SK5282001A3 - Tricyclic pyrazole derivatives - Google Patents

Abstract

This invention relates to certain 3-aryl or 3-heteroaryl pyrazoles with 4,5(3,4)-bicyclic ring fusion which are inhibitors of protein kinase activity, of which some are novel compounds, to pharmaceutical compositions containing these pyrazoles and to processes for preparing these pyrazoles.

Description

Tricyclic pyrazole derivatives

Technical field

The present invention relates to certain 3-aryl- or 3-heteroaryl-pyrazoles with a fused 4,5 (3,4) -bicyclic ring which are inhibitors of protein kinases, especially tyrosine kinases and serine / threonine kinases, some of which are novel compounds, pharmaceuticals compositions containing these pyrazoles and methods for preparing these pyrazoles.

BACKGROUND OF THE INVENTION

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

Phosphorylation reactions and counteracting phosphatase reactions, in tyrosine, serine and threonine residues, are involved in countless cellular processes that are responsive to various intracellular signals (typically mediated through cellular receptors), regulating cellular functions, and activating or deactivating cellular processes. Sequence of protein kinases is often involved in intracellular signal transduction and is required for the realization of these cellular processes. Because of their general presence in these processes, protein kinases can be found in the integral part of the plasma membrane or as cytoplasmic enzymes or located in the nucleus, often as components of the enzyme complex. In many cases, these protein kinases are an essential element of the enzyme complex and the structural protein complex that determines where and when the cellular process occurs within the cell.

Protein tyrosine kinase. Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. This post-translational modification of these substrate proteins, which are themselves often

-2 ·· ·· »· · ·

I · · · · · · · · · · · · · · · · · · ·

B enzymes act as a molecular switch that regulates cell proliferation, activation or differentiation (for review see Schlessinger and Ulrich , 1992, Neuron 9, 383-391). Different or excessive PTK activity has been observed in many disease states, including benign and malignant proliferative diseases, as well as diseases resulting from inappropriate activation of the immune system (e.g., autoimmune diseases), allograft rejection, and implant versus host disease. In addition, endothelial cell-specific PTK receptors such as KDR and Tie-2 mediate the angiogenic process and thus contribute to promoting progression of malignant tumors and other diseases causing inappropriate vascularization (e.g. diabetic retinopathy, choroidal neovascularization due to age-related macular degeneration, age related psoriasis). , arthritis, premature retinopathy, infantile hemangioma).

Tyrosine kinases can be of the receptor type (containing extracellular, transmembrane and intracellular domains) or non-receptor type (which are exclusively intracellular).

Receptors of tyrosine kinases (RTKs). Tyrosine kinase receptors include a large family of transmembrane receptors with diverse biological activities. To date, at least nineteen (19) distinct subfamily of tyrosine kinase receptors have been identified. The tyrosine kinase receptor (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 receptor tyrosine kinases is activated after ligand binding, which results in phosphorylation of the receptor and composite cellular substrates and consequently a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61, 203 212). Thus, receptor tyrosine kinase-mediated signal transduction is initiated through extracellular interaction with a specific growth factor (ligand), typically followed by dimerization of the receptor, stimulation of intrinsic protein tyrosine kinase activity, and trans-phosphorylation of the receptor. Thus, binding sites form for intracellular signal transduction molecules and result in complexes with a spectrum of cytoplasmic signaling molecules, facilitating appropriate cellular responses (e.g., cell division, differentiation, metabolic effects, changes)

-3 in the extracellular microenvironment) see Schlessinger and Ullrich, 1992, Neuron 9, 1. •····································· · ··· · · ··· · · · · ················

20th

Proteins with SH2 domains (src homology -2) or phosphotyrosine binding (PTB) bind activated tyrosine kinase receptors and their substrates with high affinity to transduce signals into cells. Both of the domains recognize phosphotyrosine. (Fantle et al., 1992, Cell 69, 413-423; Songyant 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, Schoelson, Curr Opin, Chem Biol (1997), 1 (2), 227-234, Cowburn, Curr Opin, Struct Biol (1997), 7 (6), 835-838). Some intercellular substrate proteins that are associated with receptor tyrosine kinases (RTKs) have been identified. These can be divided into two basic groups: (1) substrates having a catalytic domain; and (2) substrates which lack such a domain but serve as adapters and associate with catalytically active molecules (Songyang et al., 1993, Cell 72, 767-778). The specificity of the interactions between receptors or proteins and 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 amino acid sequences flanking phosphots coincide with new residues at individual receptors are correlated with observed differences in their substrate phosphorylation profiles (Songyang et al., 1993, Cell 72, 767-778). Observations suggest that the function of each receptor tyrosine kinase is determined not only by its pattern of expression and ligand availability, but also by the alignment of progressive signal transduction pathways that are activated by the action of a specific receptor, as well as the synchronization and duration of these stimuli. Phosphorylation thus provides a significant regulatory step that determines the selectivity of signaling pathways generated by specific growth factor receptors as well as differentiation factor receptors.

