., Cancer Res. 55:1278-1284 (1998) and references therein), can inhibit and minimize hyperpermeability, as well as the associated extravasation, subsequent edema formation and matrix deposition, and angiogenic responses.

One group of preferred compounds of the present invention has the ability to inhibit KDR tyrosine kinase activity without significantly inhibiting Flt-1 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 the binding of VEGF to KDR tyrosine kinase receptors and Flt-1 tyrosine kinase receptors, respectively. Since Flt-1 tyrosine kinase activity may mediate important events in endothelial vasculature and vascular function, inhibition of the activity of this enzyme may have toxic or adverse effects. At the very least, such inhibition is unnecessary due to the blocking of angiogenic responses, induction of vascular hyperpermeability, and edema formation, so that it is not strictly necessary and does not confer any benefit to the recipient. Certain preferred compounds of the present invention are unique in that they inhibit the activity of a single VEGF• · · · • · · ·

100 receptor tyrosine kinase (KDR), which is activated by the activated ligand, but do not inhibit other receptor tyrosine kinases, e.g. Flt-1, which are also activated by certain activated ligands. Therefore, preferred compounds of the present invention are selective inhibitors of tyrosine kinase activity.

The compounds of the present invention are also effective in the treatment of bacterial, fungal, Mooren ulcers and ulcerative colitis.

The compounds of the present invention are also effective in treating conditions in which unwanted angiogenesis, edema or stromal deposition occurs in viral infections, e.g. Herpes simplex, Herpes Zoster, AIDS, parapoxvirus, psoriasis, Kaposi's sarcoma, protozoal infections and toxoplasmosis, endometriosis, ovarian hyperstimulation syndrome, preeclampsia, menometrorrhagia, systemic lupus, sarcoidosis, synovitis, inflammatory bowel disease, Crohn's disease, sickle cell anemia, Lyme disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rend disease, chronic inflammation, chronic obstructive pulmonary disease, asthma, rheumatoid arthritis and osteoarthritis and edema following trauma, burns, radiation or stroke.

The compounds of the present invention are also effective in the treatment of ocular conditions such as, for example, ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, physiological papillary excavation, chronic retinal detachment, complications following laser treatment, conjunctivitis, Stargardt's disease and Eales' disease in addition to retinopathy and macular degeneration.

The compounds of the present invention are also effective in the treatment of cardiovascular conditions, e.g., atherosclerosis, restenosis, vascular occlusion, and carotid obstructive disease.

The compounds of the present invention are also effective in the treatment of cancer-related indications such as, for example, solid tumors, sarcomas (especially Ewing's sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcomas, neuroblastoma, hematopoietic malignancies, including leukemia and lymphoma, tumor-induced pleural or pericardial effusions, and malignant ascites.

The compounds of the present invention are also effective in the treatment of Crow-Fukase syndrome (POEMS) and diabetic conditions, e.g., glaucoma, diabetic retinopathy, and microangiopathy.

The above disorders are believed to be significantly mediated by the activity of protein tyrosine kinases including VEGF receptors (e.g. KDR and Flt-1). Inhibition

101

By inhibiting the activity of these receptor tyrosine kinases, the progression of the disorders is inhibited, as the angiogenic component of the disease state is strongly reduced. The action of the compounds of the present invention, due to selectivity for specific tyrosine kinases, leads to the minimization of side effects that could occur if less selective tyrosine kinase inhibitors were used.

In a further aspect, the present invention provides compounds of formula (I) as defined above (including exceptions) for use as medicaments, in particular as inhibitors of protein kinase activity, e.g. tyrosine kinase, serine kinase and threonine kinase activity. In yet another aspect, the present invention provides the use of compounds of formula (I) as defined above (including exceptions) in the manufacture of a medicament for inhibiting protein kinase activity.

The following terms are used in the present invention:

The term "physiologically acceptable salts" refers to those salts which retain the biological activity and properties of the free bases and which are prepared by the reaction of inorganic acids, e.g. hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, or organic acids, e.g. sulfuric, carboxylic, organophosphoric, methanesulfonic, ethanesulfonic, /?-toluenesulfonic, salicylic, lactic, tartaric acids, etc.

The term "alkyl group" refers to an aliphatic hydrocarbon including straight and branched chain groups having 1 to 6 carbon atoms or cyclic hydrocarbons having 3 to 6 carbon atoms.

The term "alkoxy" refers to an "O-alkyl" group, in which "alkyl" is defined above.

Pharmaceutical formulations

The compounds of the present invention may be administered to human or animal subjects as such or in pharmaceutical formulations in which they are mixed with suitable carriers or excipients in doses sufficient to treat or ameliorate vascular hyperpermeability, edema and related disorders. Mixtures of these compounds may also be administered to patients as a single mixture or in suitable prepared pharmaceutical formulations. A therapeutically effective dose further refers to an amount of the compound or compounds sufficient to prevent or • « · ·

102 attenuation of inappropriate neovascularization, progression of hyperproliferative disorders, edema, VEGF-related hyperpermeability, and/or VEGF-related hypotension. Techniques for preparing and administering the compounds can be found in "Remington's Pharmaceutical Sciences", Mack Publishing Co., Easton, PA, latest edition.

Methods of administration

Suitable routes of administration may be, for example, oral, in the form of eye drops, rectal, transmucosal, topical or intestinal administration, parenteral delivery including intramuscular, subcutaneous and intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections.

Alternatively, the compound can be administered in a local rather than systemic manner, e.g., by injecting the compound directly into the site of edema, often in a depot or sustained-release formulation.

Furthermore, the drug can be administered as a target-specific delivery, e.g., in a liposome coated with an endothelial, cell-specific antibody.

Preparations/Formulations

The pharmaceutical preparations of the present invention can be manufactured in a standard manner, e.g. by standard mixing, dissolving, granulating, dragee-making, grinding, emulsifying, encapsulating, enclosing or lyophilizing.

Pharmaceutical compositions for use according to the present invention may thus be prepared in a standard manner using one or more physiologically acceptable carriers containing excipients and auxiliaries which facilitate the processing of the active compounds into preparations for use in the pharmaceutical method. The actual preparation depends on the chosen route of administration.

For injection, the agents of the present invention can be prepared in aqueous solutions, preferably in physiologically compatible buffers, such as Hanks' solution, Ringer's solution or saline-based buffers. For transmucosal administration, penetrants suitable for overcoming the barrier are used in the formulation. These penetrants are generally known.

0

0 0 0

103

For oral administration, the compounds can be readily prepared by combining the active compounds with standard pharmaceutically acceptable carriers. These carriers enable the compounds of the present invention to be prepared in the form of tablets, pills, dragees, capsules, solutions, gels, syrups, injection mixtures, suspensions, etc., for oral administration of the drug by the patient to be treated. Pharmaceutical preparations for oral use can be prepared by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and after adding suitable auxiliaries, if necessary, processing the mixture of granules, whereby tablets or dragees can be obtained. Suitable excipients are in particular fillers, e.g. sugars including lactose, sucrose, mannitol or sorbitol; cellulose preparations, e.g. corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose, hydroxypropyl methyl cellulose, sodium carboxymethyl cellulose and/or polyvinylpyrrolidone (PVP). If necessary, disintegrating agents may be added to ensure the tablet disintegration after ingestion, e.g. cross-linked polyvinylpyrrolidone, agar or alginic acid or their salts, e.g. sodium alginate.

The dragees are provided with suitable surface layers. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol and/or titanium dioxide, shellac solutions and suitable organic solvents or solvent mixtures. Organic dyes or pigments may be added to the tablets or coating layers of the dragee to identify or characterize different combinations of doses of the active compound.

Pharmaceutical preparations which can be used orally include capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, e.g. glycerol or sorbitol. The capsules may contain the active ingredients in admixture with fillers, e.g. lactose, binders, e.g. starches, and/or lubricants, such as e.g. talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, e.g. fatty oils, mineral oil or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such a route of administration.

For buccal administration, the preparations may be in the form of tablets or lozenges prepared in a standard manner.

For administration by inhalation, the compounds of the present invention are typically supplied in the form of an aerosol spray in a nebulizer or in a compressed air pack.

104 content with a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of a compressed aerosol, a "valve" may be used for dosing, which will allow the release of a precise amount of substance. Capsules and cartridges, e.g. gelatin, for use in an inhaler or inhaler may be prepared by a method in which a powder mixture of the compound and a suitable powder base, e.g. lactose or starch, are combined.

Compounds) may be prepared for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be in unit dosage form, e.g., in ampoules or in multidose containers, with an added preservative. The preparations may be, e.g., in the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain auxiliary agents, e.g., suspending, stabilizing, and/or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in a form that is soluble in water. Suspensions of the active compounds can also be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, e.g. sesame oil, or synthetic fatty acid esters, e.g. ethyl oleate or triglycerides, or liposomes.

Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, e.g. sodium carboxymethyl cellulose, sorbitol or dextran. Optionally, the suspensions may also contain suitable stabilizers or agents which increase the solubility of the compounds, thereby enabling highly concentrated solutions to be prepared.

Alternatively, the active ingredient may be in powder form for incorporation into a suitable carrier, e.g., sterile, pyrogen-free water.

The compounds may also be formulated as rectal preparations, e.g., suppositories or retention enemas, containing standard suppository bases, e.g., cocoa butter or other glycerides.

In addition to the above formulations, the compounds can also be prepared as a depot preparation. These long-acting formulations can be administered by implantation (e.g., subcutaneously or intramuscularly or by intramuscular injection). In this way, the compounds can be prepared with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchangers or as sparingly soluble derivatives, e.g., sparingly soluble salts.

• ·> * 4 • *

105

An example of a pharmaceutical carrier for hydrophobic compounds according to the present invention is a cosolvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. The cosolvent system may be a VPD cosolvent system. VPD is a solution of 3% by volume benzyl alcohol, 8% by volume non-polar surfactant polysorbate 80 and 65% by volume polyethylene glycol 300 and made up to the final volume with absolute ethanol. The VPD cosolvent system (VPD:5W) consists of VPD diluted 1:1 with 5% dextrose in aqueous solution. This cosolvent system dissolves hydrophobic compounds well and itself has low toxicity after systemic administration. Naturally, the proportions of the cosolvent system can be varied considerably, however, so as to maintain its solubility and toxicity characteristics. In addition, the individual components of the cosolvent system can be varied: e.g. Other non-polar surfactants with low toxicity may be used instead of polysorbate 80; the particle size of the polyethylene glycol may vary; other biocompatible polymers, such as polyvinylpyrrolidone, may replace polyethylene glycol; and other sugars or polysaccharides may replace dextrose.

Alternatively, another delivery system may be used for hydrophobic pharmaceutical compounds. For hydrophobic drugs, liposomes and emulsions are standard examples of vehicles and carriers used in this method. Certain organic solvents, e.g., dimethyl sulfoxide, may be used, however, usually at the expense of increased toxicity. Additionally, the compounds may be delivered by a sustained release system, e.g., semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release agents have been introduced in this technique. Sustained release capsules may release compounds over a period of several weeks to 100 days, depending on their chemical nature. Additional protein stabilization strategies may be used, depending on the chemical nature and biological stability of the therapeutic agent.

The pharmaceutical compositions may also contain suitable solid or gel 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, e.g., polyethylene glycols.

A large number of the compounds of the present invention may be in the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be prepared with many acids including, but not limited to, the acids «· #4* *

106 hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. The salts tend to be much more soluble in aqueous or other protonated solvents than their corresponding free bases.

Effective dose

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an effective amount to achieve the desired effect. In particular, a therapeutically effective amount means an amount sufficient to prevent or ameliorate the existing symptoms in the subject being treated. Determination of effective amounts is within standard routine.

For any compound used in the method of the present invention, a therapeutically effective dose may first be determined from cell culture assays. For example, the dose may be tested in cell and animal models to achieve a circulating concentration that includes the IC50 determined from cell culture assays (i.e., the concentration of the test compound required to achieve 50% inhibition of the activity of a given protein kinase). In some embodiments, it is convenient to determine the IC50 in the presence of 3 to 5% serum albumin, as this assay approximates the binding effects of plasma proteins to the compound. This information may be used in human subjects to more accurately determine effective doses. The most preferred compounds for systemic administration effectively inhibit protein kinase signaling in intact cells at levels that are safely achievable in plasma.

A therapeutically effective dose is that amount of a compound that results in an improvement in the patient's symptoms. The toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical methods in cell cultures or experimental animals, e.g., to determine the maximum tolerated dose (MTD) and ED50 (the concentration of a substance that produces 50% of the maximum effect of the dose). The dose ratio between toxic and therapeutic effects is determined by the therapeutic index and can be expressed as the ratio of the MTD to the ED50. Compounds that have high therapeutic indices are preferred. Data obtained from cell culture tests and animal studies can be used to determine the dose range for human subjects. The dose of such a compound is preferably within a range of concentrations in the systemic circulation that include the ED50 with little or no toxicity. The dose may vary within this range.

107 depending on the dosage form and route of administration used. The exact formulation, route of administration and dose can be selected by the attending physician depending on the patient's condition (see Fingl et al., 1975, in "Pharmacological Basis of Therapeutics", chap. 1 p. 1). In the treatment of crises, an acute bolus or infusion may be used to achieve a rapid response to achieve the MTD.

The dosage amount and interval can be individually adjusted to achieve a plasma level of the active moiety that is sufficient to maintain kinase modulating effects or a minimum effective concentration (MEC). The MEC value will vary for each compound, but can be determined based on in vitro data; e.g., the concentration required to achieve 50-90% inhibition of a protein kinase using the assays described in the present invention. The doses required to achieve the MEC will depend on the individual characteristics and route of administration. However, HPLC or bioassays can be used to determine plasma concentrations.

Dose intervals can also be determined using the MEC value. The compounds should be administered according to a regimen that maintains plasma levels above the MEC value for 10-90% of the time, preferably between 30-90% and most preferably 50-90%, until the desired improvement in the symptoms is achieved. In cases of local administration or selective uptake, the effective local concentration of the drug may not correspond to the plasma concentration.

The amount of product administered will depend on the subject being treated, their weight, the severity of the impairment, the route of administration and the judgment of the attending physician.

Packaging technique

The compositions, if desired, may be in the form of a package or container of the drug, which may contain one or more unit dosage forms containing the active ingredient. The package may, for example, comprise a metal or plastic foil, e.g. a soft transparent package. The package or container of the drug may be distributed together with instructions for administration. Compositions may also be prepared comprising a compound of the present invention prepared in a compatible pharmaceutical carrier, which are placed in an appropriate container and labeled for the treatment of the indicated condition.

• · ·

108

In some formulations, it may be beneficial to use the compounds of the present invention in the form of very small particle sizes, e.g., those obtained by fluid energy milling.

The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is described in the following description. In this description, the term "active compound" means any compound of the present invention, but in particular any compound which is the final product of one of the above examples.

a) Capsules

In preparing capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose may be deaggregated and mixed. The mixture may be filled into hard gelatin capsules, each capsule containing a unit dose or a portion of a unit dose of the active compound.

b) Tablets

Tablets can be prepared from the following ingredients.

Mass fractions

Active compound 10

Lactose 190

Cornstarch 22

Polyvinylpyrrolidone 10

Magnesium stearate 3

The active compound, lactose and a portion of the starch may be deaggregated, mixed and the resulting mixture granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate may be mixed with magnesium stearate and the remainder of the starch. The mixture is then compressed in a tabletting machine, each tablet containing a unit dose or a portion of a unit dose of the active compound.

c) Enteric-coated tablets

Tablets may be prepared as described above in (b). The tablets may then be enteric coated in a standard manner with a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in a mixture of ethanol and water (1:1).

d) Suppositories • · · · · · «· · · · · • · · · ·

109

In preparing suppositories, 100 parts by weight of the active compound may be mixed with 1300 parts by weight of a triglyceride-based suppository matrix and the resulting mixture may be dosed into suppositories, each containing a therapeutically effective amount of the active ingredient.

In the compositions of the present invention, the active compound may be combined with other compatible pharmacologically active ingredients, if desired. For example, the compounds of the present invention may be administered in combination with one or more other pharmaceutical agents that inhibit or prevent VEGF production, attenuate intracellular responses to VEGF, block intracellular signal transduction, inhibit vascular hyperpermeability, attenuate inflammation, or inhibit or prevent edema or neovascularization. The compounds of the present invention may be administered before, after, or simultaneously with the other pharmaceutical agent, by any suitable route of administration. Other pharmaceutical agents include, but are not limited to, anti-edema steroids, NSAIDS, 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 present invention and other pharmaceutical agents act either additively or synergistically. Thus, administration of another such combination of agents that inhibits angiogenesis, vascular hyperpermeability and/or inhibits edema formation may provide greater alleviation of the deleterious effects of hyperproliferative diseases, angiogenesis, vascular hyperpermeability or edema than administration of either agent alone. Combinations with antiproliferative or cytotoxic chemotherapies or radiation are contemplated in the treatment of malignant disorders.

The present invention also includes the use of a compound of formula I as a pharmaceutical composition.

Both the Src and Syk kinase families play pivotal roles in the regulation of immune functions. The Src family currently includes Fyn, Lek, Fgr, Fes, Lyn, Src, Yes, Flek and Blk. The Syk family currently includes only Zap and Syk. The Janus kinase family is involved in the transduction of growth factor and pro-inflammatory cytokine signals involving multiple receptors. Although BTK and ITK, members of the Tec family of kinases, play a less studied role in immunobiology, their modulation by inhibitors may have therapeutic benefit. The kinases RIP, IRAK-1, IRAK-2, NIK, TPL-2/COT, IKK-1 and IKK-2 are involved in the signal transduction pathways of the key pro-inflammatory cytokines TNF and IL-1. The compounds of general formula (I) may, by their ability to effectively inhibit one or more of these kinases, act as immunomodulators • · · ·

110 agents that are effective in stabilizing allografts and treating autoimmune diseases. Due to their ability to regulate T-cell activation or potentiate inflammatory processes, these compounds could be used to treat these autoimmune diseases. Transplants due to the phenomenon of rejection, whether graft-versus-host disease in solid organs or graft-versus-host disease in bone marrow, are limited by the toxicity of commonly available immunosuppressants, and therefore an effective drug with an improved therapeutic index would be very beneficial. Gene-targeted experiments have shown an essential role for Src in the biology of osteoclasts, which are cells responsible for bone resorption. Compounds of general formula (I) may also be effective in the treatment of osteoporosis, osteopetrosis, Paget's disease, tumor-induced hypercalcemia and in the treatment of bone metastases, due to their ability to regulate Src!.

A large number of protein kinases have been shown to be proto-oncogenes. Chromosomal disruption (at the Itk kinase breakpoint on chromosome 5), translocation as in the case of the Abl gene with the BCR (Philadelphia Chromosome), truncation as in the case of c-Kit or EGFR, or mutation (e.g. Met) results in the generation of dysregulated proteins that cause the conversion of proto-oncogene products to oncogenic products. In the case of other tumors, oncogenesis is driven by autocrine or paracrine interactions between the ligand and the growth factor receptor. Members of the src kinase family typically participate in downstream signal transduction, thereby potentiating oncogenesis, and can themselves become oncogenic through overexpression or mutation. Inhibition of the protein kinase activity of these proteins can cure these diseases. Vascular restenosis may involve the process of FGF and/or PDGF-promoted proliferation of smooth muscle and endothelial cells. Ligand stimulation in vivo of FGFR, PDGFR, IGF1-R and c-Met is proangiogenic and potentiates angiogenesis-dependent disorders. Inhibition of FGFr, PDGFr, c-Met or IGF1-R kinase activity may be an effective strategy to inhibit this phenomenon. Therefore, compounds of general formula (I) that inhibit the kinase activity of normal or aberrant c-kit, c-met, c-fms, src family members, EGFr, erbB2, erbB4, BCR-Abl, PDGFr, FGFr, IGF1-R and other receptor or cytosolic tyrosine kinases may play an important role in the treatment of benign and neoplastic proliferative diseases.

In many pathological conditions (e.g., solid primary tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inappropriate ocular neovascularization, psoriasis, and atherosclerosis), disease progression is contingent upon persistent angiogenesis. Polypeptide growth factors, often produced by diseased tissue or accompanying inflammatory cells, and their corresponding specific

9k · > ·

9 9 Endothelial cell receptor tyrosine kinases (e.g., KDR/VEGFR-2, Flt-1/VEGFR-1, Tie-2/Tek and Tie) are essential for stimulating endothelial cell growth, migration, organization, differentiation, and the assembly of new functional vasculature. Due to the “vascular permeability factor” activity of VEGF in mediating vascular hyperpermeability, VEGF-stimulation of VEGFR kinase is thought to play an important role in the development of tumor ascites, cerebral and pulmonary edema, pleural and pericardial effusions, delayed-type hypersensitivity reactions, tissue edema and organ dysfunction following trauma, burns, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), hypotension and hyperpermeability associated with post-cardiopulmonary bypass, and ocular edema resulting in glaucoma or blindness due to inappropriate neovascularization. In addition to VEGF, the recently identified VEGF-C and VEGF-D and the virally encoded VEGF-E or HIV-Tat protein can also cause a vascular hyperpermeability response mediated by stimulation of VEGFR kinase. Tie-2 is also expressed in a select population of hematopoietic stem cells, in which it can cause their proliferation, adhesion, regulation and differentiation (Blood, 4317-4326 (1997)), this population expressing Tie-2 may serve as circulating angiogenic endothelial progenitors. Certain agents represented by general formula (I) capable of blocking the kinase activity of specific endothelial cell kinases could therefore inhibit the progression of diseases involving these conditions.

Therefore, compounds of formula (I) or their salts or pharmaceutical compositions containing a therapeutically effective amount thereof can be used in the treatment of benign and neoplastic proliferative diseases and immune system disorders. These diseases include autoimmune diseases, e.g. 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 (e.g. kidney rejection, graft versus host), benign and neoplastic proliferative diseases, human cancers, e.g. lung, breast, stomach, bladder, colon, pancreas, ovary, prostate and rectal cancers and hematopoietic malignancies (leukemia and lymphoma) and diseases involving inappropriate vascularization, e.g. diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangiomas in human subjects. In addition, these inhibitors may be effective in treating disorders involving VEGF-mediated edema, ascites, effusions, and exudates, including, for example, macular edema, • · • ····· · ··· · « · ♦··· ···· ·· ·· ♦· ··

112 cerebral edema, acute lung injury, and adult respiratory distress syndrome (ARDS).

The compounds of the present invention may also be effective in the prophylaxis of the above diseases.

In another aspect of the present invention there is provided the use of a compound of general formula (I) or a salt thereof in the manufacture of a medicament for the treatment of vascular hyperpermeability, angiogenesis-dependent disorders, proliferative diseases and/or immune system disorders in mammals, particularly humans.

The present invention also provides a method of treating vascular hyperpermeability, inappropriate neovascularization, proliferative diseases and/or immune system disorders, which comprises administering a therapeutically effective amount of a compound of general formula (I) to a mammal, particularly a human, in need of such treatment.

The in vitro efficacy of compounds in inhibiting these protein kinases can be determined by the methods listed below.

The efficacy of compounds can be determined by the amount of inhibition of phosphorylation of an exogenous substrate (e.g., a synthetic peptide (Z. Songyang et al., Nature. 373:536-539) by comparing the test compound with a control.

Production of KDR tyrosine kinase using the Baculovirus system:

The coding sequence for the human KDR intracellular domain (aa789-1354) was generated by PCR and cDNA fragments isolated from HUVEC cells. A poly-His6 sequence was introduced at the A-terminus of this protein. This fragment was cloned into the transfection vector pVL1393 at the XbaI and Not1 sites. Recombinant baculovirus (BV) was generated by cotransfection with BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified by Western analysis. For protein production, SF-9 cells were grown in SF-900-II medium at 2 x 106/ml and infected at a plaque-forming amount per cell (MOI) of 0.5. Cells were harvested 48 hours after infection.

• · • · · ·

113

Purification of DRC

SF-9 cells expressing (His)6KDR(aa789-1354) were lysed by adding 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 10 pg/ml aprotinin, 1 ug/ml leupeptin) to the cell pellets from 1 l of cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS34 rotor for 30 min at 4°C. The cell lysate was applied to a 5 ml NiCl ₂ chelating sepharose column equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. KDR was eluted with the same buffer containing 0.25 M imidazole. Column fractions were analyzed by SDS-PAGE and ELISA (see below) to measure kinase activity. Purified KDR was poured into 25 mM HEPES, pH 7.5, 25 mM NaCl, 5 mM DTT buffer and stored at -80°C.

Production and purification of human Tie-2 kinase

The coding sequence for the human intracellular domain of Tie-2 (aa775-1124) was generated by PCR using cDNA pieces isolated from human placenta as templates. A poly-His ₆ sequence was introduced into the A-terminus and this construct was cloned into the transfection vector pVL 1939 at the Xba 1 and Not 1 sites. Recombinant BV was generated by cotransfection with BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified by Western blot analysis. For protein production, insect SF-9 cells were grown in SF-900-II medium at 2 x 106/ml and infected at a plaque-forming unit per cell (MOI) of 0.5. The purification of the His-tagged kinase used in the screening was similar to that for KDR.

Production and purification of human Flt-1 tyrosine kinase

The baculovirus expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. The nucleotide sequence encoding poly-His6 was placed in the 5' nucleotide region encoding the entire intracellular kinase domain of human Flt-1 (amino acids 7861338). The nucleotide sequence encoding the kinase domain was generated by PCR and cDNA libraries isolated from HUVEC cells. The histidine residues allowed affinity purification of the protein in a manner similar to that of KDR and ZAP70. Infected SF-9 cells were infected at a multiplicity of 0.5 and harvested 48 hours after infection.

• · · ·

114

·· ·· • · · * • · ·

Source of EGFR tyrosine kinase

EGFR was purchased from Sigma (Cat # E-3641; 500 units/50 μΐ) and EGF ligand was obtained from Oncogen Research Products/Calbiochem (Cat # PF011-100).

ZAP70 expression

The baculovirus expression vector pVL1393 (Phar Mingen, Los Angeles, CA) was used. The nucleotide sequence encoding the amino acids M(H)6 of LVPRgS was placed in the 5' nucleotide region encoding the entire ZAP70 (amino acids 1-619). The nucleotide sequence encoding the ZAP70 region was generated by PCR and cDNA libraries isolated from Jurkat immortalized T cells. Histidine residues allowed affinity purification of the protein (see infra). LVPRgS is bridged by a recognition sequence for proteolytic cleavage by thrombin, allowing removal of the affinity tag from the enzyme. Infected SF-9 cells were infected at a multiplicity of infection of 0.5 and harvested 48 hours after 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 mM PMSF, 10 pg/ml aprotinin, 1 ug/ml leupeptin and 1 mM sodium orthovanadate). The soluble lysate was applied to a HiTrap sepharose chelating column (Pharmacia) equilibrated in 50 mM F1EPES, pH 7.5, 0.3 M NaCl. The fusion protein was eluted with 250 mM imidazole. The enzyme was stored in a buffer containing 25 mM HEPES, pH 7.5, 25 mM NaCl, 5 mM DTT buffer.

Source: Lek

Lek or shortened forms of Lek can be obtained from commercial sources (e.g., from Upstate Biotechnology Inc. (Saranac Lake, N.Y.) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified by standard methods from known natural or recombinant sources.

• 4 · ·

115

Enzyme-linked immunosorbent assay (ELISA) performed with PTK

Enzyme-linked immunosorbent assay (ELISA) was used to detect and measure the presence of tyrosine kinase activity. ELISA was performed according to a standard method described, for example, in Voliér, et al., 1980, “Enzyme-linked Immunosorbent Assay,” In: Manual of Clinical Immunology, 2d ed., edited by Rose and Friedman, 359-371 Am.Soc. of Microbiology, Washington, D.C.

The method has been adapted to determine activity with respect to a specific PTK. For example, preferred methods for performing ELISA experiments are listed below. It is standard practice to adapt these protocols to determine the activities of compounds for other members of the receptor PTK family, as well as non-receptor tyrosine kinases. For the purpose of determining inhibitor selectivity, a universal PTK substrate (e.g., a poly(Glu4 Tyr)-based random copolymer with a molecular weight of 20,000-50,000) was used together with ATP (typically 5 μΜ) at approximately double the Km from the assays.

The following procedure was used to determine the inhibitory effect of the compounds of the present invention on the activity of KDR, Flt-1, Flt-4 VEGFR-3, Tie-2, EGFR, FGFR, PDGFR, IGF-1-R, c-Met and ZAP70 tyrosine kinases:

Buffers and solutions:

PGTPoly (Glu, Tyr) 4:1

Store powder at -20°C. Dissolve powder in phosphate buffered saline (PBS) to a volume of 50 mg/mL. Store 1 mL aliquots at -20°C. If preparing plates, dilute to 250 pg/mL in Gibco PBS.

Reaction buffer: 100 mM Hepes, 20 mM MgCl ₂ , 4 mM MnCl ₂ , 5 mM DTT, 0.02% BSA, 200 μΜ NaVO ₄ , pH 7.10.

ATP: Store 100 mM aliquots at -20°C. Dilute to a volume of 20 μΜ in water.

Wash buffer: PBS with 0.1% Tween 20

Antibody Dilution Buffer: 0.1% Bovine Serum Albumin (BSA) in PBS

TMB Substrate: Mix TMB Substrate and Peroxide Solution 9:1 just before use or use Neogen K-Blue Substrate Blocking Solution: 1M Phosphoric Acid Procedure

1. Plate preparation • Γ ř · » ·

116

Dilute PGT stock solution (50 mg/ml, frozen) in PBS to 250 pg/ml. Add (125 μΐ/well) to high affinity ELISA plates with modified primers (Corning # 25805-96). Add 125 μΐ PBS to blank wells. Cover with sealing tape and incubate overnight at 37°C. Wash 1x with 250 μΐ wash buffer and dry for 2 hours at 37°C in a dry incubator.

Store coated plates in a closed container at 4°C

2. Reaction with t\Toxin kinase:

-preparation of inhibitor solutions in fourfold concentration in 20% DMSO in water.

-preparation of reaction buffer

-preparation of enzyme solution so that the required units are in 50 μΐ, e.g. for KDR lng/μΐ out of a total of 50 ng/well in the reactions. Storage on ice.

-preparation of 4xATP solution with a concentration of 20 μΜ from a 100 mM stock solution in water. Storage on ice.

-adding 50 μΐ enzyme solution per well (typically 5-50 ng enzyme per well depending on the specific kinase activity)

-adding 25 μΐ 4xinbibitor

-adding 25 μΐ 4xATP to determine inhibition

-incubation at room temperature for 10 minutes

-stop the reaction by adding 50 μΐ 0.05N HC1 per well

-plate washing **Final concentration for reaction: 5 μΜ ATP, 5% DMSO

3. Antibody binding

-dilution of 1 mg/ml aliquot of PY20-HRP (Pierce) antibody (phosphotyrosine antibody) to 50 ngfrnl in 0.1% BSA in PBS by 2 step dilution (100x, then 200x) -add 100 μΐ Ab per well. Incubate at room temperature for 1 hour. Incubate at 4°C for 1 hour.

-4x plate washing

4. Color reactions

-preparation of TMB substrate and addition of 100 μΐ per well

-monitoring OD at 650 nm until a value of 0.6 is reached

-stopping the reaction with 1M phosphoric acid. Shaking on the plate detector.

-instant OD reading at 450 nm φ * • »'*·

117

Optimal incubation times and enzyme reaction conditions may vary slightly and are determined empirically for each batch.

For Lek, a reaction buffer with the composition of 100 mM MOPSO, pH 6.5, 4 mM MnCl ₂ , 20 mM MgCl ₂ , 5 mM DTT, 0.2% BSA, 200 mM NaVO ₄ was used under similar conditions.

Compounds of formula (I) may be therapeutically effective in the treatment of diseases involving both identified, including those not listed herein, and as yet unidentified protein tyrosine kinases that are inhibited by compounds of formula (I). All of the compounds of the present invention significantly inhibit KDR kinase at concentrations of 50 micromolar or less. Some of the compounds of the present invention also significantly inhibit other PTKs, e.g., lek at concentrations of 50 micromolar or less.

Source Cdc2

The human recombinant enzyme and assay buffer can be obtained from commercial sources (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources by standard methods.

Cdc2 test

The procedure used slightly modified reagents obtained from commercial sources. The reaction was carried out in a buffer of the composition 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl ₂ (commercial buffer) supplemented with fresh 300 μΜ ATP (31 pCi/rnl) and 30 μg/ml histone type IIIss as final concentrations. The reaction volume was 80 μί with the enzyme units contained. The reaction was carried out for 20 minutes at 25°C in the presence or absence of inhibitor and was terminated by the addition of 120 μί 10% acetic acid. The substrate was separated from the unincorporated label by applying the mixture to phosphocellulose paper, washing for 5 minutes (3 x 75 mM phosphoric acid). The pulses were measured in the presence of a liquid scintillator on a beta-radiation measuring device.

Certain compounds of the present invention significantly inhibited cdc2 at concentrations of 50μΜ or lower.

Source of PKC kinase

The catalytic subunit of PKC can be obtained from commercial sources (Calbiochem). PKC kinase assay

Λ « «» · U - *

118

The radiochemical assay procedure used was based on the published method, see Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Bichemical and Biophysical Research Communication 3:166, 1220-1227 (1990). All reactions were performed in kinase buffer consisting of 50 mM Tris-HCl pH 7.5, 10 mM MgCl2, 2 mM DTT, 1 mM EGTA, 100 μΜ ATP, 8 μΜ peptide, 5% DMSO and ³³ P ATP (8 Ci mM). The compound and enzyme were mixed in a reaction flask and the reaction was initiated by the addition of ATP and substrate mixture. After termination of the reaction by the addition of 10 μΐ of stopping buffer (5 mM ATP in 75 mM phosphoric acid), an aliquot of the mixture was applied to a phosphocellulose filter. The loaded samples were washed (3x) in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. The incorporation of the radiolabel was determined by liquid scintillation counting.

Source of the Erk2 enzyme

Recombinant mouse enzyme and assay buffer can be purchased from commercial sources (New England Biolabs, Beverly MA. USA) or purified from natural or recombinant sources by standard methods.

Erk2 enzyme test

The reaction was carried out in a buffer consisting of 50 mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and 10 mM MgCl (commercial buffer) supplemented with fresh 100 μΜ ATP (31 pCi/ml) and 30 μΜ myelin basic protein under conditions recommended by the supplier. Reaction volumes and assay for incorporated radiolabel are described for PKC assays (see supra).

In vitro models of T-cell activation

Upon activation by mitogen or antigen, T cells are induced to secrete IL-2, a growth factor that promotes their subsequent proliferative phase. Therefore, either IL-2 production or cell proliferation of primary T cells or relevant T cell lines can be measured as surrogates for T cell activation. Both of these assays and the individual parameters are well described in the literature (in Current Protocols in Immunology, Vol 2, 7.10.1-7.11.2).

T cells can be activated by co-culture with allogeneic stimulator cells, a process referred to as an irreversible mixed lymphocyte reaction. Responder and • « • · • · ·

119 peripheral blood monocyte stimulator is purified by Ficoll-Hypaque gradient (Pharmacia) according to the supplier's instructions. Stimulator cells are mitotically inactivated by reaction with mitomycin C (Sigma) or gamma irradiation. Responder and stimulator cells are cocultured at a 2:1 ratio in the presence or absence of test compound. Typically, ¹⁰⁵ responders are mixed with 5 x ¹⁰⁴ stimulators and plated (in a volume of 200 µl) in a U-bottom microtiter plate (Costar Scientific). 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 105 M ² -mercaptoethanol, and 0.5% DMSO. One day before harvesting (typically day 3), cultures were incorporated with 0.5 pCi ³ H thymidine (Amersham). Cultures were harvested (Betaplate harvester, Wallac) and isotope uptake was assessed by liquid scintillation counting (Betaplate, Wallac).

The same culture system can be used to determine T-cell activation by measuring IL-2 production. Eighteen to twenty-four hours after initiation of culture, the supernatant was removed and the IL-2 concentration was measured by ELISA (R and D Systems) according to the supplier's instructions.

In vivo models of T-cell activation

The in vivo efficacy of compounds can be tested in known animal models by directly measuring T-cell activation or T-cells that have been shown to be effectors. T-cells can be activated in vivo by ligation of the constant region of the T-cell receptor with an anti-CD3 monoclonal antibody (Ab). In this model, BALB/c mice were given 10 pg of anti-CD3 Ab intraperitoneally 2 hours before exsanguination. Animals that were to receive the test drug were pretreated with a single dose of compound one hour before administration of the anti-CD3 Ab. Serum levels of the anti-inflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), indicators of T-cell activation, were measured by ELISA. A similar model utilizes in vivo activation of T-cells with a specific antigen, e.g. keyhole limpet hemocyanin (KLH), and subsequent secondary in vitro exposure of drained lymph node cells to the same antigen. As mentioned above, cytokine production measurements were used to determine the activation status of the cultured cells. On day zero, C57BL/6 mice were immunized subcutaneously with 100 pg KLH emulsified in complete Freund's adjuvant (CFA). Animals were fasted one day before immunization and • · · ·

AND

120 • · t · » · • · · subsequently pretreated with the compound on the first, second and third days after immunization. Drained lymph nodes were collected on the fourth day and their cells were cultured at 6 x 10 ⁶ per ml in tissue culture medium (RPMI 1640 supplemented with heat-inactivated fetal bovine serum (Hyclone Laboratories 5 x 10' ⁵ M 2-mercaptoethanol and 0.5% DMSO) for 24 and 48 hours. The culture supernatants were then assayed for autocrine T-cell growth factor Interleukin-2 (IL-2) and/or IFN-γ levels by ELISA.

Compounds can also be tested in animal models simulating human disease. These are represented by experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CLA). EAE models that mimic aspects of human multiple sclerosis have been described in both mice and rats (reviewed in FASEB J. 5:2560-2566, 1991 mouse model: Lab. Invest. 4(3):278, 1981; rodent model: J. Immunol. 146(4):1163-8, 1991). Mice and rats were immunized with an emulsion of myelin basic protein (MBP) or its neurogenic peptide derivatives and CFA. Acute disease can be induced by the addition of bacterial toxins, e.g., Bordetella pertussis. Relapsing/remitting disease is induced by adoptive transfer of T cells from animals immunized with MBP/peptide.

CIA can be induced in DBA/1 mice by immunization with type II collagen (J. Immunol: 142(7):2237-2243). In mice, this produces signs of arthritis as early as ten days after antigen challenge, which may be evident as late as ninety days after immunization. In both EAE and CIA models, the compound can be administered either prophylactically or at the time of disease onset. Effective drugs should reduce the severity and/or extent of the disease.

Certain compounds of the present invention that inhibit one or more angiogenic receptor PTKs and/or protein kinases, e.g., drugs involved in mediating inflammatory responses, can reduce the severity and extent of arthritis in these models.

Compounds can also be tested in murine allograft models, either skin (reviewed in Ann. Rev. Immunol., 10:333-58, 1992; Transplantation: 57(12):170117D6, 1994) or heart (Am. J. Anat.:1 13:273, 1963). Complete epidermal grafts have been transplanted from C57BL/6 mice to BALB/c mice. The grafts can be monitored daily for rejection starting on day six. In the murine neonatal heart transplant model, neonatal hearts are ectopically transplanted from C57BL/6 mice into the auricle of adult CBA/J mice. The hearts begin to function four to seven days after transplantation, and rejection can be visually examined under a dissecting microscope to monitor cardiac arrest.

121

Cellular recipe PTK assays

The following cellular assay was used to determine the level of activity and effect of various compounds of the present invention on KDR/VEGFR2. Similar receptor PTK assays utilizing specific ligand stimulation can be designed along the same lines for other tyrosine kinases using standard techniques.

VEGF-induced KDR phosphorylation in human umbilical vein endothelial cells (HUVEC) can be measured by Western blotting:

1. HUVEC cells (from pooled donors) were purchased from Clonetics (San Diego, CA) and cultured according to the supplier's instructions. Only early passages (3-8) were used for these assays. Cells were cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth, England) with complete EBM medium (Clonetics).

2. To evaluate the inhibitory activity of the compounds, cells were trypsinized and seeded at 0.5-1.0 x 10 ⁵ cells per well into each well of clustered plates (6 wells each) (Costar; Cambridge, MA).

3. 3-4 days after seeding, continuous growth was observed in 90-100% of the plates. The medium was removed from all wells, the cells were washed with 5-10 ml PBS and incubated for 18-24 hours with 5 ml EBM basal medium without any added supplements (i.e. serum deprivation).

4. Serial dilutions of inhibitors in 1 ml of EBM (25 μΜ, 5 μΜ or 1 μΜ final concentration) were added to the cells and the cells were incubated for 1 hour at 37°C. Human recombinant VEGF165 (R & D Systems) was then added to all wells in 2 ml of EBM at a final concentration of 50 ng/ml and incubation continued for 10 minutes at 37°C. Control cells treated or untreated with VEGF were used to determine background phosphorylation and phosphorylation induction of VEGF. All wells were then washed with 5-10 ml of cold PBS containing 1 mM sodium orthovanadate (Sigma). Cells were lysed and washed in 200 μΐ of R1PA buffer (50 mM Tris-HCl) pH 7, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA) containing protease inhibitors (PMSF 1 mM, aprotinin 1 pg/ml, pepstatin 1 pg/ml, leupeptin 1 pg/ml. Na vanadate 1 mM, Na fluoride 1 mM) and 1 pg/ml DNase (all chemicals were from Sigma Chemical Company, St Louis, MO). The lysate was centrifuged at 14,000 rpm for 30 minutes to eliminate nuclei.

• · · · • · • *

122

Equivalent amounts of proteins were then precipitated by adding cold (-20°C) ethanol (2 volumes) for a min. of 1 hour and a max. overnight. The pellets were reconstituted in Laemli sample buffer containing 5% mercaptoethanol (BioRad Hercules, CA) and heated for 5 minutes. Proteins were redissolved by gel electrophoresis on a polyacrylamide gel (6%, 1.5 mm Novex, San Diego, CA) and transferred to a nitrocellulose membrane using the Novex system. After blocking with bovine serum albumin (3%), proteins were labeled with polyclonal anti-KDR antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or monoclonal antiphosphotyrosine antibody (4G10, Upstate Biotechnology, Lake Placid, NY) at 4°C overnight. After washing and incubation with HRP-conjugated F(ab) ₂ goat anti-rabbit or goat anti-mouse IgG, individual bands were visualized by emission chemiluminescence (ECL) (Amersham Life Sciences, Arlington Heights, IL).

Certain compounds of the examples of the present invention significantly inhibit cellular VEGF-induced phosphorylation of KDR tyrosine kinases at concentrations that are less than 50 pM.

In vivo model of uterine edema

In this assay, the capacity of compounds to inhibit acute uterine weight gain in mice, which occurs within the first few hours after estrogen stimulation, was measured. This rapid increase in uterine weight is known to be a process of edema due to increased permeability of the uterine vasculature. Cullinan-Bove and Koss {Endocrinology (1993), 133: 829837) showed a close temporal relationship between estrogen-stimulated uterine edema and increased VEGF mRNA expression in the uterus. These results were confirmed using a neutralizing monoclonal antibody to VEGF, which significantly reduced acute uterine weight gain after estrogen stimulation (WO 97/42187). Therefore, this system can serve as a 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 the supplier's instructions. Carrier components (DMSO, Cremaphor EL) were purchased from Sigma (St. Louis, MO).

• ·

123

Mice (Balb/c, 8-12 weeks old) were purchased from Taconic (Germantown, NY) and housed in a pathogen-free facility in accordance with the Institutional Animal Care and Use Committee Guidelines.