It is believed that some receptor tyrosine kinases and the growth factors that bind to them play a role in angiogenesis, although some may promote 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 receptor tyrosine kinases.

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An alternative term for human FLK-1 is "kinase insert domain-containing receptor (KDR)" (Terman et al., Oncogene 6, 1767-1683, 1991). Another alternative designation for FLK-1 / KDR is "vascular endothelial cell growth factor receptor 2" VEGFR-2 because it binds VEGF with high affinity. The murine version of FLK-1 / VEGFR-2 was also called NYK (Oelrichs et al., Oncogene 8, (1): 11-15, 1993). Acid DNAs encoding murine, rat and human FLK-1 have been isolated, and nucleotides and coding amino acid sequences have been published (Matthews et al., Proc. Natl. Acad. Sci. USA, 88, 9026-9030, 1991; Terman et al., 1991) Terman et al., Biochem. Biophys. Res Comm. 187. 1579-1586, 1992; Sarzani et al., as above; and Millauer et al., Cell 72, 835-846, 1993). Numerous studies, such as those published by Millauer et al., As mentioned above, suggest that VEGF and FLK-1 / KDR / VEGFR-2 are a ligand-receptor pair that plays an important role in vascular endothelial cell proliferation and formation and blood vessel growth, timed vasculogenesis, and angiogenesis.

Another type III RTK subclass referred to as "fms-like tyrosine kinase-1 (Flt-1)" refers to FLK-1 / KDR (DeVries et al. Science 255. 989-991, 1992; Shibuya et al., Oncogene 5, 519-524, 1990). An alternative term for Flt-1 is "vascular endothelial cell growth factor receptor 1 (VEGFR-1)". To date, it has been found that members of the FLK-1 / KDR / VEGFR-2 and Flt-1 / VEGFR-1 subfamily are primarily expressed in endothelial cells. These members of the subclass are specifically stimulated by members of the vascular endothelial cell growth factor (VEGF) of the ligand family (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7, 259, 270, 1996). Vascular endothelial cell growth factor (VEGF) binds to Flt-1 with a higher affinity than FLK-1 / KDR and is mitogenic to vascular endothelial cells (Terman et al., 1992 as above; Mustonen et al. As as described above; DeVries et al., supra). Flt-1 is believed to be essential for endothelial organization during vascular development. Expression of Flt-1 is associated with early vascular development in mouse embryos and with neovascularization during wound healing (Mustonen and Aiitalo as above). Expression of Flt-1 in adult organs such as kidney glomeruli suggests

-5 ·············································· An additional function for this receptor that is not associated with cell growth (Mustonen and Alitalo as above).

As mentioned above, recent evidence suggests that VEGF plays a role in stimulating both normal and pathological angiogenesis (Jakeman et al., Endocrinology 133: 848-859, 1993; Kolch et al., Breast Cancer Research and Treatment 36, 139). 155, 1995; Ferrara et al., Endocrine Reviews 18 (1); 4-25, 1997; Ferrara et al., Regulation of Angiogenesis (ed. LD Goldberg and EM Rosen), 209-232, 1997). In addition, VEGF has been implicated in the regulation and improvement of vascular permeability (Connolly et al., J. Biol. Chem. 264. 20017-20024, 1989; Brown et al., Regulation of Angiogenesis (ed. LD Goldberg and EM Rosen), 233 269, 1997).

Various forms of VEGF resulting from alternative mRNA splicing, including the four species described by Ferrara et al. (J. Cell. Biochem. 47,

211-218 (1991). Ferrara et al. (see above), both species, both secreted and predominantly cell-associated VEGF species, have been identified and the protein is known to exist in the form of disulfide-linked dimers.

Recently, several related VEGF homologues have been identified. However, their role in normal physiological and disease processes has not yet been explained. In addition, members of the VEGF family are often co-expressed with VEGF in a variety of tissues and are generally capable of forming heterodimers with VEGF. This property is likely to alter receptor specificity and biological effects of heterodimers and further complicate the elucidation of their specific functions, as explained below (Korpelainen and Alitalo, Curr. Opin. Cell Biol., 159, 164, 1998 and references cited therein).

Placenta growth factor (PIGF) contains an amino acid sequence that shows significant homology to the VEGF sequence (Park et al., J. Biol. Chem. 269, 25646-25654, 1994; Maglione et al. Oncogene 8, 925 931) , 1993). As with VEGF, a variety of PIGF species derive from alternative mRNA splicing, and the protein exists in dimeric form (Park et al., Supra). PIGF-1 and PIGF-2 bind to Flt-1 with high affinity, and PIGF-2 also readily binds to neuropilin-1 (Migdal et al., J. Biol. Chem. 273 (35): 22272 -6). · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

22278), but does not bind FLK-1 / KDR at all (Park et al., Supra). PIGF has been reported to potentiate both the vascular permeability and the mitogenic effect of VEGF in endothelial cells when VEGF is present at low concentrations (allegedly due to heterodimer formation) (Park et al., Supra).

VEGF-B is produced as two isoforms (167 and 185 residues), which also appear to bind to FIM / VEGFR-1. This may play a role in regulating extracellular matrix degradation, cell adhesion and migration through modulation of urokinase-type plasminogen activator expression and activity and plasminogen activator inhibitor 1 (Pepper et al., Proc. Natl. Acad. Sci. USA (1998), 95, (20). ): 11709-11714).

VEGF-C was originally cloned as a ligand for VEGFR-3 / Flt-4, which is primarily expressed by lymphatic endothelial cells. This is a fully mature form, VEGF-C can also bind KDR / VEGFR-2 and stimulate endothelial cell proliferation and migration in vitro and angiogenesis in in vivo models (Lymboussaki et al., Am. J. Pathol. (1998), 153. ( 2): 395-403, Witzenbichler et al, Am J. Pathol (1998), 153 (2), 381-394). Transgenic overexpression of VEGF-C causes the proliferation and widening of only lymphatic vessels, and blood vessels are unaffected. In contrast to VEGF, VEGF-C expression is not induced by hypoxia (Ristimaki et al., J. Biol. Chem. (1998), 273, (14), 8413-8418).

The recently discovered VEGF-D is structurally very similar to VEGF-C. VEGF-D is said to bind and activate at least two VEGFRs, VEGFR-3 / Flt-4 and KDR / VEGFR-2. It was originally cloned as a c-fos inducible mitogen for fibroblasts and is most prominent in mesenchymal lung and skin cells (Achen et al., Proc. Natl. Acad. Sci. USA (1998), 95, (2), 548-553 and there references).

VEGF-C and VEGF-D have been reported to induce an increase in vascular permeability in vivo in the Miles assay when injected into skin tissue (PCT / US97 / 14696; WO98 / 07832, Witzenbichler et al., Supra). Physiological role and significance of these ligands in modulating vascular

-7 Hyperpermeability and endothelial responses in tissues -7 ················· · · · · · · · · · · · · · · · · · · · · · · · · · · · in which they are expressed remains unclear.

Based on the discovery of other VEGF and VEGFR homologues and precedents for ligand and receptor heterodimerization, the effect of such VEGF homologs may include formation of VEGF ligand heterodimers and / or receptor heterodimerization, or binding to undiscovered VEGFR (Witzenbichler et al., Supra), as noted above. Also, recent studies suggest the possible involvement of neuropilin-1 (Migdal et al., As above) or VEGFR-3 / Flt4 (Witzenbichler et al., As above), and also that other receptors such as KDR / VEGFR- 2 are responsible for induction of vascular permeability (Stacker, S.

A., Vitali, A., Domagala, T., Nice, E. and Wilks, A.F., Angiogenesis and Cancer Conference, Amer. Assoc. Cancer Res. Orlando, FL; Williams, Diabetelogia 40. S118-120 (1997)). To date, no direct evidence of the essential role of KDR in VEGF-mediated vascular hyperpermeability has been reported.

Non-receptor tyrosine kinases. Non-receptor tyrosine kinases are a collection of cellular enzymes lacking extracellular and transmembrane sequences.

More than twenty-four individual non-receptor tyrosine kinases containing eleven (11) subfamilies have been identified (Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK). Currently, the Src subfamily of non-receptor tyrosine kinases consists of the largest number of protein tyrosine kinases and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes binds to oncogenesis. A more detailed discussion of non-receptor tyrosine kinases is given in the literature: Bolen, 1993, Oncogene 8, 2025-2031, which is hereby incorporated by reference.

Many tyrosine kinases, whether RTK or non-receptor tyrosine kinase, have been found to be involved in cellular signaling pathways involved in numerous pathogenic conditions, including cancer, psoriasis and other hyperproliferative diseases or hyperimmune responses.

Development of compounds for modulating protein tyrosine kinases. In view of the supposed importance of protein tyrosine kinases for control, regulation and modulation

-8 ············································ Many proliferation attempts have been made to identify receptor and non-receptor tyrosine kinase inhibitors, using a variety of approaches, including the use of mutant ligands (U.S. Pat. No. 4,966,849), soluble receptors and antibodies (International Application No. WO 94/10202; Kendall & Thomas, 1994, Proc. Natl. Acad. Sci 90, 10705-10709; Kim et al., 1993, Nature 362. 841 RNA ligands (Jellinek et al., Biochemistry 33, 10450-10456; Takano et al., 1993, Mol. Bio. Cell 4, 358A; Kinsella, et al. 1992, Exp. Cell Res.

199. 56-62; Wright et al., 1992, J. Cellular Phys. 152, 448-457) 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).

More recently, attempts have been made to identify small molecules that act as tyrosine kinase inhibitors. For example, bismonocyclic, bicyclic or heterocyclic aryl compounds (PCT International Patent Publication WO 92/20642) and vinylene-azaindole derivatives (PCT International Patent Publication WO 94/14808) have generally been 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 (European Patent Application EP 0 566 266 A1); Expert Opin. Ther. Pat. (1998), 8 (4): 475-478, seleoindoles and selenides (PCT International Patent Publication WO 94/03427), tricyclic polyhydroxyl compounds (PCT International Patent Publication WO 92/21660) and benzylphosphonic acid compounds (PCT International Patent Publication WO 91/15495) have been described as being useful as tyrosine kinase inhibitors for use in the treatment of cancer. Anilinocinolines (PCT International Patent Publication WO 97/34876) and Quinazoline Derivative Compounds (PCT International Patent Documents WO 97/22596;

PCTs (WO 97/42187) have been described as inhibitors of angiogenesis and vascular permeability.