Way:

Day 1: Balb/c mice were injected intraperitoneally (i.p.) with 12.5 units of pregnant mare serum gonadotropin (PMSG).

Day 3: mice were administered 15 units of human chorionic gonadotropin (hCG) i.p.

Day 4: Mice were randomly divided into groups of 5-10. Test compounds were administered i.p., i.v. or p.o. depending on the solubility of the vehicle at doses ranging from 1-100 mg/kg. The control group received vehicle only and two groups were untreated.

After 30 minutes of the experiment, the control group and one of the untreated groups were given an i.p. injection of 17-estradiol (500 μg/kg). After 2-3 hours, the animals were killed by CO2 inhalation. After a midline incision, each uterus was isolated and removed by an incision made below the cervix and at the junction of the uterus and fallopian tubes. Fat and connective tissue were carefully removed so as not to disrupt the integrity of the uterus before weighing (wet weight). The fluid was removed from the uteri by pressing between two filter papers with a one-liter glass bottle filled with water. The uteri were weighed after removing the fluids (weighing after fluid removal). The difference in weight before and after fluid removal was determined as the amount of fluid in the uterus. The mean fluid content of the treated groups was compared with the untreated or control groups. Statistical parameters were determined by Student's t-test. An unstimulated control group was used to monitor the response to estradiol.

The results show that certain compounds of the present invention, when administered systemically by various routes, inhibit edema formation.

Certain compounds of the present invention that are inhibitors of angiogenic receptor tyrosine kinases may also exhibit activity in the Matrigel implant neovascularization model. The Matrigel neovascularization model involves the formation of new blood vessels within a pure "marble" extracellular matrix implanted subcutaneously, which is induced by the presence of a proangiogenic factor produced by tumor cells (see: Passaniti, A., et al, Lab. Investig. (1992), 67 (4), 519528; Anat. Rec. (1997), 249 (1), 63-73; Int. J. Cancer (1995), 63 (5), 694-701; Vasc. Biol. (1995), 15 (11), 1857-6). The model is preferably usable within 3-4 days and the outputs include macroscopic • · · * ·» - -.• U· ··♦ ·· • ..... · ··· · • · · · * · ·· ««··· «» * * ···

124 optical/imaging evaluation of neovascularization, microscopic determination of microvessel density and determination of hemoglobin amount (Drabkin method) and subsequent removal of the implant against controls in animals not treated with inhibitors. In this model, bFGF or HGF can alternatively be used as a stimulant.

Certain compounds of the present invention that inhibit one or more oncogenic, proto-oncogenic or proliferation-dependent protein kinases or angiogenic receptor PTKs also inhibit the growth of primary mouse, rat or human xenograft tumors in mice or inhibit metastasis in mouse models.

• · ♦ *

125 • » · · · · ·

.. .· ·* ····

Examples of embodiments of the invention

The core structure of the compounds of the present invention was synthesized by a base-catalyzed aldol condensation followed by elimination. Scheme I is a general representation of this reaction. The appropriate starting materials, II and III, for the preparation of compounds of general formula IV of the present invention, which are synthesized in accordance with Scheme I, are commercially available and/or can be prepared by standard methods and/or are available according to the method described herein.

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-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 reduced pressure, the solid residue was purified by flash column chromatography using ethyl acetate:hexanes (3:7) as the mobile phase, and then purified by recrystallization from toluene.

• ·

126

Example 40

3-7tert-Butylureido-4-[(pyrrol-2-yl)methylenej-2-pyrazolin-5-one.

A reaction mixture of 3-amino-4-[(pyrrol-2-yl)methylene]-2-pyrazolin-5-one (1.7 mmol) and tert-butyl isocyanate (1 mL) in ethyl acetate (5 mL) was stirred at 80°C for 2 hours. The product was collected by filtration and recrystallized from ethanol.

Example 88

4-{[4-(2-Dimethylaminoethoxycarbonyl)-3,5-dimethylpyrrol-2-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 oxalyl dichloride (0.2 ml) and stirred for 24 hours. A solution of dimethylaminoethanol (0.6 g, 6.7 mmol) in dichloromethane (5 ml) was then added and stirring was continued for another 24 hours. The solvent was completely evaporated and the solid residue was treated with NaHCO3 (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-dimethylpyrrol-2-yl]methylene}-3-pyrazinyl-2-pyrazolin-5-one-V-oxide

A mixture of the compound 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 for 48 hours. The solvent was completely removed and the residue was purified by flash chromatography (dichloromethane/ethanol 9:1). The yield was 30%, melting point 192°C (ethanol).

Table 1

Other synthesized compounds having structural formula (V).

Ex. Substituent on the ring A R ¹ Recrystallization solvent Exc. % Method 1 4,5-dimethyl cyclopropyl toluene 30 see example 1

• · • · · ·

127

2 none benzyl toluene:heptane 64 see example 1 3 none 4-methoxy- phenyloxy- methyl methanol 36 see example 1 4 none phenyloxy- methyl ON 33 see example 1 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 ON 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 ON 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 ON 50 see example 1

• · • · · ·

128

20 none indol-3-yl ethanol 90 see example 1 21 none 3- methoxybenzyl 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 tolueneheptane 60 see example 1 27 none 4-hydroxy- 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 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 phenylethyl heptane 49 see example 1 38 1 -(4-hydroxy-butyl) isopropoxy ON 80 see example 1 39 none cyclopentyloxy methanol 75 see example 1

• · · · · * • · * 4 · · ♦ ·

129

40 none tert- butylureido ethanol 87 see example 40 41 4-methyl isopropoxy toluene 34 see example 1 42 4-methyl 4-amino- phenylethyl ON 27 see example 1 43 1-methyl isopropoxy toluene 55 see example 1 44 5-methyl isopropoxy methane water 30 see example 1 45 3,5-dimethyl-4- ethyl 4- aminophenyl- ethyl toluene 50 see example 1 46 5-methyl ethoxy ethanol 58 see example 1 47 3,5-dimethyl-4- ethyl 4-carbamoyl- phenyl ethyl DMF:water 82 see example 1 48 3,5-dimethyl-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- phenyl ethyl isopropanol 35 see example 1 53 none Ethoxycarbonyl- methyl ethanol 35 see example 1 54 none 4-methoxy- phenylamino- carbonylmethyl methanol 46 see example 1 55 3-(2-carboxyethyl)- 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

130

59 1-(3,5-dichloro- phenyl) cyclopropyl ethanol 30 see example 1 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- yi 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 pyrrol-2-yl methanol 88 see example 1 68 4-methyl cyclopropyl ethanol 35 see example 1 69 4-methyl benzothiazol-2- yi ethanol 48 see example 1 70 3,5-dimethyl 3-pyridyl ethanol 24 see example 1 71 3,5-dimethyl-4- ethyl 3-pyridyl 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 ON 49 see example 1 78 none methyl ON 6 see example 1 79 none 4-isopropyl- phenylamino ON 50 see example 1 80 none 3-phenylamino ON 80 see example 1

• ·

131

81 1 -(4-hydroxy-butyl) cyclopropyl ethanol 34 see example 1 82 4-(2-carboxyethyl)- 3-methyl isopropoxy ethanol 46 see example 1 83 4-carboxy-3,5- dimethyl isopropoxy ON 41 see example 1 84 4,5-tetramethylene isopropoxy ethanol 77 see example 1 85 3,4-dimethyl-4- morpholino methyl isopropoxy ON 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- dimethylaminoethyl -oxy-carbonyl) isopropoxy heptane 40 see example 88 89 3,5-dimethyl-4-(2- dimethylaminoethyl aminocarbonyl) isopropoxy tolueneheptane 41 see example 88 90 5-ethoxycarbonyl isopropoxy methanol 79 see example 1 91 5-carboxy isopropoxy toluene 83 see example 1 92 none 4- chlorophenylami- nocarbonyl- methyl DMF/water 50 see example 1 93 5-phenyl cyclopropyl ethanol 72 see example 1 94 3,5-dimethyl- 4- ethyl tetrahydrofuran -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

• · • · · · • · · · ♦ • · · · ·

132

97 3,5-dimethyl-4- morpholino methyl cyclopropyl ON 34 see example 1 98 3,4-dimethyl pyrazinyl methanol 60 see example 1 99 4-(2-carboxyethyl)- 3-methyl cyclopropyl methanol 51 see example 1 100 3,5-dimethyl-4- dimethylamino- methyl cyclopropyl ON 67 see example 1 101 5-ethoxycarbonyl cyclopropyl ethanol 91 see example 1 102 4,5-tetramethylene cyclopropyl ethanol 84 see example 1 103 none 2-methoxy- carbonylethyl ethanol 56 see example 1 104 none ethoxycarbonyl ON 40 see example 1 105 none Isopropyl ON 44 see example 1 106 none trans-2- phenylcyclo- propyl toluene 46 see example 1 107 none cyclohexyl toluene 32 see example 1 108 4,5-tetramethylene cyclopropyl amino ethanol 50 see example 1 109 5-morpholino-methyl cyclopropyl ethyl acetate 72 see example 1 110 5-carboxy cyclopropyl ethanol 50 see example 1 111 4-Chlorine ethoxy ethanol 88 see example 1 112 4-bromo ethoxy ethanol 70 see example 1 113 5-Chlorine ethoxy ON 37 see example 1 114 4-Chlorine 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

• · • » · ·

133

119 3,5-dimethyl-4-(2- dimethylaminoethyl -oxycarbonyl) cyclopropyl ON 71 see example 88 120 3,5-dimethyl-4-(2- dimethylaminoethyl oxycarbonyl pyrazinyl ON 20 see example 88 121 3,5-dimethyl-4- dimethylamino- methyl pyrazinyl toluene 76 see example 1 122 3,5-dimethyl-4- dimethylamino- methyl maleate pyrazinyl ethanol 98 maleate salt formed from the free base of the compound according to Example 121 (see explanatory note) 123 3,5-dimethyl-4-(2- morpholinoethyl- aminocarbonyl) 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-fours 1 ethanol 51 see example 1 128 3,5-dimethyl-4- morpholinomethyl pyrazinyl ON 28 see example 1 129 3,5-dimethyl 2-thienyl ethanol 25 see example 1 130 4-ethoxycarbonyl cyclopropyl ethanol 68 see example 1 131 3,5-dimethyl-4- trifluoro-acetamido- methyl cyclopropyl ethanol 70 see example 1 132 4-aminomethyl-3,5- dimethyl cyclopropyl ethanol 30 see example 1

134

133 3,5-dimethyl benzothiazol-2- yi ethanol 40 see example 1 134 3,5-dimethyl-4- morpholinomethyl benzothiazol-2- yi 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 1 137 4-carboxy pyrazinyl methanol 70 see example 1 138 3,5-dimethyl-4- di ethanol amino- methyl pyrazinyl ethanol 50 see example 1 139 3,5-dimethyl-4- trifluoroacetamido- methyl pyrazinyl ON 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- dimethyl- aminomethyl 2-furyl toluene 20 see example 1 143 3,5-dimethyl-4- dimethyl- aminomethyl 2-thienyl toluene 48 see example 1 144 3,5-dimethyl-4- dimethyl- aminomethyl 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- ethoxy ethanol 54 see example 1

135

carbonyl) 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-dimethyl-4- ethoxycarbonyl 1-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 1 153 4-nitro ethoxy toluene 95 see example 1 154 4-carboxy ethoxy ON 40 see example 1 155 3,5-dimethyl-4-(2- dimethylaminoethyl aminocarbonyl) 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-methyl ethoxy ON 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 trifluoromethyl ethanol 45 see example 1 161 3,5-dimethyl-4- ethoxycarbonyl 5-isoxazolyl DMF: water 74 see example 1 162 3,5-dimethyl-4- ethoxycarbonyl 3-amino-phenyl ethanol 76 see example 1 163 4-morpholino- ethylaminocarbonyl ethoxy ON 30 see example 88 164 4-ethoxycarbonyl-3- pyrazinyl toluene 70 see example 1

: · . . .......

.and.............

136

phenyl 165 4-(4-methyl-1- piperazinylmethyl)- 3,5-dimethyl pyrazinyl DMF 58 see example 1 166 4-diethylamino- m ethyl-3,5-dimethyl pyrazinyl ON 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 ON 35 see example 1 169 3,5-dimethyl-4- dimethylamino- methyl- 5-isoxazolyl ON 30 see example 1 170 5-methvl-4- dimethylamino- methyl pyrazinyl toluene-heptane 75 see example 1 171 3,5-Dimethyl-4-[A- (2-dimethyl- aminoethyl)-//- methyl- aminomethyl] pyrazinyl methanol 40 see example 1 172 3-dimethylamino- methyl-4,5- tetramethylene cyclopropyl ON 30 see example 1 173 3-dimethylamino- methyl-4,5- tetramethylene pyrazinyl ON 30 see example 1 174 3,5-dimethyl-4- dimethylamino- methyl maleate cyclopropyl ethanol 90 maleate salt formed from the free base of the compound according to Example 100 (see

137

explanations) 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- methvl) 5-methyl-3- isoxazolyl toluene/heptane 40 see example 1 178 3,5-Dimethyl-4-(4- hydroxypiperidino- methyl) pyrazinyl methanol 40 see example 1 179 4-Aminomethyl- 3,5-dimethylmaleate pyrazinyl methanol 76 see example 1 180 4-(4- Benzylpiperidino- methyl)-3,5- dimethyl pyrazinyl toluene 80 see example 1 181 3,5-Dimethyl-4-(2- hydroxyethyl) pyrazinyl ON 80 see example 1 182 3,5-Dimethyl-4-[2- (1-pyrrolidinyl- ethyl)] pyrazinyl toluene 67 see example 1 183 3,5-Dimethyl-4-[2- (and- pyrrolidinylethyl)] cyclopropyl toluene 20 see example 1 184 3,5-Dimethyl-4-(2- hydroxyethyl) cyclopropyl ON 23 see example 1 185 3,5-Dimethyl-4-(2- ethylaminoethyl) pyrazinyl ON 35 see example 1 186 4-(3-Diethylamino- propyl)-3,5- pyrazinyl ethanol 52 see example 1

φφ ·»· ·

138

dimethyl 187 3,5-Dimethyl-4-(3- hydroxypropyl) pyrazinyl ethanol 82 see example 1 188 3,5-Dimethyl-4- dimethyl- aminoacetyl- hydrochloride pyrazinyl ethanol/ethyl ether 51 see example 1 189 3,5-Dimethyl-4- dimethyl- aminoacetyl ethoxy ethanol/ethyl ether 44 see example 1 190 4-(2- diethylaminoethyl)- 3,5-Dimethyl cyclopropyl heptane 54 see example 1 191 3,5-Dimethyl-4-(2- dimethyl- aminoethyl) pyrazinyl toluene 48 see example 1 192 3,5-Dimethyl-4-(4- hydroxybutyl) pyrazinyl methanol 58 see example 1 193 4-(4-Diethyl- aminobutyl)-3,5- dimethyl pyrazinyl toluene 60 see example 1 194 4-(2-Diethylamino- ethyl-A-oxide)-3,5- dimethyl pyrazinyl ethanol 30 see example 194 195 3,5-Dimethyl-4-(l- pyrrolidinylacetyl pyrazinyl ON 57 see example 1 196 4- diethylaminoacetyl- 3,5-dimethyl pyrazinyl ON 52 see example 1 197 3-Isopropyl-5- methyl pyrazinyl ethanol 44 see example 1 198 3,5-Dimethyl-4-[3- pyrazinyl ethanol 30 see example 1

»· »*· +

139

(1-pyrrolidinyl- propyl 199 4-Dimethyl aminomethyl-3- isopropyl-5-methyl pyrazinyl toluene 40 see example 1 200 4-Dimethyl- aminomethyl-3- isopropyl-5-methyl cyclopropyl toluene 40 see example 1 201 3,5-Dimethyl-4-(2- ethoxy-oxalyl) pyrazinyl ethanol 40 see example 1 202 3,5-Dimethyl-4-(2- ethylaminoethyl) cyclopropyl ON 60 see example I 203 3,5-Dimethyl-4-(2- cyclopropyl- aminoethyl pyrazinyl toluene 40 see example 1 204 3,5-Dimethyl-4-[2- (4-pyridyl- methylamino)ethyl pyrazinyl ON 40 see example 1 205 3,5-Dimethyl-4-(2- cyclopropylaminoeth bullfinch) cyclopropyl toluene 36 see example 1 206 3,5-Dimethyl-4-(2- diethylaminoethyl) 2-pyrimidinyl toluene 35 see example 1 207 3,5-Dimethyl-4-(2- diethylaminoethyl) 3-pyridazinesI toluene 40 see example 1 208 3,5-Dimethyl-4-(2- diethylaminoethyl 4-pyrimidinyl toluene 50 see example 1 209 3,5-Dimethyl-4-(2- diethylaminoethyl 4-pyridazinyl toluene 30 see example 1

·· »»»·

140

Table ΙΑ

Physical data of synthesized compounds having structural formula V.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. ⁱⁿ yp· Name. Off. Name. 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 _H2O )* 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 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 _H2O )* 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

φφ ·»·* • · • · Η ··

141

24 (0.25 _H2O )' 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 18.31 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 ₂ O)* 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 1699 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

142 *« ···· ·· ··*·

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 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) dissolution 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 _H2O )* 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 ^{! ?} C and 'H NMR and analytical c LC/MS data match the given 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

143

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) dissolution 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) dissolution 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) dissolution 56.06 56.46 4.27 4.37 17.83 17.54

• · • · ·

144

115 210(d) dissolution 47.16 47.60 3.59 3.85 15.00 14.57 116 253-255 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) dissolution 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 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

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 20.29 170 193-195 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) disintegration 57.92 58.32 4.61 4.82 19.08 19.26

• · · • · · • 0 · · · · • · » • · · · • · · «

146

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 _H2O )* 255-257 61.68 61.48 6.47 6.45 21.58 21.68 179 (0.5 _H2O *) 205-208 54.15 54.27 5.02 4.97 19.94 19.63 180 (0.25) 211-214 70.64 70.56 6.69 7.06 18.30 17.93 181 306-308 61.72 61.64 5.50 5.45 22.49 22.41 182 (0.17 _H2O ) 190-192 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 16.86 184 244-246 65.91 65.52 7.00 6.98 15.37 15.05 185 192-194 Data from HRM’ Si and EM correspond to the given structure 186 (3·Η ₂ Ο) 208.10 58.05 58.21 7.88 7.39 19.73 19.47 187 273-275 62.75 63.01 5.88 5.76 21.52 21.33 188 (C1H»2H,O) >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 17.06 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 _H2O ) 220 61.94 61.66 5.93 5.72 21.68 21.54 196 ( _0.5H2O ) 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 23.99 198 202-204 66.64 66.24 6.92 6.99 22.20 22.00 199 227 64.75 64.90 6.86 6.99 23.85 23.88 200 190-192 68.75 68.86 8.33 8.46 17.82 17.51

147

201 223 58.85 58.96 4.66 4.73 19.06 19.03 202 (0.4 _H2O ) 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 _H2O ) 203-205 65.23 65.05 5.82 5.84 24.20 23.77 205 (0.4 _H2O ) 158-160 67.64 67.93 7.81 7.74 17.53 17.40 206 (0.2 _H2O ) 144-146 64.91 64.87 7.19 7.30 22.71 22.53 207 (0.2 _H2O ) 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 22.53 209 212-216 65.55 65.49 7.15 7.38 22.93 22.31

$ ------Molecular weight calculated for elemental analysis includes solvent in the amount indicated.

Explanation: Maleate salts were prepared by adding an ethanolic solution of maleic acid to the free base in ethanol at room temperature, cooling, and filtering the crystalline product.

II. 4-[(Indol-3-yl)methylene]-2-pyrazolin-5-ones (VI)

Example 210

3-Benzyl-4-[(indol-3-yl)methylene]-2-pyrazolin-5-one

Reaction mixture of 3-benzyl-2-pyrazolin-5-one (905 mg, 5.2 mmol),

3-indolecarboxaldehyde (800 mg, 5.6 mmol) and piperidine (100 mg) in ethanol (50 mL) were • ♦

148 is stirred at 90°C for 3 hours. After cooling overnight, the product is collected by filtration and purified by recrystallization from ethanol.

Table 2

Other synthesized compounds having structural formula (VI).

Ex. Substituent on indole R ¹ Recrystallization solvent Exc. % Method of preparation 210 none benzyl ethanol 76 see example 210 211 1-(4-hydroxy-butyl) 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 210 221 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 1-(4-hydroxybutyl) 4-methoxybenzyl DMF: water 89 see example 210 225 none 4-chlorophenylamino DMF: water 86 see example 210 226 none 3-methoxybenzyl DMF:water 99 see example 210 227 none 3,4-dimethoxy- DMF: water 88 see example 210

149 • · • «

benzyl 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- phenyl ethyl isopropanol 88 see example 210 232 none 4-phenyl- phenyloxymethyl ON 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 1-(4-hydroxy-butyl) isopropoxy toluene:heptane 43 see example 210 239 1-(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 methane 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 tolueneheptane 71 see example 210

• ·

150

251 1-methyl 4-hydroxy- phenylethyl ethanol 50 see example 210 252 none isopropyl ethanol 76 see example 210 253 none 4-chlorophenyl aminocarbonyl methyl DMF: water 40 see example 210 254 none ethoxycarbonyl- 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 1-(4-hydroxy-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 1-(4-hydroxy-butyl) cyclohexyl toluene 41 see example 210 267 1-(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

151

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 ON 63 see example 210 277 none methyl ON 68 see example 210 278 none trifluoromethyl ON 14 see example 210 279 1-(4-hydroxy-butyl) hydrogen atom ON 62 see example 210 280 1-(4-hydroxy-butyl) methyl ON 36 see example 210 281 1-(4-hydroxy-butyl) trifluoromethyl ON 7 see example 210 282 1-(4-hydroxy-butyl) 7-tert-butyl ON 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-1- cyclopropyl ethanol 92 see example 210 286 1-(4-hydroxy-butyl) cyclobutyl ethanol 26 see example 210 287 6-carboxy-1-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- yi ethanol 78 see example 2 1 0 292 1-methyl cyclopropyl-amino ethanol 54 see example 2 1 0 293 6-carboxy-1-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

152

297 1-methyl trifluoroacetamido methanol 70 see example 210 298 1-methyl 4-aminophenylethyl 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 tert-butyl ethanol 92 see example 210 304 6-carboxy-1-methyl pyrazinyl DMF 98 see example 210 305 1-methyl-6-[2-(4- morpholmo) ethyl] amino carbonyl pyrazinyl ON 20 see example 210

Table 2A

Physical data of the synthesized compounds having structural formula VI.