In addition, attempts have been made to identify small molecules that act as serine / threonine kinase inhibitors. In particular, bis (indolyl maleaimide) compounds have been described as inhibiting, in particular, the isoforms of the PKC serine / threonine kinase, in particular the PKC serine / threonine kinase isoforms. Whose dysfunction is associated with altered VEGF-related vascular diseases (International Patent WO97 / 40830; PCT WO97 / 40831).

Therefore, it is appropriate to identify potent macromolecules and small organic compounds that specifically inhibit tyrosine signal transduction by modulating receptor and non-receptor tyrosine kinase activity to regulate and modulate abnormal or inappropriate cell proliferation, differentiation or metabolism. In particular, it would be useful to identify methods and compounds that specifically inhibit the function of tyrosine kinases that is essential for the formation of vascular hyperpermeability leading to edema, effusions, exudates and macromolecular extravasation and deposition as well as related diseases.

permeability to PCT documents

SUMMARY OF THE INVENTION

The present invention relates to a method for inhibiting the kinase activity of tyrosine kinases and serine / threonine kinases, which comprises administering a compound represented by the general formula I:

and pharmaceutically acceptable salts thereof, wherein: a) substituted methylene, b) carbonyl, c) oxygen, d) -C = NOR ⁷ , wherein R ⁷ is K or C 1-4 alkyl, e) NR ⁸ , wherein R ⁸ represents H, an optionally substituted C 1-4 alkyl group or an optionally substituted phenyl, f) a group of formula (CH 2) _n . wherein n is 1, 2 or 3, or g) a group of formula S (O) _P , wherein p is 0, 1 or 2;

R ¹ represents H;

-10 · ··································· ·· ·· ·· ·· ··

R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted;

R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) C 0-6 alkyl optionally substituted by one or more of the following groups, such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j have the meanings defined below, d) a C 1-6 -alkoxy group optionally substituted by one or more of the following groups, such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j have the meanings defined below, provided that these groups are not attached to the carbon that is attached to the oxygen of the alkoxy group; e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a , wherein R ^a represents a hydroxyl group, a C 1-4 -alkoxy group or R ^a represents a group of the formula NR ^b R ^c in which R ^b and R ^{c are} , independently of one another, hydrogen, C 1-6 -alkyl or phenyl, the alkyl the group and phenyl are optionally substituted by one or more of the following groups, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 -alkyl or wherein R ^h and R ^j , together with the nitrogen atom to which they are attached, represent a five- or seven-membered saturated heterocyclic ring which optionally contains another heteroatom selected from O, S or N and is optionally substituted with a C 1-6 -alkyl group; NR ^d R ^e , wherein R ^d and R ^d are independently selected from the group consisting of hydrogen, C 1-6 -alkyl, C 3-12 -cycloalkyl or phenyl or a group of formula COR ^f , where R ^f is hydrogen, C 1-2 alkyl C 3-12 cycloalkyl, phenyl-C 1-4 alkyl or phenyl, in each case the alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following: substituents such as: halogen, hydroxy, nitro or amino of the formula NR ^h R ^j , wherein R ^h and R 'are as defined above i) a group of the formula O (CH 2) _m R ⁹ in which m is 2,

3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula

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NR ^d R ®, wherein R ^d and R ® are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above and m is 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 -alkyl, I) optionally substituted phenyl- C-alkoxy, m) cyano or o) C2 ^ -alkenyl, or C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: C ^ -alkyl a group, a C 1-4 -alkoxy group or a halogen, provided that:

1) when X is carbonyl or substituted methylene, R ¹ is hydrogen and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not pyridyl, phenyl or phenyl substituted with a substituent such as a C 1-2 -alkyl group a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; and

2) when X represents a group of formula (CH ₂ ) _n in which n represents 1, 2 or 3, R ¹ represents hydrogen and two of the substituents R ³ , R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, halogen with an atomic mass of from about 19 to 36, a C 1-6 -alkyl, a C 1-6 -alkoxy or a trifluoromethyl group and the other two represent hydrogen when R ² is thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted or phenyl containing two; fewer substituents wherein the substituents are halogen having an atomic mass of from about 19 to 36, a C 1-4 -alkyl group, a C 1-4 -alkoxy group or a trifluoromethyl group;

to said kinase at a sufficient concentration to inhibit the enzyme activity of said kinase.

In other embodiments, R ³ , R ⁴ , R ⁵ and R ⁶ , independently of each other, are a) H, b) halogen, c) and a C 1-6 alkyl group optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below;

_6- alkoxy, optionally substituted with one or more

-12 of the following substituents, such as: a hydroxyl group, a C 1-6 -alkoxy group, a halogen or an amino group of the formula NR ^h R ^j , where R ^h and R ^j are as defined below, provided that these groups are not attached to the carbon that is attached to the oxygen of the alkoxy group; optionally substituted phenoxy,

f) a hydroxyl group, g) a group of the formula COR ^a in which R ^a represents a hydroxyl group, a C 1-6 -alkoxy group or R ^a represents a group of the formula NR ^b R ^c in which R ^b and R ^c represent each other independently of one another hydrogen, C 1-6 alkyl or phenyl, wherein the alkyl group and phenyl are optionally substituted with one or more of the following substituents such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^h independently of one another represent hydrogen or (C 1 -C 6) heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent five- , a six- or seven-membered saturated heterocyclic ring which optionally contains another heteroatom selected from O, S or N and is optionally substituted with a C 1-6 -alkyl group; h) a group of the formula NR ^d R ® in which R ^d and R ® are each other no independently selected from the group consisting of hydrogen, C 1-12 alkyl, C 3-12 -cycloalkyl or phenyl or a group of formula COR ^f , wherein R ^f represents hydrogen, C 1-12 -alkyl, C 3-12 -cycloalkyl, phenyl- C 1-4 alkyl or phenyl, in each case the alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents, such as: halogen, hydroxyl, nitro or amino of the formula NR ^h R ^j , wherein R ^h and R 'are as defined above i) a group of formula O (CH 2) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ^a , wherein R ^a is as defined above and m represents 1,2,3,4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 alkyl, I) optionally substituted phenyl-C 1-4 -alkoxy m) cyano or o) C ^ ₂ -alkenyl or C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents are: Cl. _6- alkyl, C 1-4 -alkoxy or halogen.

Certain compounds of formula I are known in the literature. Compounds of formula I wherein X is methylene, ethylene, trimethylene, vinylene, substituted methylene are described in US Patent Documents US 3,932,430, US 3,843,665 and US 3,848,666. Compounds in which X represents carbonyl are described in JP 60-130521. Compounds in which X is O and R ¹ , R 3, R ⁴ , R ⁵ and R ⁶ are hydrogen and R ² is phenyl, 2,4-dimethylphenyl, 2-thienyl, 3-thienyl and 2-pyrrolyl are described in J. Het. Chem. 1984, 21 (4): 937-943, J. Org. Chem. 1972, 37 (15) 2402 and J Het Chem. 1971, 855-859. A compound in which X represents S and R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen and R ² represents 2,4-dichlorophenyl is described in Monatsh Chem. 1974, 105, 869. A compound of formula I wherein X is SO 2 and R ¹ , R ³ , R ⁴ , R ⁵ and R ^{6 are} each hydrogen and R ² is phenyl is described in Liebigs Ann. Chem. 1974.1248.

WO 97/15308 discloses that 3- (4-methylphenyl) indeno [1,2-c] pyrazole-4 (1H) -one oxime can be used to treat bone deficiency conditions. 3- (3,4-Dimethoxyphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime is commercially available.

Certain condensed pyrazoles of formula I are commercially available, but no pharmacological activity has been reported for these compounds. The compounds that are commercially available are the following:

3- (2-thienyl) indeno [1,2-c] pyrazol-4 (1H) -one and 3-phenyl-1H-benzofuro [3,2-c] pyrazole.

The present invention further relates to a first group of novel compounds of formula I and pharmaceutically acceptable salts thereof, wherein:

X is a group of formula S (O) _P wherein p is 0, 1 or 2;

R ¹ is H;

R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and

R ^3, R ^4, R ⁵ and R ⁶ are as defined above;

provided that:

1) when R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen and X represents SO ₂ , then

R ² is not phenyl, and

-14 • ········································

2) when X represents S and R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not 2,4-dichlorophenyl.

The present invention still further relates to a second group of novel compounds of formula I and pharmaceutically acceptable salts thereof, wherein:

X represents oxygen;

R ¹ represents H;

R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and

R ^3, R ^4, R ⁵ and R ⁶ are as defined above;

with the proviso that when each of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ represents hydrogen, then R ^{2 is} not phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl.

The present invention still further relates to a third group of novel compounds and pharmaceutically acceptable salts thereof, wherein:

X is NR ⁸ ;

R ¹ represents H;

R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and

R ^3, R ^4, R ⁵ and R ⁶ are as defined above.

The present invention still further relates to a fourth group of novel compounds of formula I and pharmaceutically acceptable salts thereof, wherein:

X is -C = NOR ⁷ wherein R ⁷ is H or Chalkyl;

R ¹ represents H;

R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and

R ^3, R ^4, R ⁵ and R ⁶ are as defined above;

-15 · · 15 15 • · 15 15 15 15 15 15 15 15 pod pod pod pod pod pod pod pod pod pod pod pod pod pod pod R ^{@ 1} , R ^{@ 3} , R ^{@ 4} , R ^{@ 5} and R ^{@ 6} are hydrogen and X is C.dbd.NOH then R @ ^{2 is} not 4-methylphenyl;

3,4-dimethoxyphenyl.