Example Melting temperature (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 210 292-295 75.73 75.74 5.02 5.28 13.94 13.85 211 217-220 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 18.35 221 255-257 69.11 69.30 5.30 5.07 16.98 16.99

153 • · ·· ··· · · ·· • · * · · · · · ···· · ··· · ··· · • · · · · · ·

(0.75 _H2O )* 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 _CH3OH )* 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 _H2O )* 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 _CH3OH )* 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 EtOAc)* 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 CH3OH)* 262-264 66.99 66.78 6.22 6.09 14.42 14.46

•« ···· · · • · · · · • · · ·

154

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 14.57 254 235-237 64.63 64.81 5.08 5.04 14.13 14.22 255(0.5 H ₂ 0)* >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 _H2O )* 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

155 -

274 286-288 72.73 72.14 5.69 5.91 15.83 15.60 275 (0.5 _H2O )* 230-232 69.44 69.89 4.85 4.84 17.99 18.10 276-282 ¹³ C and 'H NMR and analytical data from LC/MS are consistent with the structures shown 283 250(d) dissolution 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) dissolution 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) dissolution 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 22.54 300 271-272 68.67 68.59 4.61 5.04 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

• « ··· · · · · · • · · · · «

156 ····· · «·· · · • · · · · · · · · • · · · · · · · · · * ·

305 240-241 61.52 61.67 5.59 5.67 20.92 20.91

The molecular weight calculated for elemental analysis includes the solvent in the amount indicated.

Explanation: Maleate salts were prepared by adding an ethanol solution of maleic acid to the free base in ethanol at room temperature, cooling, and filtering the crystalline product.

III. 4-[(Indol-2-yl)methylene]-2-pyrazolin-5-one (VII).

Table 3

Synthesized compounds having structural formula VII.

Example Substituent on indole R ¹ Recrystallization solvent Exc. % Method of preparation 306 none isopropoxy ethanol 81 see example 210 307 none 4-hydroxy- phenylethyl ethanol 45 see example 210 308 none 4-amino-phenylethyl ON 20 see example 210 309 none 4-methoxy- carbonyl- phenylethyl toluene 75 see example 210 310 none 4-carbamoyl- phenylethyl DMF:water 90 see example 210 311 none cyclopropyl ethanol 35 see example 210 312 3-dimethyl- aminomethyl cyclopropyl ON 20 see example 210 313 none 3-pyridyl ethanol 62 see example 210

157 • ·» ·· * ·»· n · · • · » · · · · · · · · * ····· · ··· « · ··· ·· ·· ·· «· ··»·

314 5-methoxy isopropoxy methanol 78 see example 210 315 1-methyl isopropoxy DMF: water 89 see example 210 316 none tetrahydrofuran-3- yi ethyl acetate 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 210 323 3-(2-methoxy- ko ri β n y 1 -1 «χ,/α >*> fWs1 ti isopropoxy 3/ tolueneheptane 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 ethyl acetate 46 see example 210 327 5-methoxy pyrazinyl ON 91 see example 210 328 5-methoxy 2-pyridyl ON 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-oxo-1,5,6,7- tetrahydro pyrazinyl toluene 40 see example 210 332 3-dimethyl- aminomethyl ethoxy toluene- heptane 41 see example 210

158 • t ·· ·»»* ·· · · • · ·· · ·««« • ····· · ··« · · β β ···· # · · • · a · · ·· · · *· · a » ·

Table 3A

Physical data of the synthesized compounds having structural formula VII.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 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 _H2O )* 263-265 69.44 69.51 5.09 5.05 15.43 15.21 311 (0.75 _H2O )* 238-240 68.04 67.68 5.55 5.11 15.87 15.75 312 (0.25 _H2O )* 202(d) dissolution 69.10 69.13 6.60 6.46 17.91 17.56 313 (0.5 _H2O )* 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

• *

159 • 0 9 » » a »*» · • · « · ·· o · · · · ··· · · · ♦ · · « ····· a · · · · «

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 14.35 330 (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 elemental analysis includes the solvent in the amount indicated.

IV. 4-[(7-Azaindol-3-yl)methylene]-2-pyrazolin-5-ones (VIII).

Table 4

Synthesized compounds having structural formula VIII.

Example Substituent on azaindole R ¹ Recrystallization solvent Exc. % Method of preparation 333 none benzyl DMF: water 71 see example 2 1 0 334 1-(4-hydroxy- butyl) benzyl ethyl acetate 30 see example 210 335 none 4-methoxy- phenyloxymethyl DMF:water 80 see example 2 1 0 336 none isopropoxy methanol 61 see example 210

160

• ·4 • 4 4 · · · 4· >4 44 4 » 4 « • 4 • 4 · 4 • · · • 4 4 • • · 4 • 4 • and »4 ·· • « 44 4 4 · C 4 * • » Γ·4·

337 none amino DMF: water 92 see example 210 338 none 4-methoxybenzyl DMF.water 96 see example 2 1 0 339 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 1-(4-hydroxy- butyl) 4-hydroxy- phenylethyl methanol 80 see example 210 343 none isopropyl ethanol 30 see example 2 1 0 344 none cyclopropyl ethanol 50 see example 2 1 0 345 none cyclobutyl ethanol 74 see example 210 346 none 3-pyridyl ethanol 40 see example 210 347 none phenyl ON 56 see example 210 348 none 4-fluorophenylamino ON 14 see example 210 349 none propyl ON 24 see example 210 350 none methyl ON 77 see example 210 351 none trifluoromethyl ON 17 see example 210 352 none tert-butyl ON 80 see example 210 353 1-(4-hydroxy- butyl) trifluoromethyl ON 6 see example 210 354 none 4-isopropyl- phenylamino ON 30 see example 210 355 none 3-methyl- phenylamino ON 70 see example 210 356 1-(4-hydroxy- butyl) 3-methyl- phenylamino ON 30 see example 210 357 none phenylethyl DMF: water 63 see example 210

161

Table 4A

Physical data of the synthesized compounds having structural formula VIII.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 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 ( _1H2O )* >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 ( _1H2O )* 249-252 63.54 63.45 4.70 4.75 21.79 21.68 340 (0.5 _H2O )* >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) dissolution 66.12 65.91 5.54 5.57 22.03 21.89 344 (0.25 _H2O )* 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 ¹ 'C and 'H NMR and analytical data from LC/MS are consistent with the stated structure 357 3Π-319 72.13 71.69 5.09 5.04 17.70 17.65

The molecular weight calculated for elemental analysis includes the solvent in the amount indicated.

• · • > · · • ·

....... · · • ····· · · · ♦ · ·

A · »··· ···

... ·· ·· ·· ·* ···*

162

Explanation: Maleate salts were prepared by adding an ethanolic solution of maleic acid to the free base in ethanol at room temperature, cooling, and filtering the crystalline product.

V. 4-(Phenylmethylene)-2-pyrazolin-5-ones (IX).

Synthesized compounds having structural formula IX.

Example Substituent on ring A R ¹ Recrystallization solvent Exc. % Method of preparation 358 4-dimethylamino benzyl ethanol 32 see example 210 359 4-dimethylamino isopropoxy tolueneheptane 51 see example 210 360 4-dimethylamino phenylethyl ON 45 see example 210 361 4-dimethylamino cyclopropyl ethanol 77 see example 210

Table 5A

Physical data of the synthesized compounds having structural formula IX.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off- Name. Off. Name. 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

VI. 4-[(Pyrazol-4-yl)methylene]-2-pyrazolin-5-ones (X).

• « • · ·

163

X.

Table 6

Synthesized compounds having structural formula X.

Example Substituent on ring A R ¹ Recrystallization solvent Exc.% Method 362 3-methyl isopropoxy ethyl acetate 80 see example 210 363 3-methyl cyclopropyl toluene 51 see example 210

Table 6A

Physical data of synthesized compounds having structural formula X.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 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

VII.

4-[(Imidazol-2-yl)methylene]-2-pyrazolin-5-ones (XI).

XI.

164

Table 7

Synthesized compounds having structural formula XI.

Example Substituent of Ring A on R ¹ Recrystallization solvent Exc. % Method of preparation 364 none isopropoxy toluene 45 see example 210 365 none cyclopropyl ethanol 42 see example 210

Table 7A

Physical data of the synthesized compounds having structural formula XI.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 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

VIII. 4-[(Imidazol-4-yl)methylene]-2-pyrazolin-5-ones (XII).

XI.

Table 8

Synthesized compound having structural formula XII.

Example Substituent of Ring A on R ¹ Recrystallization solvent Exc. % Method of preparation 366 none isopropoxy ethanol 81 see example 210

• ·

Physical data of the synthesized compound having structural formula XII.

165

Table 8A

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 366 259-260 54.53 54.84 5.49 5.68 25.43 25.37

IX.

4-[(Thien-2-yl)methylene]-2-pyrazolin-5-ones (XIII).

Table 9

Synthesized compound having structural formula XIII.

Example Substituent on ring A R ¹ Recrystallization solvent Exc. % Method of preparation 367 none cyclopropyl ethanol 20 see example 210

Table 9A

Physical data of the synthesized compound having structural formula XIII.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 367 275-277 60.53 60.68 4.61 4.74 12.83 12.50

X. 4-[(Indol-3-yl)methylene]-1-methyl-2-pyrazolin-5-ones (XIV).

• · · ·

Table 10

A synthesized compound having the structural formula XIV.

Example Substituent of Ring A on R ¹ Recrystallization solvent Exc. % Method of preparation 368 none isopropyl ethanol 54 see example 210

Table 10A

Physical data of the synthesized compound having structural formula XIV.

Example Melting temperature (°C) Elementary analysis Carbon Hydrogen Nitrogen Off· Name. Off· Name. Off. Name. 368 241-242 71.88 71.73 6.41 6.47 15.72 15.71

4-[(Pyrrol-3-yl)methylene]-2-pyrazolin-5-ones (XV).

XV.

XI.

• · · ·

167

Table 11

A synthesized compound having structural formula XV.

Example Substituent of pyrrole on R ¹ Solvent recrystallization to Exc. % Method of preparation 369 none isopropoxy methanol 70 see example 210

Table 11A

Physical data of the synthesized compound having structural formula XV.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 369 252-255 60.26 60.35 5.98 5.82 19.17 19.13

XII. 4-[(Quinolin-5-yl)methylene]-2-pyrazolin-5-ones (XVI).

Table 12

A synthesized compound having the structural formula XVI.

Example Substituent on quinoline R ¹ Recrystallization solvent Exc. % Method of preparation 370 8-hydroxy isopropoxy methanol 40 see example 210

• ·

168

Table 12A

Physical data of the synthesized compound having structural formula XVI.

Example Melting point (°C) Elementary analysis Carbon Hydrogen Nitrogen Off. Name. Off. Name. Off. Name. 370 >300 64.64 64.43 5.09 5.01 14.13 13.98

X. Synthesis of starting materials.

A. Synthesis of 3-ketoesters (XIX).

The general method used to synthesize 3-ketoesters is shown in Scheme II.

Scheme II

Synthesis of 3-ketoesters

Example 371

Ethyl 3-(2,2,3,3-tetramethylcyclopropyl)-3-oxopropionate

Pyridine (5 g, 0.063 mol) and 2,2,3,3-tetramethylcyclopropylcarbonyl chloride (5 g,

0.031 mol) were added to an ice-cold solution of 2,2-dimethyl-1,3-dioxane-4,7-dione (4.7 g, 0.032 mol) in anhydrous dichloromethane (37 ml) under a nitrogen atmosphere. The temperature was • · · · · · « · · · · · · « · * · • * • · · · «

169 was kept at 0°C for 1 hour, then allowed to warm to room temperature overnight. The mixture was then poured into 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, which was refluxed for 3 hours in 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) while maintaining the temperature below 25°C, then 2-ethoxycarbonyl-2-(6-methoxy)benzothiazole (5.25 g, 0.022 mol) was added. The mixture was heated at gentle reflux 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. After precipitation, the product was collected by filtration, washed with water and dried.

Example 378

Ethyl 4-(4-phenylphenyloxy)-3-oxobutanoate.

Sodium hydride (5.0 g, 0.114 mol) and 4-phenylphenol (15.3 g, 0.09 mol) were stirred at 0°C in 75 ml of dimethylformamide (hereinafter DMF) for 2 hours. Ethyl 4-chloroacetoacetate (5.0 g, 0.03 mol) in DMF (75 ml) was then added. The mixture was stirred for 1 hour at 0°C and for 12 hours at room temperature, then neutralized with 50% phosphoric acid and extracted with dichloromethane. The product obtained was purified by chromatography on a silica gel column in a mobile phase of toluene/ethanol (8:2).

Table 13

Synthesized compounds having structural formula XIX.

Example R ¹ Exc. % Boiling point (°C) Melting point (°C) Method 371 2,2,3,3-tetramethyl- cyclopropyl 67 68 (0.2 mmHg) ON see example 371 372 2-methylcyclopropyl 50 62-4 (0.2 mmHg) ON see example 371

• · · · · ·

170

373 trans-2-phenyl- cyclopropyl 64 138-40 (0.2 mmHg) ON see example 371 374 tetrahydrofuran-3-yl 60 82-6 (0.2 mmHg ON see example 371 375 3-methoxy- phenylmethyl 62 132(0.2mmHg) ON see example 371 376 phenylethyl 55 110 (0.2 mmHg ON see example 371 377 6-methoxy- benzothiazol-2-yl 65 ON 160 see example 377 378 4-phenylphenoxy- methyl 33 ON 83 see example 378 379 3-chloro- phenoxymethyl 32 147 (8 mmHg) ON see example 378 380 pyrazinyl 71 ON 82 see example 377

B. Synthesis of ethyl cyclopentyloxythiocarbonyl acetate.

NC

XX.

+ HO-R ⁸

XXI.

HCI

Scheme III. Synthesis of ethylalkyloxy or aryloxycarbonimidoyl acetate hydrochloride (substituent R ⁹ is a substituted or unsubstituted aliphatic or aromatic group).

Example 381

Synthesis of ethyl cyclopentyloxycarbonimidoyl acetate hydrochloride (ΧΧΠ).

A mixture of dry ethyl cyanoacetate (14 g, 0.12 mol) and dry cyclopentanol (12 g,

0.15 mol) is saturated at 0°C with gaseous hydrogen chloride for 3 hours, kept at 0°C overnight, then diluted with diethyl ether. After precipitation, the product is collected by filtration and washed with ether.

Yield 22.4 g (77%), melting point 110-112°C.

• · · · • » · • · · • · *

171

With

• * • · • · » * • ·

Scheme IV: Synthesis of ethyl-alkyloxythio or aryloxythiocarbonyl acetate.

Example 382

Ethyl cyclopentyloxythiocarbonyl acetate (XXIV)

A mixture of ethyl cyclopentyloxycarbonimidoyl acetate hydrochloride (22 g, 0.09 mol) in anhydrous pyridine (150 ml) was reacted with hydrogen sulfide for 8 hours and kept at room temperature for 48 hours. The reaction mixture was acidified with concentrated hydrochloric acid and extracted with diethyl ether. The ether phase was washed with water, dried and purified by distillation.

Yield 15 g, (75%), boiling point 140-142°C (15 mmHg).

C. Synthesis of 2-p\Tazolin-5-ones.

2-Pyrazolin-5-ones are synthesized by the following four methods.

_H2N - _NH2

XXV.

Scheme V: Synthesis of 2-pyrazolin-5-ones according to method 1.

s O h ₂ n—nh ₂

XXVII.

XXVIII.

Scheme VI: Synthesis of 2-pyrazolin-5-ones according to method 2.

• ·

172

XXIX,

XXX.

Scheme VII: Synthesis of 2-pyrazolin-5-ones according to method 3.

Scheme VIII: Synthesis of 2-pyrazolin-5-ones according to method 4.

Example 383

3-(2,2,3,3-Tetramethylcyclopropyl)-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 was refluxed for 3 h, cooled, the solvent was evaporated, and the residue was triturated with hexanes to give a white solid.

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 to -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), then the aqueous phase was separated • ·

173 and basified with 5% sodium bicarbonate solution. The resulting precipitate is filtered and crystallized from methanol.

Example 413

3-(4-Carbarmoylphenylethyl)-2-pyrazolin-5-one.

A mixture of 3-(4-methoxycarbonylphenylethyl)-2-pyrazolin-5-one (7.7 mmol) in 25% ammonium hydroxide solution (30 mL) was stirred at room temperature for 12 hours. The solvent was concentrated in vacuo and the resulting solid was filtered and dried.

Example 414

3-(2-Aminocarbonylethyl)-2-pyrazolin-5-one.

A mixture of 3-(ethoxycarbonylmethyl)-2-pyrazolin-5-one (1 g, 5.8 mmol) and NaCN (28 mg, 0.58 mmol) in 30 mL of 9M ammonia in MeOH was heated at 45°C in a sealed flask 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 mol) in 50 ml of acetic acid was refluxed for 4 hours. The solvent was evaporated and the residue was suspended in water. The solid was filtered and crystallized from methanol.

Table 14

Synthesized compounds having structural formula XXVI.

Example R ¹ Exc. % Melting point (°C) Recrystallization solvent Method 383 2,2,3,3-tetramethyl- cyclopropyl 44 195-7 ON see example 383 384 ethoxycarbonylmethyl 44 115-6 toluene see example 383 385 pyrrol-2-yl 30 205-8 ON see example 383

« · · · · · • · · · · · · · ·

174

386 indol-3-yl 69 250-3 ON see example 383 387 6-methoxy\benzothiazol-2-yl 40 269-70 ON 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 tetrahydrofuran-3-yl 36 204-5 ethanol see example 383 391 4-methoxybenzyl 73 192-5 ON 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 ON see example 383 395 3,4-dimethoxybenzyl 69 193-5 ON see example 383 396 phenylethyl 72 204-7 ON see example 383 397 2-phenylpropyl 72 215 ON 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 ON see example 383 401 4-chlorophenylethyl 63 243 ON see example 383 402 4-nitrophenylethyl 69 247 DMF: water see example 383 403 4-aminophenylethyl 61 220-2 ON see example 383 404 4-methoxyv- 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-chlorophenyloxymethyl 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 ON see example 414 415 2-dimethylamino- carbonyl ethyl 38 203-9 ON see example 414

• * · ·

175

416 4-methoxyphenylamino 30 232-4 methanol see example 416 417 4-chlorophenylamino 28 262-4 ethanol see example 416 418 4-fluorophenylamino 35 259-60 ON see example 416 419 cyclopropylamino 82 155-158 ON 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-pyridazmyl 83 294-95 ethanol see example 383 424 4-pyrimidinyl 72 290-300 ethanol see example 383 425 4-pyrimidinyl 60 288-291 ethanol see example 383

D. Synthesis of aldehydes

Example 426 1-(4-Acetoxybutyl)-azaindole-3-carboxaldehyde

A solution of 7-azaindole-3-carboxaldehyde (4.19 g, 28 mmol) in dry A,A-dimethylformamide (50 ml) was added dropwise to a stirred suspension of 60% sodium hydride (oil dispersion) (1.2 g, 30 mmol) in dry DMF (65 ml) under nitrogen, maintaining the temperature between 5-10°C. After the addition was complete, stirring was continued at the same temperature for 30 minutes, then a solution of 4-bromobutyl acetate (6.16 g, 31 mmol) in dry A,A-dimethylformamide (15 ml) was added dropwise. The mixture was allowed to warm to room temperature and stirred at room temperature for 137 hours. Water (100 ml) was then added and the mixture was extracted with dichloromethane (2 x 100 ml). The organic phase was washed with water (3 x 100 ml), dried over anhydrous magnesium sulfate, filtered and the solvent was removed under reduced pressure to give an oil (6.8 g, 93%) which was used without purification.

Example 427 1-(4-Hydroxybutyl)-7-azaindole-3-carboxaldehyde

To a solution of 1-(4-acetoxybutyl)-7-azaindole-3-carboxaldehyde (2.3 g, 8.8 mmol) in methanol (40 mL) was added a solution of sodium hydroxide (0.2 g, 17.5 mmol) in water (35 mL).

176

The mixture is heated at 60°C for 0.5 hour, then the solvent is completely evaporated. The residue is dissolved in a mixture of ethyl acetate and water (50 ml:50 ml) and the aqueous layer is separated. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated to dryness. The residue is used without purification. The yield is 78%, melting point 90°C.

Example 428 1-(4-Hydroxybutyl)pyrrole-2-carboxaldehyde.

The product was obtained by the procedure of Example 51, but using pyrrole-2-carboxaldehyde instead of 7-azaindole-3-carboxaldehyde. The product was purified by column chromatography on silica gel using (5:5) ethyl acetate:hexanes as the mobile phase. The yield was 67%.

Example 429

3-Isopropyl-5-methylpyrrole-2-carboxaldehyde.

To a solution of anhydrous DMF (2.1 ml, 27 mmol) in anhydrous dichloroethane (50 ml) at 0°C under nitrogen atmosphere was added POCl3 (2.1 ml, 23 mmol). The solution was allowed to warm to room temperature over 1 hour. The suspension was then cooled to 0°C and a solution of 3-isopropyl-5-methylpyrrole (2g, 16 mmol) in dichloroethane (20 ml) was added dropwise over 20 minutes. After stirring at room temperature for 24 hours, water and NaOH were added to adjust the pH to 8. The organic layer was extracted, dried and the solvent was completely removed. The residue was purified by flash chromatography. The yield was 67%, melting point 90-93°C.

Example 430

3,5-Dimethyl-4-morpholino-methylpyrrole-2-carboxaldehyde.

3,5-Dimethylpyrrole-2-carboxaldehyde (0.5g, 4 mmol) was added to a solution of morpholine (0.35g, 4 mmol), 37% formaldehyde (0.32g, 4 mmol) and acetic acid (2 mL). The mixture was stirred overnight at room temperature under nitrogen, then the reaction was diluted with NaHCO ₃ to pH=8. The aqueous solution was extracted with ethyl acetate and the organic layer was dried over MgSO 4 . The ethyl acetate was evaporated in vacuo to give 0.4 g of pure solid.

The following compounds were synthesized in a manner analogous to that described in Example 430:

• ·

177

3.5-Dimethyl-4-diinethylaminomethylpyrrole-2-carboxaldehyde,

3-(4-morpholino)methyl-indole-2-carboxaldehyde,

3.5-dimethyl-4-diethylaminomethylpyrrole-2-carboxaldehyde,

3.5-dimethyl-4-piperidinomethylpyrrole-2-carboxaldehyde,

3.5-dimethyl-4-[(4-methyl-1-piperazinyl)methyl]pyrrole-2-carboxaldehyde,

3.5-dimethyl-4-(1-pyrrolidinylmethyl)pyrrole-2-carboxaldehyde,

5-methyl-4-dimethylaminomethylpyrrole-2-carboxaldehyde,

3.5-dimethyl-4-[V-methyl-Y-(2-dimethylaminoethyl)aminomethyl]pyrrole-2carboxaldehyde,

3.5-dimethyl-4-diethanolaminomethylpyrrole-2-carboxaldehyde,

4-(4-benzylpiperidinomethyl)-3,5-dimethylpyrrole-2-carboxaldehyde,

4-dimethylaminomethyl-3-isopropyl-5-methylpyrrole-2-carboxaldehyde,

3.5-dimethyl-4-(4-hydroxypiperidinomethyl)pyrrole-2-carboxaldehyde a

3-dimethylaminomethyl-4,5-tetramethylenepyrrole-2-carboxaldehyde.

Example 431

3.5-Dimethyl-4-trifluoroacetamidomethylpyrrole-2-carboxaldehyde.

A mixture of 3,5-dimethylpyrrole-2-carboxaldehyde (2.6 g, 0.02 mol) and N-(hydroxymethyl)trifluoroacetamide (3 g, 0.02 mol) was added portionwise to sulfuric acid (15 ml), keeping the temperature below 10°C. The reaction mixture was allowed to warm to room temperature over 4 hours, poured into ice water (100 ml). The precipitated solid was filtered and washed with water. The white solid (yield 78%) was used without purification. Melting point 200°C.

Example 432

4- Aminomethyl-3,5-dimethylpyrrole-2-carboxaldehyde.

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 1 hour, then the solution was concentrated under reduced pressure to half the original volume. Water was added and the precipitated solid was filtered. The yield was 72%, melting point 210-220°C (decomposition).

• «

178

• · · · * ·

Example 433

3-Acetyl-4-oxopentyl acetate.

A mechanically stirred mixture of pentane-2,4-dione (60 g, 0.6 mol), 2-bromoethyl acetate (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 at reflux for 24 hours. The 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 was completely removed and the residue was distilled to give 38 g of acetate. The boiling point was 75-80°C (0.1 mm Hg).

4-Acetyl-5-oxohexylacetate [yield 60%, bp 110°C (0.2 mm Hg)] and 5-acetyl-6-oxoheptylacetate [yield 77%, bp 102°C (0.2 mm Hg)] were prepared according to the method of Example 433.

Example 434 tert-Butyl 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxylate.

A stirred solution of tert-butyl acetoacetate (26 g, 0.165 mol) in acetic acid (48 ml) was treated dropwise with sodium nitrite (11.3 g, 0.165 mol) in water ( ¹⁷ ml) at a temperature below 20°C. The reaction mixture was allowed to stand overnight. A solution of 3-acetyl-4-oxopentyl acetate (30 g, 0.161 mol) in acetic acid (56 ml) was heated to 80°C, then a mixture of zinc powder (26.2 g, 0.40 mol) and sodium acetate (26.3 g, 0.32 mol) was added portionwise, while the hydroxyimino derivative (97 ml, 0.165 mol) was added dropwise. The reaction mixture is stirred vigorously during the addition, which is controlled so that zinc is always in excess and the temperature is kept between 90-100°C. After the addition, the mixture is carefully heated for 15 minutes and stirred at room temperature overnight. The reaction mixture is poured into ice water and left to stand for 2 hours. The solid is filtered and washed with water and recrystallized from aqueous ethanol. The yield is 78%, melting point 92°C.

tert-Butyl 4-(3-acetoxypropyl)-3,5-dimethylpyrrole-2-carboxylate [yield 60%, melting point 73°C (hexane)] and tert-butyl 4-(4-acetoxybutyl)-3,5-dimethylpyrrole-2-carboxylate [yield 52%, melting point 62°C (hexane)] were prepared according to the method of Example 434.

• · · · · ♦ • ·

179

Example 435

3.5- Dimethyl-4-(2-hydroxyethyl)pyrrole-2-carboxaldehyde.

Tert-Butyl 4-(2-acetoxyethyl)-3,5-dimethylpyrrole-2-carboxylate (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-triethyl orthoformate (9.6 mL, 58 mmol) was added dropwise. The mixture was then allowed to warm to 20°C and stirred for 1 h before pouring into ice water, extracting with dichloromethane and washing the extracts successively with 10% aqueous ammonia and water and drying over MgSO4. 4-(2-Acetoxyethyl)3,5-dimethylpyrrole-2-carboxaldehyde was purified by column chromatography on silica gel using ethyl acetate:hexanes (7:3) as the mobile phase. The yield is 45%, the melting point is 125-127°C (water).

To a solution of the above compound (5g, 23 mmol) in ethanol (20 ml), 10% NaOH solution (10 ml) was added. The mixture was stirred at room temperature for 30 minutes and the final solution was concentrated, diluted with water and extracted with dichloromethane. The organic extracts were dried and the solvent was completely removed. The yield was 98%, melting point 100°C (ethyl acetate).

3,5-Dimethyl-4-(3-hydroxypropyl)pyrrole-2-carboxaldehyde [yield 60%, melting point 85°C (ethyl acetate/hexane)] and 3,5-dimethyl-4-(4-hydroxybutyl)pyrrole-2-carboxaldehyde [yield 38%, melting point 99°C (hexane)] were prepared according to the method of Example 435.

Example 436

4-(2-Diethylaminoethyl)-3,5-dimethylpyrrole-2-carboxaldehyde.

Methanesulfonyl chloride (4 mL, 51 mmol) in anhydrous THF (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 anhydrous THF (60 mL) at 0-5°C and the mixture was stirred for 1 hour at room temperature. Water was then added to the mixture and the precipitated solid was filtered. The yield was 89%, mp 142-44°C.

A mixture of the above mesylate (23 mmol), K2CO3 (23 mmol), diethylamine (90 mmol) and 2-propanol (70 ml) was heated at 100°C for 0.5 h. The solvent was completely removed and the residue was treated with water and extracted with methylene chloride. The organic extracts were dried and the solvent was completely evaporated. The yield was 70%, melting point 70°C ((-heptane).

• « · » · *

180

3.5-Dimethyl-4-[2-(1-pyrrolidinylethyl)]pyrrole-2-carboxaldehyde, 3,5-dimethyl-4-(2ethylaminoethyl)pyrrole-2-carboxaldehyde, 4-(3-diethylaminopropyl)-3,5-dimethylpyrrole-2-carboxaldehyde, 4-(4-diethylaminobutyl)-3,5-dimethylpyrrole-2-carboxaldehyde, 3,5-dimethyl-4-[3-(1-pyrrolidinylpropyl)]pyrrole-2-carboxaldehyde are isolated in the form of an oil and prepared in a manner analogous to that described in Example 436.

Example 437

4-(2-Chloroacetyl)-3,5-dimethylpyrrole-2-carboxaldehyde.

Anhydrous aluminum chloride (42 g, 315 mmol) was added dropwise over 30 minutes to a solution of 3,5-dimethylpyrrole-2-carboxaldehyde (5 g, 40 mmol) in 1,2-dichloroethane (50 ml) under nitrogen atmosphere at room temperature. After stirring for 15 minutes, chloroacetyl chloride (17 g, 150 mmol) was added dropwise over 1 hour. After addition, the mixture was stirred at room temperature for 16 hours. The mixture was poured onto crushed ice, the organic layer was separated, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The yield was 57%, melting point 205-209°C (toluene).

Example 438

3.5- Dimethyl-4-(2-diethylaminoacetyl)pyrrole-2-carboxaldehyde

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 pressure and the residue was treated with water, NaHCO3 (5%) and extracted with dichloromethane. After drying and filtration, the solvent was removed and the residue was used without purification.

3.5-Dimethyl-4-(2-dimethylaminoacetyl)pyrrole-2-carboxaldehyde, 3,5-dimethyl-4[2-(1-pyrrolidinyl)acetyl]pyrrole-2-carboxaldehyde is prepared by a method analogous to that described in Example 438.

Example 439

3.5- Dimethyl-4-ethoxyoxalylpyrrole-2-carboxaldehyde.

Anhydrous aluminum chloride (37 g, 277 mmol) was added dropwise over 30 minutes to a solution of 3,5-dimethylpyrrole-2-carboxaldehyde (7.6 g, 62 mmol) in 1.2* · · · · • · · · ·

181 dichloroethane (140 ml) under nitrogen atmosphere and at room temperature. After stirring for 30 minutes, nitromethane (11.2 ml, 179 mmol) is added and the mixture is cooled to 0°C and ethyl chloroxoacetate (12.8 g, 94 mmol) is added dropwise over 1 hour. After addition, the mixture is stirred at room temperature for 4 hours, poured onto crushed ice and the organic layer is separated, dried and evaporated to give a white solid. The yield is 45%, melting point is 125-127°C (toluene).

All compounds from the above examples had NMR spectra that were consistent with their chemical structures.

While the present invention has been shown and described in detail with reference to preferred embodiments, it is apparent that various changes may be made without departing from the scope and character of the present invention, which is fully defined in the appended claims.

Claims (45)