The present invention still further relates to a fifth group of novel compounds of formula

I and pharmaceutically acceptable salts thereof, in which:

X represents a substituted methylene group or a carbonyl group;

R ¹ represents H;

R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and

R ^3, R ^4, R ⁵ and R ⁶ are as defined above;

provided that:

1) when X is carbonyl or substituted methylene, R ¹ is hydrogen and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not pyridyl, 2-thienyl, 3-thienyl, phenyl or phenyl substituted with a substituent such as: A C 1-2 alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group;

2) when X is methylene, R ¹ is hydrogen and two of R ³ , R ⁴ , R ⁵ and R ⁶ are independently from each other hydrogen, halogen having an atomic mass of from about 19 to 36, C _1-4 alkyl, C 1-4 alkyl, alkoxy or trifluoromethyl and the other two represent hydrogen, then ^R2 does not represent a thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl having two or less substituents wherein the substituents are halogen having an atomic weight of about 19 to 36 C 4-alkyl, C1-alkoxy or trifluoromethyl;

and

3) when X is carbonyl, R ² is phenyl, 4-chlorophenyl or 4-methoxyphenyl, then ^{R3, R4, R5} and ^R6 are not trifluoromethyl;

-16 ············································· · 9 · 9 9 9 9 9 9 9 9

999 99 99 99

4) when X is carbonyl, ^R2 is phenyl, ^R3 represents bromo, ^R4 represents hydroxy and ^R5 represents methoxy, then ^R6 is not hydrogen, and

5) when X is a carbonyl group and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, then R ^{6 is} not aryl.

The present invention still further relates to a sixth group of novel compounds of formula I and pharmaceutically acceptable salts thereof, wherein:

X is a group of formula (CH ₂ ) _n wherein n is 1, 2 or 3

R ¹ represents H;

R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and

R ³ , R ⁴ , R ⁵ , and R ⁶ are as defined above, provided that as X is a group of formula (CH ₂ ) _n wherein n is 1, or 3, R ¹ is hydrogen and two of R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen having an atomic mass of from about 19 to 36,

4-alkyl, C 1-4 -alkoxy or trifluoromethyl and the other two represent hydrogen, then R ^{2 is} not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl containing two or fewer substituents, the substituents being: halogen atomic by weight, from about 19 to 36, C 1-6 -alkyl, C 1-4 alkoxy or trifluoromethyl, and provided that when n is 2 and each of R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen or methoxy, then R ² is not 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid-2-yl or 2-carboxyphenyl.

The present invention still further relates to a seventh group of novel compounds of formula I and pharmaceutically acceptable salts thereof, wherein:

- 17 represents a) substituted methylene b) carbonyl, c) oxygen, d) a group of the formula -C = NOR ⁷ in which R ⁷ is H or a C 1-6 -alkyl group e) a group of the formula NR ⁸ in which R ⁸ is H, an optionally substituted C 1-4 -alkyl group or an optionally substituted phenyl, f) a group of formula (CH ₂ ) _n in which n is 1, 2 or 3, or g) a group of formula S (O) _P in which p is 0, 1 or 2;

represents H;

R ²

R ³ is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted;

R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen,

c) a C 1-6 alkyl group which is optionally substituted with one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j have the meanings defined below, d) C 1-6 -alkoxy a group which is optionally substituted by one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , where R ^h and R * are as defined below, provided that these groups are not bonded to a carbon which is attached to the oxygen of the alkoxy group; or halo e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a in which R ^a represents a hydroxyl group, a C 1-6 alkoxy group or R ^a represents a group of the formula NR ^b R ^c in which R ^b and R ^c , independently of one another, are hydrogen, C 1-6 -alkyl or phenyl, the alkyl and phenyl being optionally substituted with one or more of the following substituents, such as: hydroxyl or amino of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or a C 1-6 -alkyl group or wherein R ^b and R 'together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered saturated heterocyclic ring optionally containing a further a heteroatom selected from O, S or N and is optionally substituted with a C 1-6 alkyl group; h) a group of the formula NR ^d R ^e , wherein R ^d and R ^e are independently selected from the group consisting of: hydrogen, C 1-6 -alkyl

-189 •

·· · · · · · · · · · ·

998 9 9 • 9 9 9

9 9 9

9 999

9 9

A group or phenyl or groups of formula COR ^f , wherein R ^f represents hydrogen, C 1-4 -alkyl, C 1-4 -cycloalkyl or phenyl, in each case the alkyl, cycloalkyl and phenyl being optionally substituted by one or more of the following substituents i) a group of the formula O (CH 2) m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ is a hydroxy group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above; represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ^e are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above and m is 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 -alkyl, I) optionally substituted phenyl-C 1-6- alkoxy or o) C2 ^ -alkenyl or C ₂ -4-alkinyllová group, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: C ^ -alkyl, CV ₆ alkoxy or halogen, provided that at least one of R ³ , R ⁴ , R ⁵ and R ⁶ or a substituent on R ² represents one of the following substituents such as: (a) a group of the formula O (CH ₂ ) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ is a hydroxy group or a group of the formula NR ^d R ^e , wherein R ^d and R ® are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above ^and m is 1, 2, 3, 4 or 5; b) C 1-6 -alkyl substituted by one or more of the following substituents such as: hydroxyl or amino of formula NR ^h R ^j , wherein R ^h and R ^j are as defined above; a β-alkoxy group optionally substituted by one or more of the following substituents such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , where R ^h and R * are as defined above, provided that these groups are not carbon-bound; which is attached to the oxygen of the alkoxy group,