PATENT CLAIMS A method for inhibiting the activity of one or more protein kinases, comprising administering a compound of the formula and physiologically acceptable salts and biologically active metabolites thereof, wherein R is selected from the group consisting of substituted or unsubstituted: aliphatic groups, aromatic groups , (C 5 -C 6 cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 6 -C 6 cycloalkyl-alkyl groups and heterocyclyl alkyl groups); R ¹ is hydrogen or -AZ; R ² is hydrogen or is selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (C3-C6) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C3-C6) cycloalkylalkyl and heterocyclyl alkyl groups ; A is - (CH ₂ ) _n -, - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ -; Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of (C 3 -C 6) cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and N -oxides thereof, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl. R ³ O-, HO-, HOC (O) -, R ³ OC (O) -, trihalomethyl, nitro, aryl, -CN, -C (O) NR ⁴ R ⁵ and-NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl 183 • Φ Φ ·· »Φ« • φ Φ Φ · Φ Φ Λ Φ Φ Φ · · · · · · · · · • • • · · · · · 1 φ Φ · * Φ groups, aromatic groups, (C3-C6) cycloalkyl groups, heterocyclic groups, aralkyl groups. (C 6 -C 6 cycloalkyl-alkyl and heterocyclyl-alkyl; substituent) R ⁴ and R ⁶ ; in each case, they are independently hydrogen or selected from the group consisting of substituted or unsubstituted; lower alkyl groups, aromatic groups, (C 3 -C ₆ ) cycloalkyl groups, heterocyclic groups, aralkyl groups). (C3-C6) cycloalkyl-alkyl and heterocyclyl-alkyl; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each is optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 3 -C ₆ ) cycloalkyl, heterocyclic, aralkyl, (C ₃ -C ₆ ) cycloalkyl-alkyl and heterocyclyl-alkyl groups; and n is an integer ranging from 0 to 3. The method of claim 1, wherein the inhibition of said protein kinase is in a recipient in need thereof. The method of claim 2, wherein the compound is a mixture of stereoisomers. The method of claim 3, wherein the stereoisomers are enantiomers. The method of claim 3, wherein the stereoisomers are E and Z isomers. The process of claim 2, wherein the compound is a mixture of structural isomers. The method of claim 6, wherein the structural isomers are tautomers. The method of claim 2, wherein said protein kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase. · · · * * * * * * * * * * * * * * * * * 184 The method of claim 8, wherein said tyrosine kinase is selected from the group consisting of KDR, Flt-1, TIE-2, FGFR, PDGFR, IGF-1-R, c-Met, Lck, Src, fyn, Lyn, Blk and yes. 10. A method of treating or significantly inhibiting hyperproliferative disorders or inflammatory diseases in a recipient in need thereof, comprising administering to said recipient a compound of the formula and its physiologically acceptable salts and biologically active metabolites, wherein R is selected from the group consisting of substituted or unsubstituted: aliphatic groups, aromatic groups, (C ₃ -C ₆ ) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C ₃ -C 6) cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; R ¹ is hydrogen or -AZ; R ² is hydrogen or is selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (C ₃ -C 6) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C ₃ -CE) cycloalkylalkyl and heterocyclyl alkyl groups; A is - (CH ₂ ) _n -, - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ -; Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of C ₃ -C ₆ cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, pyrazole, pyrazole thiazole and their A-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower 185 alkyl groups, R ³ O-, HO-, HOC (O) -, R ³ OC (O) -, trihalomethyl, nitro, aryl, -CN, -C (O) NR ⁴ R ⁵ and -NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C 5 -C 6 cycloalkyl, heterocyclic, aralkyl) (C 1 -C 6 cycloalkyl-alkyl and heterocyclyl- R ⁴ and R ⁵ in each case are independently hydrogen or selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 1 -C 6) cycloalkyl, heterocyclic, aralkyl, (C 3 -C 6) alkyl; cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 5 -C 6 cycloalkyl, heterocyclic, aralkyl, (C 3 -C 6 cycloalkyl-alkyl and heterocyclyl-alkyl) and the index n is an integer ranging from 0 to 3. 11. A method of treating or inhibiting angiogenesis in a recipient in need thereof, comprising administering to said recipient a compound of formula and its physiologically acceptable salts and biologically active metabolites, wherein R is selected from the group consisting of substituted or unsubstituted: aliphatic groups, aromatic groups, (C 3 -C ₆ ) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 3 -C ₆ ) cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; 186 R ¹ is a substituent R ¹ is a hydrogen atom or -AZ; R ² is hydrogen or selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C ₆ ) cycloalkyl, heterocyclic, aralkyl, (C 3 -C ₆ ) cycloalkylalkyl, and heterocyclyl- alkyl groups; A is - (CH ₂ ) _n -, - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ -; Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring a system selected from the group consisting of (C 3 -C 6) cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, pyrazole, , thiazole and their oxid-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R ³ O-, HO-, HOC (O) -, R ³ OC (O ) -, trihalomethyl, nitro, aryl, -CN, -C (O) NR ⁴ R ⁵ or -NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C ₅ -C ₆ ) cycloalkyl, heterocyclic, aralkyl, (C ₃ -C ₆ ) cycloalkyl -alkyl groups and heterocyclyl-alkyl groups; R ⁴ and R ⁵ in each case are each independently hydrogen or selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C 6) cycloalkyl, heterocyclic, aralkyl. (C ₃ -C ₆ ) cycloalkyl-alkyl and heterocyclyl-alkyl; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 3 -C ₆ ) cycloalkyl, heterocyclic, aralkyl, (C 3 -C ₆ cycloalkyl-alkyl and heterocyclyl) and n is an integer having a value of 0 to 3. 187 12. A method of inducing an anti-angiogenic effect in a recipient in need thereof, characterized in. comprising administering a compound of formula and its physiologically acceptable salts and biologically active metabolites to said recipient, wherein R is selected from the group consisting of substituted or unsubstituted: aliphatic groups, aromatic groups, (C 1 -C 6 cycloalkyl groups, heterocyclic groups, aralkyl groups); groups, (C 1 -C 6 cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; R ¹ is hydrogen or -AZ; R ² is hydrogen or is selected from the group consisting of substituted or unsubstituted: lower alkyl group, aromatic group, (C3-C6) cycloalkyl groups, heterocyclic groups, aralkyl groups, _(C3-C6) cycloalkylalkyl and heterocyclyl alkyl groups; A is - (CH ₂ ) _n -, - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ -; Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of (C 3 -C 6) cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and N -oxides thereof, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl. R ³ O-, HO-, HOC (O) -, R ³ OC (O) -, trihalomethyl, nitro, aryl, -CN, -C (O) NR ⁴ R ⁵ and -NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C 3 -C ₆ ) cycloalkyl, heterocyclic, aralkyl. (C3-C6) cycloalkyl-alkyl and heterocyclyl-alkyl; · T t t β β β β β β β β β * * * * * * * * * t β β The substituents R ⁴ and R ⁵ in each case are each independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C ₃ -C 6) cycloalkyl, heterocyclic, aralkyl, (C ₃₎ -C6) cycloalkyl-alkyl and heterocyclyl-alkyl; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl group, aromatic group, (C ₃ -C _()), cycloalkyl groups, heterocyclic groups, aralkyl groups, (C ₃ Cójcykloalkyl- alkyl and heterocyclyl-alkyl, and n is an integer ranging from 0 to 3. 13. A method of treating or inhibiting the progression of a disease or condition in a recipient in need thereof, comprising administering to said recipient a compound of formula and its physiologically acceptable salts and biologically active metabolites, wherein R is selected from the group consisting of substituted or unsubstituted: aliphatic groups, aromatic groups, (C ₃ -C 6) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C ₃ -C 6) cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; R ¹ is hydrogen or -AZ; R ² is hydrogen or is selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C ₃ -C 8) cycloalkyl, heterocyclic, aralkyl, (C ₃ -C ()) cycloalkylalkyl, and heterocyclyl-alkyl groups; A is - (CH ₂ ) _n -, - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ -; · · * * * * * »» »» » 189 Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of (C ₃ -C 6) cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole , oxazole, thiazole and their A-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl, R ³ O-, HO-, HOC (O) -, R ³ OC (O) -, trihalomethyl, nitro, aryl, -CN, -C (O) NR ⁴ R ⁵ and -NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C 3 -C 6) cycloalkyl, heterocyclic, aralkyl. (C 6 -C 6 cycloalkyl-alkyl and heterocyclyl-alkyl; R ⁴ and R ⁵ in each case are each independently hydrogen or selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C ₁ -C 6) cycloalkyl, heterocyclic, aralkyl (C ₃ -C 6). cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 3 -C ₆ ) cycloalkyl, heterocyclic, aralkyl, (C ₃ -C 6) cycloalkyl- alkyl and heterocyclyl-alkyl groups; and index n is an integer having a value of 0 to 3; wherein 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, coma disease, rubeosis, neovascular glaucoma, wound healing, macular degeneration ulcer, Helicobacter-related diseases, viral-induced angiogenic disorders, fractures, diabetic retinopathy, Crohn's disease, inflammatory bowel disorders, cat scratch fever, premature retinopathy, ulcers, thyroid hyperplasia, burns, trauma, acute lung injury, chronic lung disease, chronic lung disease · · · 190 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, multi-organ dysfunction syndrome, ascites and ascites edema. 14. A method of affecting vascular hyperpermeability or edema formation in a recipient in need thereof, comprising administering to said recipient a compound of the formula and its physiologically acceptable salts and biologically active metabolites, wherein R is selected from the group consisting of substituted or unsubstituted aliphatic groups, aromatic groups, (C 3 -C 6) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 3 -C 6) cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; R ¹ is hydrogen or -AZ; R ² is hydrogen or is selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C ₆ ) cycloalkyl, heterocyclic, aralkyl, (C 3 -C ₆ ) cycloalkylalkyl, and heterocyclyl- alkyl groups; A is - (CH ₂ ) _n -, - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - (CH ₂ ) _n S (O) ₂ -; Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of (C 3 -C 6) cycloalkyl, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxaline, pyrazole, oxazole, thiazole and their A-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower 191 alkyl groups, R ³ O-, HO-, HOC (O) -, R ³ OC (O) -, trihalomethyl, nitro, aryl, -CN, -C (O) NR ⁴ R ⁵ and NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C3-C6) cycloalkyl, heterocyclic, aralkyl, (C3-C ₍ , cycloalkyl-alkyl groups and heterocyclyl-alkyl groups; R ⁴ and R ⁵ in each case are each independently hydrogen or are selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C 6) cycloalkyl, heterocyclic, aralkyl, (C 1 -C 6) cycloalkyl- alkyl and heterocyclyl-alkyl groups; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 3 -C 6) cycloalkyl, heterocyclic, aralkyl, (C 3 -C 6) cycloalkyl-alkyl and heterocyclyl- and n is an integer having a value of 0 to 3. 15. The method of claim 14, wherein the effect on edema formation is anti-oedematous. 16. The method of claim 2, wherein said protein kinase is a serine kinase. 17. The method of claim 2 wherein said protein kinase is a threonine kinase. 18. A compound represented by the following structural formula: 192 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; R ¹ is hydrogen or -AZ; A is - (CH ₂ ) _n , - (CH ₂ ) _n NH-, - (CH ₂ ) _n O-, - (CH ₂ ) _n S-, - (CH ₂ ) _n S (O) - or - ( CH ₂ ) _n S (O) ₂ -; Z is hydrogen, lower alkyl, aralkyl, trihalomethyl, trihalomethylcarbonyl, R ³ OC (O) -, -NR ⁴ R ⁵ , -C (O) NR ⁴ R ⁵ , R ³ CO-, R ³ O- or a ring system selected from the group consisting of (C 3 -C 6 cycloalkane, isoxazole, isothiazole, benzene, pyrrole, indole, pyridine, pyrazine, pyrimidine, benzothiazole, tetrahydrofuran, thiophene, imidazole, furan, triazine, benzimidazole, pyridazine, quinoxalin, pyraz, thiazole and their A-oxides, wherein said ring system may be optionally substituted with one or more moieties selected from the group consisting of halogens, lower alkyl groups R ³ O-, HO-, HOC (O) -, R ³ OC (O) -, trihalomethyl, nitro, aromatic groups, (C 3 -C 6) cycloalkyl groups, heterocyclic groups, aralkyl groups, (C 6 -C 6 cycloalkyl-alkyl groups, heterocyclyl-alkyl groups, -CN, -C (O) NR ⁴ R ^{5 and} NR ⁴ R ⁵ ; R ³ in each case is independently selected from the group consisting of substituted or unsubstituted: lower alkyl, lower alkoxy lower alkyl, aromatic, (C 6 -C 6 cycloalkyl, heterocyclic, aralkyl)}, (C 3 -C 6) cycloalkyl- alkyl and heterocyclyl-alkyl groups; R ⁴ and R ⁵ in each case are each independently hydrogen or selected from the group consisting of substituted or unsubstituted: lower alkyl, aromatic, (C 3 -C 6) cycloalkyl, heterocyclic, aralkyl. (C 3 -C 6) cycloalkyl-alkyl and heterocyclyl-alkyl; optionally R ⁴ and R ⁵ together with the nitrogen atom to which they are attached represent morpholino, pyrrolidino, piperidino, imidazol-1-yl, piperazino, thiamorpholino, azepino or perhydro-1,4-diazepin-1-yl, wherein each one is one of them. * * * * * * * · · · · · · · · · · · · · · · · · · · · · · · · · · 193 optionally substituted with one or more moieties selected from the group consisting of lower alkyl, hydroxy, lower alkoxy lower alkyl, aromatic, (C 1 -C 6 cycloalkyl, heterocyclic, aralkyl, (C 3 -C 6 cycloalkyl-alkyl and heterocyclyl-alkyl); and index n is an integer having a value of 0 to 3; provided that when R is unsubstituted indol-3-yl, then R ¹ is not -NH ₂ . The compound of claim 18, wherein: A is -NH-, -O-, -S-, -S (O) - or -S (O) ₂ -; and Z is cyclopropyl, 3-pyridyl or pyrazinyl. The compound of claim 18, wherein: A is -O-; and Z is ethyl, z-propyl or isopropyl. The compound of claim 18, wherein: A is -CH ₂ -; and Z is phenyl, wherein said phenyl is optionally substituted with one or more moieties selected from the group consisting of halogens, trihalomethyl, hydroxy, -NR ⁴ R ⁵ , nitro, -CONR ⁴ R ⁵ , lower alkyl, R ³ O-, -C (O) OR ⁴ and -OC (O) R ⁴ . 22. A compound selected from the group consisting of: 3-Cyclopropyl-4 - {[(3,5-dimethyl-4- (4-methyl-1-piperazinylmethyl) pyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(3,5-dimethyl-4- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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-pyrazolin-5-one; 194 3-Cyclopropyl-4 - [(3-dimethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(2-morpholinomethyl-4,5-tetrarnethylenepropyl) -2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(3-diethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {[3- (4-methyl-1-piperazinylmethyl) -4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [{3- (1-pyrrolidinyl) methyl-4,5-tetramethylenopyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(3-piperidinomethyl-4,5-tetramethylenopyrrol-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-Cyclopropyl-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; 3-Cyclopropyl-4 - [(4-oxo-1,5,6,7-tetrahydroindol-2-yl) methylene] -2-pyrazolin-5-one; 3-Cyclopropyl-4 - [(4-dimethylaminomethyl-5-methylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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-pyrazolin-5-one, 3-Cyclopropyl-4- [4- (2-dimethylaminoethylaminocarbonylpyrrol-2-yl) methylene] -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-5-one, 3-Cyclopropyl-4- [3- (2-dimethylaminoethylaminocarbonylindol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4- [4- (4-morpholinoethoxycarbonylpynol-2-yl) methylene] -2-pyrazolin-5-one, 195 3-Cyclopropyl-4- [4- (4-morpholinoethylaminocarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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, 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-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazol-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 - [(1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3,5-dimethylpynol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-piperidomethylpynol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 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-tetramethylenopyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - {[3- (4-Methyl-1-piperazinylmethyl) -4,5-tetramethylenepyrrol-2-yl] methylene} -3- (3-pyridyl) -2-pyrazolin-5-one, 3- (3-Pyridyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one; 196 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminoethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4- (3,5-Dibromo-4-hydroxybenzylidene) -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Oxo-1,5,6,7-tetrahydroindol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylammomethyl-5-methylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Bromopyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(4-Chloro-pyrrol-2-yl) -methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(5-Chloropyrrol-2-yl) methylene] -3- (3-pyridyl-2-pyrazolin-5-one), 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-Dimethylaminoethylaminocarbonylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-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-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, 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, 4 - {[3- (2-Acetamido-2-methoxycarbonylethyl) indol-2-yl] methylene} -3- (3-pyridyl) -2-pyrazolin-5-one, 197 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, 4 - [(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethyl-pyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4 - {[(4-methyl-1-piperazinylmethyl) pyrrol-2-yl] methyl] -3-isopropoxy-2-pyrazolin-5-one. 4 - [(3,5-Dimethyl) -4 - [(1-p-Tolidinylmethylpyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3,5-dimethyl-pyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (piperidinomethylpyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 4 - [(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 4 - [(3-Dimethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4 - [(3-morpholinomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4 - {[3- (4-methyl-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Isopropoxy-4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenopyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Isopropoxy-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-isopropoxy-2-pyrazolin-5-one, 4-f (4-Dimethylaminoethyl-3,5-dimethylpyrrol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5one. • · 198 4- (3,5-Dibromo-4-hydroxybenzylidene) -3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4 - [(4-oxo-1,5,6,7-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-Chloro-pyrrol-2-yl) -methylene] -3-isopropoxy-2-pyrazolin-5-one, 4 - [(5-Chloro-pyrrol-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-5one, 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, 4- [3- (2-Dimethylaminoethylaminocarbonylindol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 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, 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, 4 - {[3- (2-Amino-2-carboxyethyl) indol-2-yl] 4 - [(3,4-Diethoxycarbonylpynol-2-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one] 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, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-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; 199 4 - [(3,5-Dimethyl) -4 - [(1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3-ethoxy-2-pyrazolin-5-one, 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, 4 - [(4-Diethanolammomethyl-3,5-dimethyl-pyrrol-2-yl) methylene] -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-pyrazolin-5-one, 4 - [(3-Diethylammomethyl-4,5-tetramethylenopyrrol-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, 3-Ethoxy-4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-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-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-5-one, 3-Ethoxy-4 - [(4-oxo-1,5,6,7-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; 4- [4- (2-Dimethylaminoethoxycarbonylpyrrol-2-yl) methylene] -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, 4- [3- (2-Dimethylaminoethoxycarbonylindol-2-yl) methylene] -3-ethoxy-2-pyrazolin-5-one; 200 4- [3- (2-Dimethylamino-ethylaminocarbonylindol-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-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] methylene} -3-ethoxy-2-pyrazolin-5-one, 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-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3-ethoxy-2-pyrazolin-5-one, 4 - [(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(3-Morpholinomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3- (4-Methyl-1-piperazinylmethyl) -4,5-tetramethylenepyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 3-Pyrazinyl-4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenopyrrol-2-yl] methylene} -2-pyrazolin-5-one, 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-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, 4 - [(4-Diethylaminoethyl-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-Chloro-pyrrol-2-yl) -methylene] -3-pyrazinyl-2-pyrazolin-5-one, 201 4 - [(5-Chloro-pyrrol-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-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-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, 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-Morpholinoethylaminocarbonylpyridol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4- [3- (4-Morpholinoethoxycarbonylindol-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-pyrazinyl-2-pyrazolin-5-one, 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 - [(1-Methylindol-3-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one; 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-pyrazolin-5-one, 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, 4 - [(4-Bromopyrrol-2-yl) melhylene] -3- (imidazol-2-yl) -2-pyrazolin-5-one; • · · 202 4 - [(4-Chloro-pyrrol-2-yl) -methylene] -3- (imidazol-2-yl) -2-pyrazolin-5-one, 4 - [(5-chloropyrrol-2-yl) methylene] -3- (imidazol-2-yl) -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-Dimethylaminoethoxycarbonylpyn-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, 4- [3- (2-Dimethylaminoethoxycarbonylindol-2-yl) methylene] -3- (imidazol-2-yl) -2-pyrazolin-5-one, 4- [3- (2-Dimethylamino-ethylaminocarbonylindol-2-yl) -ethylene] -3- (imidazol-2-yl) -2-pyrazolin-5-one, 3- (Imidazol-2-yl) -4- [4- (4-morpholinoethoxycarbonylpyrrol-2-yl) methylene] -2-pyrazolin-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, 3- (Imidazol-2-yl) -4- [3- (4-morpholinoethylaminocarbonylindol-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 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one; 4- [3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl) methylene] -3- (imidazol-2-yl) -2-pyrazolin-5-one, 3- (Imidazol-2-yl) -4 - [(5-methoxyindol-2-yl) methylene] -2-pyrazolin-5-one; 3- (Imidazol-2-yl) -4 - [(4,5-tetramethylenopyrrol-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 (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, 203 3- (Imidazol-2-yl) -4 - ((indol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(3,4-Diethoxycarbonylpyrrol-2-yl) methylene] -3- (imidazol-2-yl) -2-pyrazolin-5-one, 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-yl) methylene] -3 (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- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - [(4-Chloropyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - [(5-Chloro-pyrrol-2-yl) -methylene] -3- (1-methyl-cyclopropyl) -2-pyrazolin-5-one, 3- (1-Methylcyclopropyl) -4 - [(5-trifluoromethylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(4-Ethoxycarbonylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one; 4- [4- (2-Dimethylaminoethoxycarbonylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4- [4- (2-Dimethylaminoethylaminocarbonylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - [(3-Ethoxycarbonylindol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4- [3- (2-Dimethylaminoethoxycarbonylindol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4- [3- (2-Dimethylaminoethylaminocarbonylindol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 3- (1-Methylcyclopropyl) -4- [4- (4-morpholinoethoxycarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3- (1-Methylcyclopropyl) -4- [4- (4-morpholinoethylaminocarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3- (1-Methylcyclopropyl) -4- [3- (4-morpholinoethoxycarbonylindol-2-yl) methylene] -2-pyrazolin-5-one, 3- (1-methylcyclopropyl) -4- [3- (4-morpholinoethylaminocarbonylindol-2-yl) methylene] -2-pyrazolin-5-one, 204 4 - [(3,5-Dimethyl-4-ethylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 3- (1-Methylcyclopropyl) -4 - [(1-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) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one; 3- (1-Methylcyclopropyl) -4 - [(4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (2-dimethylaminoethoxycarbonyl) pyrrol-2-yl] methylene} -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (2-dimethylaminoethylaminocarbonyl) pyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 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- (1-methylcyclopropyl) -2-pyrazolin-5-one; 4 - [(3,4-Diethoxycarbonylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - {[3- (2-Acetamido-2-methoxycarbonylethyl) indol-2-yl] methylene} -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - {[3- (2-Amino-2-carboxyethyl) indol-2-yl] methylene} -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - [(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - [(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3- (1-methylcyclopropyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (4-methyl-1-piperazinylmethyl) pyrrol-2-yl] methylene} -3- (2-furyl) -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (1-pyrrolidinylmethyl) pyrrol-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 - [(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 205 4 - [(4-Diethanolaminomethyl-3,5-dimethylpyaol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 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-Diethylamino-ethyl-4,5-tetramethylene-pyrrol-2-yl) -methylene] -3- (2-furyl) -2-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- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 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-dimethylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4- (3,5-Dibromo-4-hydroxybenzylidene) -3- (2-furyl) -2-pyrazolin-5-one, 3- (2-Furyl) -4 - [(4Oxo-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, 4 - [(4-Bromopyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - [(4-Chloro-pyrrol-2-yl) -methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - [(5-Chloro-pyrrol-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-one, 4- [4- (2-Dimethylaminoethylaminocarbonylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - [(3-Ethoxycarbonylindol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4- [3- (2-Dimethylaminoethoxycarbonylindol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one; 206 4- [3- (2-Dimethylaminoethylaminocarbonylindol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 3- (2-Furyl) -4- [4- (4-morpholinoethoxycarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-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-one, 4 - [(3,5-Dimethyl-4-ethylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 3- (2-Furyl) -4 - [(1-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, 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) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 3- (2-Furyl) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, 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-Diethoxycarbonylpyrrol-2-yl) methylene] -3- (3- (2-furyl)) - 2-pyrazolin-5-one, 4 - {[3- (2-Acetamido-2- methoxycarbonylethyl) indol-2-yl] methylene} -3- (2-furyl) -2-pyrazolin-5-one, 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-furyl) -2-pyrazolin-5-one, 4 - [(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4 - [(morpholinomethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (4-methyl-1-piperazinyl) methylpyrrol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one; ·· «* · · 207 4 - [(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3-Morpholinomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {[3- (4-Methyl-1-piperazinylmethyl) -4,5-tetramethylenepyrrol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {[3- (1-Pyrrolidinylmethyl) -4,5-tetramethylenepyrrol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-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, 4 - [(4-Diethylaminoethyl-3,5-dimethylpyrrol-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, 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-pyrazolin-5-one, 4 - [(4-Chopyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(5-Chloro-pyrrol-2-yl) -methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 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, 208 4- [4- (2-Dimethylaminoethylaminocarbonylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-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-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, 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, 4 - [(1-Methylindol-3-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one; 4- [3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(5-Methoxyindol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one; 4 - {[3,5-Dimethyl-4- (2-dimethylaminoethoxycarbonyl) -4- [(4,5-tetramethylenepyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one 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-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, 4 - [(3,4-Diethoxycarbonylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {[3- (2-Acetamido-2-methoxycarbonylethyl) indole- 2-yl] methylene} -3- (2-thienyl) -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-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, 209 4 - [(4-Bromopyrrol-2-yl) methylene] -3-cyclopropoxy-2-pyrazolin-5-one, 4 - [(4-Chloro-pyrrol-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-pyrazolin-5-one, 