d) a group of formula COR ^a , wherein R ^a represents a hydroxyl group, C 1-6 alkyl; ₆ alkoxy, or R ^a is a group of formula NR ^b R ^c wherein R ^b and R ^c are as defined above, e) a group of formula NR ^d R ^e in which R ^d and R® are as defined above.

-19 ·· · · · · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·

The term aryl, as used herein, means phenyl or naphthyl. The term optionally substituted as used herein means substituted with one or more of the following substituents such as a) halogen, b) C 1-6 -alkyl optionally substituted with one or more of the following substituents such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below; c) C 1-4 alkoxy optionally substituted by one or more of the following substituents such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below, provided that these groups are not bonded to the carbon that is attached to the oxygen of the alkoxy group, d) optionally substituted phenoxy,

e) hydroxy; f) a group of formula COR ^a in which R ^a represents a hydroxyl group, a C 1-4 alkoxy group or R ^a represents a group of the formula NR ^b R ^c in which R ^b and R ^c , independently of one another, represent hydrogen C 1-12 -alkyl, C 3-12. 12-cycloalkyl or phenyl, wherein the alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents such as: hydroxyl, halogen, C 3-12 -cycloalkyl or amino of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or a C 1-6 alkyl group or wherein R ^h and R 'together with the nitrogen atom to which they are attached form a five-, six- or seven-membered saturated heterocyclic ring optionally containing a further heteroatom g) a group of the formula NR ^d R ^e , wherein R ^d and R ^e , independently of one another, are selected from the group consisting of hydrogen, C 1-12- alkyl, C3.i2 cycloalkyl group or a phenyl group of the formula COR, or ^f, wherein R ^f is hydrogen, Ci.12-alkyl, C ₃ .i ₂ -cycloalkyl, phenyl-C ^ alkyl, or phenyl j, wherein in each case the alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents such as: halogen, hydroxyl, nitro or amino of the formula NR ^h R ^j , wherein R ^h and R 'are as defined above h) a group of the formula O (CH 2) m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ^e in which R ^d and R ^e are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above and m is 1, 2, 3, 4 or 5, i) nitro, j) optionally substituted phenyl-C 1-6 -alkyl, k) optionally substituted phenyl- C 1-6 -alkoxy, I) cyano, m) C 3. ₆ -20 ··· ··················· n) alkenyloxy group, n) pyridyloxy group or pyridylthio, wherein the pyridine ring is optionally substituted with one or more of the following substituents, such as: trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C 1-6 -alkyl, s) phenyl, t) ₂ C ^ -alkenyl or _C2 ^ alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: C-i_6-alkyl, C ^ alkoxy group or halo.

In other embodiments, the term optionally substituted as used herein means substituted with one or more of the following substituents, such as:

a) halogen,

b) a C 1-6 -alkyl group optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , wherein R ^h and R * are as defined below,

c) C 1-6 -alkoxy optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ^j , wherein R ^h and R ^j are as defined below, with the proviso that these groups are not bound to the carbon that is attached to the oxygen of the alkoxy group; or halogen

d) optionally substituted phenoxy;

e) hydroxyl group,

f) a group formula COR ^a or SO 2 R ^a wherein R ^a is hydroxy, (C, -C6) alkyl, (CrCeJalkoxy or R ^a is a group of formula NR ^b R ^c;

wherein R ^b and R ^c are each, independently of one another, hydrogen, m ₂ alkyl, _C3-I2 cycloalkyl group, phenyl (C ₀ -C ₆₎ alkyl or heterocyclyl (C ₀ -C ₆₎ alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl and thiophenyl), wherein the alkyl, cycloalkyl, phenyl or heterocyclyl (C 0 -C 6) alkyl group are optionally substituted with one or more of the following substituents such as: hydroxyl, (C 1 -C 6) ₆ ) -hydroxyl, halogen, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy,

-21 ···················································································