3-Cyclopropoxy-4- [4- (2-dimethylaminoethoxycarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropoxy-4- [4- (2-dimethylaminoethylaminocarbonylpyrrol-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- pyrazolin5-one, 3-Cyclopropoxy-4- [3- (2-dimethylaminoethylaminocarbonylindol-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-morpholinoethylaminocarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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, 3-Cyclopropoxy-4 - [(3,5-dimethyl-4-ethylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropoxy-4 - [(1-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-methoxyindol-2-yl) methylene] -2-pyrazolin-5-one; 3-Cyclopropoxy-4 - [(4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropoxy-4 - {[3,5-dimethyl-4- (2-dimethylaminoethoxycarbonyl) pyrrol-2-yl] methylene} -2-piperazolin-5-one, 3-Cyclopropoxy-4 - {[3,5-Dimethyl-4- (2-dimethylaminoethylaminocarbonyl) pyrrol-2-yl) methylene] -2-p} thazolin-5-one, 3-Cyclopropoxy-4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, • • • • * «* · · · · · · · · · · · 210 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-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, 4 - [(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3-cyclopropoxy-2-piperazolin-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-yl) methylene] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 3- [2- (5-pyrimidinyl-ethyl)] - 4 - [(5-trifluoromethyl-pyrrol-2-yl) -methylene] -2-pyrazolin-5-one, 4 - [(4-Ethoxycarbonylpyrrol-2-yl) methylene] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 4- [4- (2-Dimethylaminoethoxycarbonylpynol-2-yl) methylene ] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 4- [4- (2-Dimethylamino-aminocarbonyl-pyrrol-2-yl) -methylene] -3- [2- (5-pyrimidinyl-ethyl)] - 2-pyrazolin-5-one, 4 - [(3-Ethoxycarbonylindol-2-yl) methylene] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 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)] - 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-pyrazolin-5-one, 4- [3- (4-Morpholinoethylaminocarbonylindol-2-yl) methylene] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 211 4 - [(3,5-Dimethyl-4-ethylpyrrol-2-yl) methylene] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 4 - [(1-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-pyrimidinylethyl)] - 2-pyrazolin-5-one, 3- [2- (5-pyrimidinylethyl)] - 4 - [(4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-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, 4 - [(Indol-3-yl) methylene] -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 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-pyrimidinylethyl)] - 2-pyrazolin-5-one, 4 - {[3- (2-Amino-2-carboxyethyl) indol-2-yl] methylene} -3- [2- (5-pyrimidinylethyl)] - 2-pyrazolin-5-one, 4 - [(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpynol-2-yl) methylene] -3 [2- (5-pyrimidinyl-ethyl)] - 2-pyrazolin-5-one, 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-yl) methylene] -3- (2-phenylethyl) -2-pyrazolin-5-one, 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-pyrazolin-5-one; 212 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-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-phenylethyl) -2-pyrazolin-5-one, 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 - [(1-Methylindol-3-yl) methylene] -3- (2-phenylethyl) -2-pyrazolin-5-one, 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-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (2-dimethylaminoethoxycarbonyl) pyrrol-2-yl] methylene} -3- (2-phenylethyl) -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-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) methylene] -3- (2-phenylethyl) -2-pyrazolin-5-one, 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-pyrazolin-5-one, 4 - [(5-Ethoxy-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3- (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) ethyl] -2-pyrazolin-5-one; 4 - [(4-Chloropyrrol-2-yl) methylene] -3- [2- (4-hydroxyphenyl) ethyl] -2-pyrazolin-5-one; 4 - [(5-Chloropyrrol-2-yl) methylene] -3- [2- (4-hydroxyphenyl) ethyl] -2-pyrazolin-5-one; 213 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, 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-5-one, 4- [3- (2-Dimethylaminoethoxycarbonylindol-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, 3- [2- (4-hydroxyphenyl) ethyl] -4- [4- (4-morpholinoethoxycarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3- [2- (4-hydroxyphenyl) ethyl] -4- [4- (4-morpholinoethylaminocarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3- [2- (4-hydroxyphenyl) ethyl] -4- [3- (4-morpholinoethoxycarbonylindol-2-yl) methylene] -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-ethoxycarbonylpynol-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, 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, 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-hydroxyphenyl) ethyl] -2-pyrazolin-5-one; · 214 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, 4 - [(5-Chloro-4-methoxycarbonylmethyl-3-methoxycarbonylpyrrol-2-yl) methylene] -3- [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-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) methylene] -2-pyrazolin-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, 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-yl) methylene] -2-pyrazolin-5-one, 3- [2- (4-aminophenyl) ethyl] -4- [3- (2-dimethylaminoethylaminocarbonylindol-2-yl) methylene] -2-pyrazolin-5-one, 3- [2- (4-aminophenyl) ethyl] -4- [4- (4-morpholinoethoxycarbonylpynol-2-yl) methylene] -2-pyrazolin-5-one, 3- [2- (4-amino phenyl) ethyl] -4- [4- (4-morpholinoethylaminocarbonylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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, 3- [2- (4-amino-phenyl) -ethyl] -4 - [(5-methoxy-indol-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-dimethylaminoethoxycarbonyl) pyrrol-2-yl] methylene} -2-pyrazolin-5-one; · · · · 215 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 - [(pynol-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-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-aminophenyl) ethyl] -2-pyrazolin-5-one, 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-methoxycarbonylpetrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4 - {[(4-methyl-1-piperazinylmethyl) pyrrol-2-yl] methylene} -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (4-pyrimidininyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (piperidinomethylpyrrol-2-yl) methylene] -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethanolammomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (4-pyrimidinyl) -2-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, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3- (4-pyrimidinyl) 2-pyrazolin-5-one, »» 216 4 - {[3- (4-Methyl-1-piperazinyl) methyl-4,5-tetramethylenepirol-2-yl] methylene} -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 3- (4-Pyrimidinyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-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, 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, 4 - [(4-Oxo-1,5,6,7-tetrahydroindol-2-yl) methylene] -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylammomethyl-5-methylpynol-2-yl) methylene] -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 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- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-diethylaminomethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (piperidinomethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 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, 217 • · • 217 • • • 217 4 - [(3-Diethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[3- (4-Methyl-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -3- (5-pyrimidinyl) -2-pyiazol-5-one, 3- (5-Pyrimidinyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 4 - [(3-Piperidomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminoethyl-3,5-methylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4- (3,5-Dibromo-4-hydroxybenzylidene) -3- (5-pyrimidinyl) -2-pyrazolin-5-one; 4 - [(3,5-Dimethyl-4-dimethylaminomethyl-pyrrol-2-yl) -methylene] -3- (5-pyrimidinyl) -2-pyrazol-5-one, 4 - [(4-Oxo-1,5,6,7-tetrahydroindol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylaminomethyl-5-methylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -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, 4 - [(3,5-Dimethyl-4- (1-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- (piperidinomethylpyrrol-2-yl) methylene] -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethanolaminomethyl-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,, * · · • * * * * * * * 218 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-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -3- (2-pyrimidinyl) -2-pyazolin-5-one, 3- (2-Pyrimidinyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylamino-4,5,6,7-tetrahydroindol-2-yl) methylene] -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminoethyl-3,5-dimethylpyrrol-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) -2-pyrazolin-5-one, 4 - [(4-Oxo-1,5,6,7-tetrahydroindol-2-yl) methylene] -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylammomethyl-5-methylpyrrol-2-yl) methylene] -3- (2-pyrimidinyl) -2-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-1-piperazinylmethyl) pyrrol-2-yl] methylene} -3- (3 pyridazinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (1-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 - [(3,5-Dimethyl-4-piperidinomethylpyrrol-2-yl) methylene] -3- (3-pyridazinyl) -2-pyrazolin-5-one, 4 - [(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (3-pyridazinyl) -2-pyrazolin-5-one; 219 4 - [(3-Dimethylaminomethyl-4,5-tetramethylenepyrrol-2-yl) methylene] -3- (3-pyridazinyl) -2-pyrazolin-5-one, 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-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -3- (3-pyridazinyl) -2-pyrazolin-5-one, 3- (3-Pyridazinyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-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-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; 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) methylene] -3- (3-pyridazinyl) -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, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3- (4-pyridazinyl) -2-pyrazolin-5-one, 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- (1-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 - [(3,5-Dimethyl-4- (piperidinomethylpyrrol-2-yl) methylene] -3- (4-pyridazinyl) -2-pyrazolin-5-one; 220 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, 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-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -3- (4-pyridazinyl) -2-pyrazolin-5-one, 3- (4-Pyridazinyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 4 - [(3-Piperidinomethyl-4,5-tetramethylenopyrrol-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, 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; 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) methylene] -3- (4-pyridazinyl) -2-pyrazolin-5-one, 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-morpholinomethyl-pyrrol-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, 4 - [(3,5-Dimethyl-4 - [(1-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 «4444 221 4 - [(4-Diethanolaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (5-isoxazolyl) -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-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3- (5-isoxazolyl) -2-pyrazolin-5-one, 3- (5-Isoxazolyl) -4 - {[3- (4-methyl-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-piperazolin-5-one, 3- (5-isoxazolyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3- (5-Isoxazolyl) -4 - [(3-piperidinomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -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) methylene] -3- (5-isoxazolyl) -2-pyrazolin-5-one, 4- (3,5-Dibromo-4-hydroxybenzylidene) -3- (5-isoxazolyl) -2-pyrazolin-5-one, 4 - [(4-Oxo-1,5,6,7-tetrahydroindol-2-yl) methylene] -3- (5-isoxazolyl) -2-pyrazolin-5-one, 4 - [(4-Dimethylaminomethyl-5-methyl-pyrrol-2-yl) -methylene] -3- (5-isoxazolyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3- (5-methyl-3-isoxazolyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4 - {[(4-methyl-1-piperazinylmethyl) pyrrol-2-yl] methylene} -3- (5-methyl-3-isoxazolyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4 - [(1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (5-methyl-3-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; ·· * 222 4 - [(4-Diethanolaminomethyl-3,5-dimethyl-pyrrol-2-yl) methylene] -3- (5-methyl-3-isoxazolyl) -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-yl) methylene] -2-pyrazolin-5-one, 4 - [(3-Diethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3- (5-methyl-3-isoxazolyl) -2-pyrazolin-5-one, 3- (5-Methyl-3-isoxazolyl) -4 - {[3- (4-methyl-1-piperazinyl) methyl-4,5-tetramethylenepyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3- (5-Methyl-3-isoxazolyl) -4 - {[3- (1-pyrrolidinyl) methyl-4,5-tetramethylenopyrrol-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-isoxazolyl) -2-pyrazolin-5-one, 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; 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-1,5,6,7-tetrahydroindol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(4-Dimethylaminomethyl-5-methylpyrrol-2-yl) methylene] -3- (5-methyl-3-isoxazolyl) -2-pyrazolin-5-one, 3-Cyclopropyl-4- (1,3-[(dimethylamino) methyl] -4,5,6,7-tetrahydro-1 H -indolylmethylidene) -4,5-dihydro-1 H -pyrazolone maleate 3-cyclopropyl-4- (1 - 4 - [(1,1-dimethylammonio) methyl] -3,5-dimethyl-1H-2-pyrrolylmethylidene) -4,5-dihydro-1H-pyrazolone salt, 4- [1- (4 - [[2- (dimethylamino) ethyl] (methyl) amino] methyl-3,5-dimethyl-1H-2-pyrrolyl) methylidene] -3- (2-pyrazinyl) -4,5 -dihydro-1H-pyrazolone, 4- (1- 4- [2- (diethylamino) ethyl] -3,5-dimethyl-1H-2-pyrrolylmethylidene) -3- (2-pyrazinyl) 4,5-dihydro-1H-5- pyrazolone, • 223 4-1- [4- (3-chloropropanoyl) -3,5-dimethyl-1H-pyrrolyl] methylidene-3- (2-pyrazinyl) -4,5-dihydro-1H-5-pyrazolone, 4- (1-3 - [(dimethylamino) methyl] -4,5,6,7-tetrahydro-1 H -2-indolylmethylidene) -3- (2-pyrazinyl) -4,5-dihydro-1 H- -pyrazolone 4- (1-4 - [(dimethylamino) methyl] -3,5-dimethyl-1H-2-pyrrolylmethylidene) -3- (5-methyl-3-isoxazolyl) -4,5-dihydro-1 H-5 -pyrazolone 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-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-yl) methylene] -2-pyrazolin-5-one, 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, 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 - [(p-Trol-2-yl) methylene] -2-pyrazolin-5-one, 3-Phenylamino-4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one; 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 - [(pynol-2-yl) methylene] -2-pyrazolin-5-one, 3- (4-Chlorobenzyl) -4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one; 3- (4-Chloro-phenylamino) -4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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, 3- (4-Phenylphenyloxymethyl) -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; 224 4 - [(3,5-Dimethylpyrrol-2-yl) methylene] -3-phenylethyl-2-pyrazolin-5-one, 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, 3- (4-Chloro-phenylethyl) -4 - [(pyrrol-2-yl) methylene] -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, 3-Cyclopentyloxy-4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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 - [(1-methylpyrrol-2-yl) methylene] - 2-pyrazolin-5-one, 3-Isopropoxy-4 - [(5-methylpyrrol-2-yl) methylene] -2-pyrazolin-5-one; 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-Carbamoyl-phenylethyl) -4 - [(3,5-dimethyl-4-ethylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 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] -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, 3- (4-Methoxyphenylamino-carbonylmethyl) -4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - {(3- (2-Carboxyethyl) -4-methylpyrrol-2-yl] methylene} -3-isopropyl-2-pyrazolin-5-one, 225 3-Cyclopropyl-4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one; 3-Cyclobutyl-4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3- (3-Pyridyl) -4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [[1- (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-dimethylpyrrole-2) -yl) methylene] -2-pyrazolin-5-one, 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-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-pyrazolin-5-one, 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-Dimethyl-4-ethylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one; 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) 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, 3-Propyl-4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one; 3-Methyl-4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one; 3- (4-Isopropylphenylamino) -4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3- (3-Phenylamino) -4 - [(pyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {[1- (4-hydroxybutyl) pyrrol-2-yl] methylene] -2-pyrazolin-5-one, 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-pyrazolin-5-one, 226 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-dimethylaminoethyloxycarbonyl) pyrrol-2-yl] methylene} -3-isopropoxy-2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (2-dimethylaminoethylaminocarbonyl) pyrrol-2-yl] methylene} -3-isopropoxy-2-piperazolin-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, 3- (4-Chloro-phenylaminocarbonylmethyl) -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, 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-pyrazolin-5-one, 3-Cyclopropyl-4 - [(3,5-dimethyl-4-morpholinomethyl-pyrrol-2-yl) -methylene] -2-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-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, 3-Isopropyl-4 - [(pyrrol-2-yl) 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-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(5-morpholinomethylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(5-Carboxypyrrol-2-yl) methylene] -3-cyclopropyl-2-pyrazolin-5-one, 4 - [(4-Chloro-pyrrol-2-yl) -methylene] -3-ethoxy-2-pyrazolin-5-one, 4 - [(4-Bromopyrrol-2-yl) methylene] -3-ethoxy-2-pyrazolin-5-one; 227 4 - [(5-Chloro-pyrrol-2-yl) -methylene] -3-ethoxy-2-pyrazolin-5-one, 4 - [(4-Chloropyrrol-2-yl) methylene] -3-cyclopropyl-2-pyrazolin-5-one, 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-Pyridyl) -4 - [(4,5-tetramethylenopyrrol-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-yl] methylene} -2-piperazolin-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, 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) maleate methylene] -3-pyrazinyl-2-pyrazolin-5-one 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, 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) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - [(3,5-dimethyl-4-morpholinomethylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazobin-5-one, 4 - [(3,5-dimethylpyrrole-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-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-5-one, 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-pyrazobin-5-one, 4 - [(3,5-Dimethyl-4-ethylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(4-Ethoxycarbonylpyrrol-2-yl) methylene] -3- pyrazinyl-2-pyrazobin-5-one; 4 - [(4-Carboxypyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one; ; ..... ..... ·· ·· ...... 228 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, 3-Cyclopropyl-4 - [(4-ethoxycarbonyl-3-phenylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- (1-pyrrolidinylmethyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) methylene] -3- (3-pyridyl) -2-pyrazolin-5-one, 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, 4 - [(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl) methylene] -3- (2-pyridylethyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-ethoxycarbonylpyrrol-2-yl) methylene] -3- (1-methyl-2-phenylethyl) -2-pyrazolin-5-one, 4 - [(4-Carboxy-3,5-dimethylpyrrol-2-yl) methyl] -3-ethoxy-2-pyrazolin-5-one, 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, 4 - [(5-Chloro-3-methoxycarbonyl-4-methoxycarbonylmethylpyrrol-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-one, 3-Ethoxy-4 - [(4,5-tetramethylenepyrrol-2-yl) methylene] -2-pyrazolin-5-one; 229 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-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, 4 - {[4- (4-Methyl-1-piperazinylmethyl) -3,5] - [(4-ethoxycarbonyl-3-phenylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one -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, 4 - [(3,5-Dimethyl-4-piperidinomethyl-pyrrol-2-yl) -methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-piperidinomethyl-pyrrol-2-yl) -methylene] -3- (5-isoxazolyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4-dimethylaminomethylpyrrol-2-yl) methylene] -3- (5-isoxazolyl) -2-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, 3-Cyclopropyl-4 - [(3-dimethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -2-pyrazolin-5-one, 4 - [(3-Dimethylaminomethyl-4,5-tetramethylenopyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(3,5-dimethyl-4-dimethylaminomethylpyrrole) maleate salt (2-yl) methylene] -2-pyrazolin-5-one; 4 - {[4- (3-Chloropropionyl) -3,5-dimethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Diethylaminoethyl) -3,5-dimethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one; 230 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-) - malate salt dimethylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 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, 4 - {{3,5-Dimethyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4- {{3,5-dimethyl-4- (2- (1-pyrrolidinyl ethyl)] 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, 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] methylene} -3-pyrazinyl-2-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, 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, 4 - {[3,5-Dimethyl-4- (4-hydroxybutyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (4-Diethylaminobutyl) -3,5-dimethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 231 4 - {[4- (2-Diethylaminoethyl-N-oxide) -3,5-dimethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3,5-dimethyl-4- (1-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-Isopropyl-5-methylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3,5-Dimethyl-4- [3- (1-pyrrolidinylpropyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(Dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(dimethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl) methylene] -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) methylene] -2-pyrazolin-5-one; 3-Benzyl-4 - {[1- (4-hydroxybutyl) indol-3-yl] methylene} -2-pyrazolin-5-one, 4 - [(Indol-3-yl) methylene] -3- (4-methoxyphenyloxymethyl) -2-pyrazol-5-one, 4 - [(Indol-3-yl) methylene] -3-phenyloxymethyl-2-pyrazolin-5-one, 3- (4-Chloro-phenyloxymethyl) -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, 4 - [(Indol-3-yl) methylene] -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-yl) methylene] -3-phenylamino-2-pyrazolin-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, 3- (4-Chlorobenzyl) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, 4 - {[1- (4-hydroxybutyl) indol-3-yl] methylene) -3- (4-methoxybenzyl) -2-pyrazolin-5-one, 3- (4-Chloro-phenylamino) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, 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; 232 3- (4-hydroxybenzyl) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, 3- (3-Chloro-phenyloxymethyl) -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, 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-yl) 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, 3-Ethoxy-4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one; 4 - {[1- (4-Ethyloxybutyl) 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-pyrazolin-5-one; 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) methylene] -3-phenylethyl-2-pyrazolin-5-one, 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 - [(1-isopropylindol-3-yl) methylene] -2- 3- (4-Hydroxyphenylethyl) -4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one, 3-isopropyl-4 - [(indol-3-yl) pyrazolin-5-one methylene] -2-pyrazolin-5-one; 3- (4-Chloro-phenylaminocarbonylmethyl) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, 3-Ethoxycarbonylmethyl-4 - [(indol-3-yl) methyl] -2-pyrazolin-5-one, 4 - [(Indol-3-yl) methylene] -3- (4-methoxyphenylaminocarbonylmethyl) -2-pyrazolin-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; 3- (2-Dimethylaminocarbonylethyl) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one; 233 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, 4 - [(Indol-3-yl) methylene] -3- (2-methylcyclopropyl) -2-pyrazolin-5-one, 3-Cyclohexyl-4 - {[1- (4-hydroxybutyl) indol-3-yl] methylene} -2-pyrazolin-5-one; 4 - {[1- (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-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-methylindol-3-yl) methylene] -2-pyrazolin-5-one; 3-Cyclopropyl-4 - [(7-methylindol-3-yl) methylene] -2-pyrazolin-5-one; 4 - [(1-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, 4 - {[1- (4-Hydroxybutyl) indol-3-yl] methylene} -3-methyl-2-pyrazolin-5-one, 4 - {[1- (4-Hydroxybutyl) indol-3-yl] methylene} -3-trifluoromethyl-2-pyrazolin-5-one, 4 - {[1- (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) -1-cyclopropyl) -2-pyrazolin-5-one; 3-Cyclobutyl-4 - {[1- (4-hydroxybutyl) indol-3-yl] methylene} -2-pyrazolin-5-one, 4 - [(6-Carboxy-1-methylindol-3-yl) methylene] -3-cyclopropyl-2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(5-methoxy-1-methylindol-3-yl) methylene] -2-pyrazolin-5-one; 4 - [(1-Methylindol-3-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(1,7-dimethylindol-3-yl) methylene] -2-pyrazolin-5-one; 4 - [(1-Methylindol-3-yl) methylene] -3- (tetrahydrofuran-3-yl) -2-pyrazolin-5-one, 3-Cyclopropylamino-4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one; 4 - [(6-Carboxy-1-methylindol-3-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one; 234 4 - [(1,7-Dimethylindol-3-yl) methylene] -3-isopropoxy-2-pyrazolin-5-one, 3-Isopropoxy-4 - [(5-methoxy-1-methylindol-3-yl) methylene] -2-pyrazolin-5-one; 3- (4-Fluorophenylamino) -4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one, 4 - [(1-Methylindol-3-yl) methylene] -3-trifluoroacetamido-2-pyrazolin-5-one, 3- (4-Aminophenylethyl) -4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one, 3-Amino-4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one, 3- (4-Chloro-phenylethyl) -4 - [(indol-3-yl) methylene] -2-pyrazolin-5-one, 3-Ethoxy-4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one, 3- (5-Isoxazolyl) -4 - [(1-methylindol-3-yl) methylene] -2-pyrazolin-5-one, 4 - [(1-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-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-Methoxycarbonylphenylethyl) -4 - [(indol-2-yl) methylene] -2-pyrazolin-5-one, 3- (4-Carbamoyl-phenylethyl) -4 - [(indol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - [(indol-2-yl) 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-pyrazolin-5-one, 3-Isopropoxy-4 - [(1-methylindol-2-yl) methylene] -2-pyrazolin-5-one; 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-pyrazolin-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, 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; 235 3-Ethoxy-4 - {[3- (4-morpholinomethyl) indol-2-yl] methylene} -2-pyrazolin-5-one, 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, 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-1,5,6,7-dihydroindol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(3-Dimethylaminomethylindol-2-yl) methylene] -3-ethoxy-2-pyrazolin-5-one; 4 - [(7-Azaindol-3-yl) methylene] -3-benzyl-2-pyrazolin-5-one; 3-Benzyl-4 - {[1- (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, 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-pyrazolin-5-one; 4 - {[1- (4-Hydroxybutyl) -7-azaindol-3-yl] methylene} -3- (4-hydroxyphenylethyl) -2-pyrazolin-5-one, 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; 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; 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, 4 - {[1- (4-Hydroxybutyl) -7-azaindol-3-yl] methylene} -3-trifluoromethyl-2-pyrazolin-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; • · · · 236 4 - {[1- (4-Hydroxybutyl) -7-azaindol-3-yl] methylene} -3- (3-methylphenylamino) -2-pyrazolin-5-one, 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, 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, 3-Cyclopropyl-4 - [(thien-2-yl) methylene] -2-pyrazolin-5-one; 4 - [(Indol-3-yl) methylene] -3-isopropyl-1-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) -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, 4 - {[4- (2-Diethylaminoethyl) -3,5-methylpyrrol-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) -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- (1-pyrrolidinylmethylpyrro) -2-yl) methylene] -2-pyrazolin-5-one; 237 3-Cyclopropyl-4 - [(4-diethylaminomethyl-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-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, 3-Cyclopropyl-4 - [(4-diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl) methylene] -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {[4- (1-pyrrolidinylmethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {{3-isopropyl-5-methyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {[4- (2-cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {{4- [3- (1-pyrrolidinyl) propyl] -3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 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} methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {[4- (4-dimethylaminobutyl) -3-isopropyl-5-methylpyrrol-2-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- (1-pyrrolidinylmethyl) -5-methylpyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4- {{3-cyclopropyl-5-methyl-4- [2- (1-pyrrolidinyl) ethyl] pyrrol-2-yl} methylene} -2-pyrazolin-5-one; 238 3-Cyclopropyl-4- [13-cyclopropyl-4- [2-di (methoxyethyl) aminoethyl] -5-methylpyrrol-2-yl} methylene} -2-piperazolin-5-one, 3-Cyclopropyl-4 - {[3-cyclopropyl-4- (3-diethylaminopropyl) -5-methylpyrrol-2-yl] methylene} -2-piperazolin-5-one, 3-Cyclopropyl-4 - {{3-cyclopropyl-4- [3- (2,5-dimethyl-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {[3-cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -2-pyrazolin-5-one, 3-Cyclopropyl-4 - {{3-cyclopropyl-5-methyl-4- [4- (1-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, 4 - {[4- (2-Cyclopropylaminoethyl) -3,5-dimethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-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-pyrazinyl-2-pyrazolin-5-one, 4- [4- (2-Carboxyethyl) -3,5-dimethylpynol-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, 4 - {[4- (1-Pyridinylmethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Isopropyl-5-methyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 3-Pyrazinyl-4 - {{4- [3- (1-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, 3-Pyrazinyl-4 - {{4- [3- (4-pyridylmethylamino) propyl] -3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 239 • a * a and · • • * * * * * * «« a a a a a a a a a a a a a a a a 4 - {[4- (4-Dimethylaminobutyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - [(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [2- (1-pyrrolidinyl) ethyl] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cycloprop-l-4- [2-di (methoxyethyl) aminoethyl] -5-methylpyrrol-2-yl} methylene} -2-pyrazinyl] -2-pyrazolin-5-one, 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-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl} methylene} -3-pazinyl-2-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-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- (uryl) -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, 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; 240 · · 240 240 4-} [4- (1-Pyrrolidinylmethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (2-furyl) -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- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3- (2-furyl) -2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (2-furyl) -2-pyrazolin-5-one, 3- (2-Furyl) -4 - {{4- [3- (1-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} -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, 4 - [(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl) methylene] -3- (2-furyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [2- (1-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-furyl) -2-pyrazolin-5-one, 4 - {[3-Cyclopropyl-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-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3- (2-furyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one; · · · · · · · · · · · · · · · 241 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-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, 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-dimethylpynol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {[4- (1-Pyrrolidinylmethyl) -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-Cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {{4- [3- (1-Pyrrolidinyl) propyl] -3-isopropyl-5-methylpyrrol-2-yl} methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {[3-Isopropyl-5-methyl-4- (4-piperidobutyl) pyrrol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {{4- [3- (4-Pyridylmethylamino) 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-methylpyrrol-2-yl) methylene] -3- (2-thienyl) -2-pyrazolin-5-one, 4- {} 3-Cyclopropyl-5-methyl-4- [2- (1-pyrrolidinyl) ethyl] pyrrol-2-yl} methylene} -3- (2-thienyl) -2-pyrazolin-5-one; 242 4 - {{3-Cyclopropyl-4- [2-di (methoxyethyl) aminoethyl] -5-methylpyrrol-2-yl} methylene} -3 (2-thienyl) -2-pyrazolin-5-one, 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-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl} methylene} -3- (2-thienyl) -2-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3- (2-thienyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-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-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, 4 - {{3,5-dimethyl-4- [2- (4-pyridylmethylamino) ethyl] pyrrol-2-yl} methylene} -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 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, 4 - {[4- (1-Pyrrolidinylmethyl) -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; 243 4 - {[4- (2-cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 3- (4-Pyrimidinyl) -4 - {{4- [3- (1-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, 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-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [2- (1-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, 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-dimethyl-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl} methylene} -3- (4-pyrimidinyl) -2-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3- (4-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminoethyl) -3,5-dimethylpyrrol-2-yl] methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 9 · «· ······ · · · · · · · 244 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, 4 - {{3,5-dimethyl-4- [2- (4-pyridylmethylamino) ethyl] pyrrol-2-yl} methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[4- (2-Carboxyethyl) -3,5-dimethylpynol-2-yl] methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl) methylene] -3- (5-pyrimidininyl) -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- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[4- (2-cyclopropylaminoethyl) -3-isopropyl-5-methylpynol-2-yl] methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 3- (5-Pyrimidinyl) -4 - {{4- [3- (1-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-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, 4 - [(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl) methylene] -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [2- (1-pyrrolidinyl) ethyl] pyrrol-2-yl} methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-4- [2-di (methoxyethyl) aminoethyl] -5-methylpynol-2-yl} methylene} -3 (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[3-cyclopropyl-4- (3-diethylaminopropyl) -5-methylpyrrol-2-yl] methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one; · · · · · · · · 245 4 - {{3-Cyclopropyl-4- [3- (2,5-dimethyl-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl} methylene} -3- (5-pyrimidinyl) -2-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-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-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[3-Cyclopropyl-5-methyl-4- (4-cyclobutylaminobutyl) pyrrol-2-yl] methylene} -3- (5-pyrimidinyl) -2-pyrazolin-5-one, 4 - [(3,5-Dimethyl-4- (1-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-dimethylpyrrol-2-yl] methylene} -3- (2-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-phenylaminoethyl) pyrrol-2-yl] methylene} -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3,5-Dimethyl-4- [2- (4-pyridylmethylamino) ethyl] pyrrol-2-yl} 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) methylene] -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - {[4- (1-Pyrrolidinylmethyl) -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-cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 3- (2-Pyrimidinyl) -4 - {{4- [3- (1-pyrrolidinyl) propyl] -3-isopropyl-5-methylpyrrol-2-yl} methylene} -2-pyrazolin-5-one, 246 Φ · · * * * * * * * * * * * * * * * * * * * * * 4 - {[3-Isopropyl-5-methyl-4- (4-piperidinobutyl) pyrrol-2-yl] methylene} -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 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-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-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, 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-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl} methylene} -3- (2-pyrimidinyl) -2-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3- (2-pyrimidinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-pyrrolidinylmethylpynol-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-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, 247 • ························ 4 - {{3,5-dimethyl-4- [2- (4-pyridylmethylamino) 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-pyridazinyl) -2-pyrazolin-5-one, 4 - {[4- (1-Pyrrolidinylmethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (3-pyridazinyl) -2-pyrazolin-5-one, 4 - {{3-Isopropyl-5-methyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3- (3 pyridazinyl) -2-pyrazolin-5-one, 4 - {[4- (2-cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (3-pyridazinyl) -2-pyrazolin-5-one, 3- (3-Pyridazinyl) -4 - {{4- [3- (1-pyrrolidinyl) propyl] -3-isopropyl-5-methylpynol-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, 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-pyridazinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [2- (1-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, 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-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3- (3-pyridazinyl) -2-pyrazolin-5-one, 4 · · 4 248 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-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-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, 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- (1-Pyrrolidinylmethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (4-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- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3- (4-pyridazinyl) -2-pyrazolin-5-one, 4 - {[4- (2-cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (4-pyridazinyl) -2-pyrazolin-5-one, 3- (4-Pyridazinyl) -4 - ({4- [3- (1-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-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; · · · · · «« «« «« «« «« «« «« «« « 249 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-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, 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-pyrazoline-5- heu, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylammopropyl) pyrrol-2-yl] methylene} -3- (4-pyridazinyl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-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, 4 - [(3,5-Dimethyl-4- (1-pyrrolidinylmethylpyrrol-2-yl) methylene] -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - [(4-Diethylaminomethyl-3,5-dimethylpyrrol-2-yl) methylene] -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminoethyl) -3,5-dimethylpyrrol-2-yl] methylene} -3- (1,2,4-triazin-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- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {{3,5-dimethyl-4- [2- (4-pyridylmethylamino) ethyl] pyrrol-2-yl} methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazoline-5 -onu, 4 - {[4- (2-Carboxyethyl) -3,5-dimethylpyrrol-2-yl] methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 250 a * a a a a a a a a a a a a a a a a a a a·· a a a 9 9 9 · 9 9 9 99 99 9999 4 - [(4-Diethylaminomethyl-3-isopropyl-5-methylpyrrol-2-yl) methylene] -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {[4- (1-Pyrrolidinylmethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (1,2,4-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-pyrazoline- 5-onu, 4 - {[4- (2-cyclopropylaminoethyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {{4- [3- (1-Pyrrolidinyl) propyl] -3-isopropyl-5-methylpyrrol-2-yl} methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazoline- 5-onu, 4 - {[3-Isopropyl-5-methyl-4- (4-piperidinobutyl) pyrrol-2-yl] methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {{4- [3- (4-Pyridylmethylamino) propyl] -3-isopropyl-5-methylpyrrol-2-yl} methylene} -3 (1,2,4-triazin-3-yl) -2-pyrazoline -5-onu, 4 - {[4- (4-Dimethylaminobutyl) -3-isopropyl-5-methylpyrrol-2-yl] methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - [(3-Cyclopropyl-4-diethylaminomethyl-5-methylpyrrol-2-yl) methylene] -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-5-methyl-4- (2- (1-pyrrolidinyl) ethyl] pyrrol-2-yl} methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazoline -5-onu, 4 - {{3-Cyclopropyl-4- [2-di (methoxyethyl) aminoethyl] -5-methylpyrrol-2-yl} methylene} -3 (1,2,4-triazin-3-yl) -2-pyrazoline- 5-onu, 4 - {[3-Cyclopropyl-4- (3-diethylaminopropyl) -5-methylpyrrol-2-yl] methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {{3-Cyclopropyl-4- [3- (2,5-dimethyl-1-pyrrolidinyl) propyl] -5-methylpyrrol-2-yl} methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, 4 - {[3-Cyclopropyl-5-methyl-4- (3-phenylmethylaminopropyl) pyrrol-2-yl] methylene} -3 (1,2,4-triazin-3-yl) -2-pyrazolin-5-one , 4 - {{3-Cyclopropyl-5-methyl-4- [4- (1-pyrrolidinyl) butyl] pyrrol-2-yl} methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazoline -5-onu, 4 - {[3-Cyclopropyl-5-methyl-4- (4-cyclobutylaminobutyl) pyrrol-2-yl] methylene} -3- (1,2,4-triazin-3-yl) -2-pyrazolin-5-one, • · · · · 251 4 - {[4- (2-Diethylaminoethyl) -5-methyl-3-trifluoromethylpynol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-4- [2- (1-pyrrolidinylethyl)] - 3-trifluoromethylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Ethylaminoethyl) -5-methyl-3-trifluoromethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-4- [2- (4-pyridylmethylaminoethyl)] - 3-trifluoromethylpyrrol-2-yl] methylene} -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, 4 - {[4- (2-Aminoethyl) -5-methyl-3-trifluoromethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-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- (1-pyrrolidinylethyl)] - 3-tert-butylpyrrol-2-yl} methylene} -3-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-pyridylmethylaminoethyl)] - 3-tert-butylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) ethyl] -5-methyl-3-tert-butylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Aminoethyl) -5-methyl-3-tert-butylpyrrol-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, 4 - {{3-Ethyl-5-methyl-4- [2- (1-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, 4 - {{3-Ethyl-5-methyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 252 •% · · «* · · · · 252 252 252 252 252 · ·· ·· · · · · · · · 4 - {{4- [2- (1-Imidazoyl) ethyl] -5-methyl-3-ethylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Aminoethyl) -5-methyl-3-ethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3-Cyclobutyl-4- (2-diethylaminoethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cyclobutyl-5-methyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3-Cyclobutyl-4- (2-ethylaminoethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cyclobutyl-5-methyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) ethyl] -5-methyl-3-cyclobutylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Aminoethyl) -5-methyl-3-cyclobutylpyrrol-2-yl] methylene} -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- (1-pyrrolidinylethyl) pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3-Cyclopentyl-4- (2-ethylaminoethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cyclopentyl-5-methyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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-Cyclohexyl-4- (2-diethylaminoethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {} 3-Cyclohexyl-5-methyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 253 4 - {[3-Cyclohexyl-4- (2-ethylaminoethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3-Cyclohexyl-5-methyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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, 4 - {[4- (2-Diethylaminoethyl) -5-methyl-3-phenylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3-phenyl-4- [2- (1-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-pyrazolin-5-one, 4 - {{5-Methyl-3-phenyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) ethyl] -5-methyl-3-phenylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Aminoethyl) -5-methyl-3-phenylpynol-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-pyrazolin-5-one, 4 - {{5-Methyl-3- (4-methoxyphenyl) -4- [2- (1-pyrrolidinylethyl)] pyrrol-2-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-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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, 254 t «· · r r * * * * * * * * * 4 - {[4- (2-Diethylaminoethyl) -5-methyl-3- (2-pyridyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (2-pyridyl) -4- [2- (1-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, 4 - {{5-Methyl-3- (2-pyridyl) -4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3 pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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, 4 - {[4- (2-Diethylaminomethyl) -5-methyl-3-pyrazinylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3-pyrazinyl-4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Ethylaminoethyl) -5-methyl-3-pyrazinylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3-pyrazinyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -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, 4 - {[4- (2-Cyclopropylaminoethyl) -5-methyl-3-pyrazinylpynol-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- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene-3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Ethylaminoethyl) -5-methyl-3- (2-imidazoyl) pyrrol-2-yl] methylene-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (2-imidoyl) -4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazoline-5- on, · · · ···· · ··· «. · · · · · · · · 9 · · · · · · · 255 4 - {{4- [2- (1-1imidoyl) 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-pyrrolidinyl-2-pyrazolin-5-one, 4 - ([4- (2-Diethylaminoethyl) -5-methyl-3- (2-pyrimidinyl) pyrrol-2-yl] methylene} -3-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, 4 - {{5-Methyl-3- (2-pyrimidinyl) -4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl! methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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-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 - {{5-Methyl-3- (3-isoxazolyl) -4- [2- (1-pyrrolidinylethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 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- (1-Imidazoyl) ethyl] -5-methyl-3- (3-isoxazolyl) pyrrol-2-yl} methylene} -3-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, 4 - {{5-Methyl-3- (2-furyl) -4- [2- (1-pyrrolidinylethyl) pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one; · · · · · · · · · · · · · · 256 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-pyridylmethylaminoethyl)] pyridin-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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, 4 - {[4- (2-Diethylaminoethyl) -5-hydroxymethyl-3-isopropylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Hydroxymethyl-3-isopropyl-4- [2- (1-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, 4 - {{5-Hydroxymethyl-3-isopropyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) ethyl] -5-hydroxymethyl-3-isopropylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminoethyl) -5-hydroxymethyl-3-isopropylpyrrol-2-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- (1-pyrrolidinylethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4-j [4- (2-Ethylaminoethyl) -3,5-dicyclopropylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3,5-Dicyclopropyl-4- [2- (4-pyridylmethylaminoethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) ethyl] -3,5-dicyclopropylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminoethyl) -3,5-dicyclopropylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one; 0 · · · »·« «« «« «« «« «« «« 257 4 - {[4- (2-Diethylaminomethyl) -5-methyl-3-trifluoromethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Dimethylaminomethyl) -5-methyl-3-trifluoromethylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-4- [2- (1-pyrrolidinylmethyl)] - 3-trifluoromethylpyrrol-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, 4 - {{5-Methyl-4- [2- (4-pyridylmethyl-aminomethyl)] - 3-trifluoromethyl-pyrrol-2-yl] -methyl} -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-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-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-4- [2- (1-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-pyridylmethylaminomethyl)] - 3-tert-butylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3-tert-butylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Aminomethyl) -5-methyl-3-tert-butyllpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 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, 258 4 - {{3-Ethyl-5-methyl-4- [2- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3-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-pyridylmethylaminomethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {(4- [2- (1-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-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- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3 pyrazinyl-2-pyrazolin-5-one, 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-pyridylmethylaminomethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3-cyclobutylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Aminomethyl) -5-methyl-3-cyclobutylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3-Cyclopentyl-4- (2-diethylammomethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[3-Cyclopentyl-4- (2-dimethylaminomethyl) -5-methylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {] 3-Cyclopentyl-5-methyl-4- [2- (1-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, 259 4 - {{3-Cyclopentyl-5-methyl-4- [2- (4-pyridylmethylaminomethyl)] pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4- {4- [2- (1-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-2-pyrazolin-5-one, 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, 4 - {{3-Cyclohexyl-5-methyl-4- [2- (1-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-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-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, 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- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3-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-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3-phenylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one; 260 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-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-methoxyphenyl) -4- [2- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Ethylaminomethyl) -5-methyl-3- (4-methoxyphenyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (4-methoxyphenyl) -4- [2- (4-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3- (4-methoxyphenyl) pyrrol-2-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, 4 - {[4- (2-Dimethylaminomethyl) -5-methyl-3- (2-pyridyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (2-pyridyl-4- [2- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Ethylaminomethyl) -5-methyl-3- (2-pyridyl) pyrrole-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (2-pyridyl) -4- [2- (4-pyridylmethylaminomethyl)] 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-2-pyrazolin-5-one, 4 - {[4- (2-Diethylaminomethyl) -5-methyl-3-pyrazinylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one; 261 4 - {[4- (2-Dimethylaminomethyl) -5-methyl-3-pyrazinylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3-pyrazinyl-4- [2- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Ethylaminomethyl) -5-methyl-3-pyrazinylpynol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3-pyrazininyl-4- [2- (4-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3-pyrazinylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminomethyl) -5-methyl-3-pyrazinylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 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- (1-pyrrolidinylmethyl)] pyrro-2-yl} methylene} -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-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3- (2-imidazoyl) pyrrol-2-yl} methylene} -3-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, 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- (1-pyrrolidinylmethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 262 4 - {[4- (2-Ethylaminomethyl) -5-methyl-3- (2-pyrimidinyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (2-pyrimidinyl) -4- [2- (4-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3- (2-pyrimidinyl) pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 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-Dimethylamino-ethyl) -5-methyl-3- (3-isoxazolyl) pyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Methyl-3- (3-isoxazolyl) -4- [2- (1-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, 4 - {{5-Methyl-3- (3-isoxazolyl) -4- [2- (4-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-methyl-3- (3-isoxazolyl) pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {[4- (2-Cyclopropylaminomethyl) -5-methyl-3- (3-isoxazolyl) pyrrol-2-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, 4 - {{5-Methyl-3- (2-furyl) -4- [2- (1-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-furyl) -4- [2- (4-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one; · · 263 4- J} 4- [2- (1-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-isopropylpynol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{5-Hydroxymethyl-3-isopropyl-4- [2- (1-pyrrolidinylmethyl)] pyrrol-2-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-pyridylmethylaminomethyl)] pyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{4- [2- (1-Imidazoyl) methyl] -5-hydroxymethyl-3-isopropylpyrrol-2-yl} methylene} -3-pyrazinyl-2-pyrazolin-5-one, 5 - {[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-Ethylaminomethyl) -3,5-dicyclopropylpyrrol-2-yl] methylene} -3-pyrazinyl-2-pyrazolin-5-one, 4 - {{3,5-Dicyclopropyl-4- [2- (4-pyridylmethylaminomethyl)] 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, 4 - [(4-Cyclopropylaminomethyl-3,5-dicyclopropylpyrrol-2-yl) methylene] -3-pyrazinyl-2-pyrazolin-5-one; 4 4 4 5 4 5 444 44 44 · · · · 4 ··· 264 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-pyrazinyl-2-pyrazolin-5-one, 4 - {[3-dimethylaminomethyl-5-methyl-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. The compound of claim 18, wherein the compound is a mixture of stereoisomers. The compound of claim 23, wherein the stereoisomers are enantiomers. The compound of claim 24, wherein the stereoisomers are EaZ isomers. The compound of claim 18, wherein the compound is a mixture of structural isomers. The compound of claim 26, wherein the structural isomers are tautomers. 28. A method of inhibiting the activity of one or more protein kinases comprising administering a compound of claim 18. The method of claim 28, wherein said compound is administered to a recipient in need of inhibition of one or more protein kinases. The method of claim 29, wherein the compound is a mixture of stereoisomers. The method of claim 30, wherein the stereoisomers are enantiomers. 32. The method of claim 30, wherein the stereoisomers are EaZ isomers. 33. The method of claim 29, wherein the compound is a mixture of structural isomers. 265 • · · «···· 34. The method of claim 29, wherein the structural isomers are tautomers. 35. The method of claim 29, wherein said protein kinase is a tyrosine kinase. 36. The method of claim 35, wherein said tyrosine kinase is selected from the group consisting of KDR, Flt-1, TIE-2, Lck, Src, fyn, Lyn, Blk and yes. 37. A method of affecting hyperproliferative disorders in a recipient comprising administering to said recipient a compound of claim 18. 38. A method of affecting angiogenesis in a recipient comprising administering to said recipient a compound of claim 18. 39. A pharmaceutical composition comprising a compound of claim 18 and a pharmaceutically acceptable carrier or diluent. 40. A pharmaceutical composition comprising a compound of claim 22 and a pharmaceutically acceptable carrier or diluent. The compound of claim 18, wherein R is substituted with one or more substituents each independently selected from the group consisting of halogens, lower alkyl, R ³ O-, hydroxy, HOC (O) -, R ³ OC ( O) -, R ³ OC (O) R ⁶ -, R ³ OR ⁶ -, trihalomethyl, trihalomethylcarbonyl, nitro, -C (O) NR ⁴ R ⁵ , -NR ⁴ R ⁵ , R ³ CO-, - (CH 2) ) n R ⁷ , -O (CH 2) _n R ⁷ , -C (O) NR ⁴ (CH 2) n R ⁷ , -C (O) (CH 2) _n -R ⁷ , -C (O) (CH 2) n C (O ) -R ⁷ , -C (O) O (CH 2) _n R ⁷ , -OC (O) (CH 2) n R ⁷ , -NR ⁴ C (O) (CH 2) _n R ⁷ , -R ⁶ NR ⁴ R ⁵ -R ⁶ N (R ⁴ ) -R ⁶ -R ⁷ , -R ⁶ C (O) O (CH 2) n R ⁷ , -R ⁶ OC (O) (CH 2) _n R ⁷ , -R ⁶ N (R) ⁶ -R ⁷ ) ₂ , -R ⁶ C (O) NR ⁴ (CH 2) n R ⁷ , R ⁶ NR ⁴ C (O) (CH 2) _n R ⁷ , -R ⁶ CH (C (O) OR ⁴ ) (NR ⁵ C (O) R ⁴ ) optionally substituted aryl groups and optionally substituted aralkyl groups; wherein optionally substituted aryl groups and optionally substituted aralkyl groups are optionally substituted with one or more substituents selected from the group consisting of: 266 consisting of halogen, trihalomethyl, hydroxy, -NR ⁴ R ⁵ , nitro, -CONR ⁴ R ⁵ , lower alkyl, R ³ O-, -C (O) OR ⁴ and -OC (O) R ³ ; R ⁶ is lower alkyl or aryl; and R ⁷ is alkoxy, haloalkyl, lower alkyl piperazine, hydroxy, RO-, R ³ C (O) - or -NR ⁴ R ⁵ . The compound of claim 41, wherein R is pyrrolyl, indolyl, azaindolyl, phenyl, pyrazolyl, imidazolyl, thienyl, 4,5,6,7-tetrahydroindolyl or quinolinyl. The 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, imidazole- 2-yl, imidazol-4-yl, thien-2-yl or quinolin-5-yl. A compound according to claim 18 or 43 wherein R ¹ is trifluoromethyl, amino, cyclopropylamino, methyl, ethyl, propyl, isopropyl, cyclopropyl, 2-methylcyclopropyl, 2,2,3,3-tetramethylcyclopropyl, 2-phenylcyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, - (CH ₂ ) _p -O-phenyl, - (CH ₂ ) _p -O- (4-methoxyphenyl), - (CH ₂ ) _p -O- (4-chlorophenyl), - (CH ₂ ) _p -O- (4-methylphenyl), - (CH ₂ ) _p -O- (3-methylphenyl), - (CH ₂ ) _p -O- (4-phenylphenyl), - (CH ₂ ) _p -O- (4-hydroxyphenyl) -, - (CH ₂ ) _p -O- (4-nitrophenyl), - (CH ₂ ) _p -O- (4-aminophenyl), - (CH ₂ ) _p -O- (4-carbamoylphenyl), - (CH ₂ ) _p- O- (4-methoxycarbonylphenyl), -NHphenyl, -NH- (4-methoxyphenyl), -NH- (4-chlorophenyl), -NH- (4-fluorophenyl), -NH- (4-isopropylphenyl), isopropoxy, ethoxy , cyclopentyloxy, - (CH ₂ ) _p indolyl, - (CH ₂ ) _p -pyridyl, - (CH ₂ ) _p -benzothiazolyl, - (CH ₂ ) _p -pyrrolyl, - (CH ₂ ) _p tetrahydrofuryl, - (CH ₂₎ ) _p pyrazinyl, - (CH ₂ ) _p -furyl, - (CH ₂ ) _p -thienyl, - (CH ₂ ) _p -phenyl, - (CH ₂ ) _p (5-methylisoxazo) lyl), - (CH ₂ ) _p -isoxazolyl, - (CH ₂ ) _p -pyridazinyl, - (CH ₂ ) _p -pyrimidinyl, - (CH ₂ ) _n -C (O) -OMe, - (CH ₂ ) _n -C (O) -OEt and benzyl optionally substituted with one or more Cl, F, OMe, methyl or amino groups; where index p is an integer ranging from 1 to 3. The compound of claim 44, wherein R is optionally substituted with one or more moieties selected from the group consisting of Br, Cl, F, aminomethyl, N, N-dimethylaminomethyl, carboxy, carboxymethyl, carboxyethyl; · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 267 carbonylmethyl, carbonylethyl, methoxycarbonyl, ethoxycarbonyl, phenyl, 4-morpholinomethyl, -C (O) -O- (CH _{2) 2} -N (Me) _2, -C (O) -O- (CH _{2) 2} -N (Et) ₂ , -C (O) -O-CH ₂ N (Me) ₂ , -C (O) -O- (CH ₂ ) ₂ -N (Me) ₂ , -C (O) -NH- ( CH ₂ ) ₂ -N (Me) ₂ , -CH ₂ -NH-C (O) -CF _3, and optionally substituted moieties selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl and phenyl, said optionally substituted the moiety is optionally substituted with one or more groups selected from Br, Cl, F, hydroxy, nitro, amino or lower alkyl.