-0- _(Ci-C6) alkyl-OH, _C-3 .i2 cycloalkyl group or an amino group of formula NR ^h R ^J;

wherein R ^h and R ^j are each independently hydrogen, (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, (C 3 -C 6) heterocycloalkyl- (C ₀ -C 6) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine , imidazole, triazole, morpholine and piperazine), (C ₁ -C ₆ ) alkenyl, (C ₁ -C ₆ ) -alkynyl, (C 3 -C 6) cycloalkenyl (C ₀ -C ₆ ) alkyl, hydroxy (C 1 -C 6) -alkyl, amino (C ₁ -C ₆ alkyl, (C ₁ -C ₆ ) -C ₆ ) alkoxy (C 1 -C 6) alkyl, mono- or di- (C 1 -C 6) alkylamino (C 1 -C 6) alkyl, morpholinyl (C 1 -C ₆ ) alkyl, pyrrolidinyl (C 1 -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C 6 alkyl) and (C 1 -C 6 alkyl) or R ^h and R 'together with the nitrogen atom to which they are attached represent a four-, five-, six- or seven-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N and is drink or substituted with a C 1-4 -alkyl or heterocycle, or R ^b and R ^c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered ring, said ring optionally containing one or a plurality of other heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted with a substituent such as (C 1 -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C 2 -C ₆ ) alkenyl wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of Br, Cl, F, J, hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C 6) alkyl and (C 1 -C 6) alkyl -C ₆ ) alkoxy;

g) a group of the formula NR ^d R ^e , wherein R ^d and R ^e are, independently of each other, selected from the group consisting of hydrogen, C 1-12 -alkyl, C 3. ₁₂ -cycloalkyl, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- (C 1 -C ₆ ) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group comprising O, S and N, or R ^d and R ^e each, independently of one another, is a group of formula COR ^f wherein R ^f represents hydrogen, NR ^b R ^c , (C 1 -C ₆ alkoxy, amino- (C 1 -C ₆ ) alkoxy - (C ₁ -C ₆ ) alkoxy, mono-C 1 -C 6 alkyl-amino-C 1 -C 6 alkoxy-C 1 -C 6 alkoxy, N, N-di-

C 1-6 alkyl-amino-C 1 -C 6 alkoxy-C 1 -C 6 alkoxy, C 1-12 -alkyl, C ₃ . ₁₂ -22 · cycloalkyl, phenyl -C 1-6 -alkyl or phenyl, in each case alkoxy, alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents, such as: halogen, hydroxy, nitro, (C 1 -C 6) alkyl, (C 1 -C 6) ₆₎ alkoxy, di (C, -C6) alkyl-amino- (C6) alkoxy, pyrrolidine which is optionally substituted by (C _{r C6)} alkyl, or an amino group of formula R ^ NI ^1, wherein R ^h and R ¹ are as defined meaning

h) O (CH 2) _m R ⁹ . wherein m is 2, 3, 4 or 5 and R ⁹ is a hydroxyl group or a group of the formula NR ^d R ®, wherein R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ®, wherein R ^a is as defined above ^and m represents 1, 2, 3, 4 or 5,

(i) nitro;

j) optionally substituted phenyl-C 1-6 -alkyl,

k) optionally substituted phenyl-C 1-6 alkyl; ₆ -alkoxy,

(l) cyano;

m) _C3 ^ alkenyl (oxy group,

n) a pyridyloxy or pyridylthio group, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro;

o) hydroxyamidino group,

p) aminomethyl group,

q) formamidomethyl group,

r) C 1-6 alkyl,

s) phenyl group,

t) C ₂ -4 alkenyl group or a C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: Ci-e-alkyl, C1.6alkoxylová a group or halogen,

u) CHO,

-23 ··························································

v) dihydroxyborane

(w) tetrazolyl.

When R ² is an optionally substituted pyridyl the pyridine ring may be in the form of its N-oxide.

When NR ^d R ® is a saturated heterocyclic ring, the ring is preferably morpholino, perhydrothiazin-4-yl, piperidine, pyrrolidin-1-yl, piperazin-1-yl or 4-methylpiperazin-4-yl.

The term substituted methylene means for example methylene substituted by one or more of the following substituents: hydroxy or C ^ -alkyl, which alkyl group is optionally further substituted by a group of formula NR ^r R ^s wherein R ^r and R ^s, independently of themselves represent H or a C 1-6 -alkyl group.

It will be appreciated that any of the above groups that contain a chain of three or more atoms refers to a group in which the chain may be linear or branched. For example, an alkyl group may include propyl which is n-propyl and isopropyl, and butyl which is n-butyl, sec-butyl, isobutyl and tert-butyl. The term C 3-12 cycloalkyl includes bridged groups such as adamantyl. The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine.

The compounds of formula I may exist in the form of salts with pharmaceutically acceptable acids. The present invention includes such salts. Examples of such salts are hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates [for example (+) - tartrates, (-) - tartrates or mixtures thereof, including racemic mixtures], succinates, benzoates and salts with amino acids such as glutamic acid. These salts can be prepared using procedures known to those skilled in the art.

Certain compounds of formula I having acidic substituents may exist in the form of salts with pharmaceutically acceptable bases. The present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts, and the like

-24 ················································································· Arginine salts. These salts can be prepared using procedures known to those skilled in the art.

Certain compounds of formula I and salts thereof may exist in more than one crystalline form, and the present invention includes all crystalline forms and mixtures thereof.

Certain compounds of formula I and salts thereof may also exist in the form of solvates, for example hydrates, and the present invention includes all solvates and mixtures thereof.

Certain compounds of Formula I may contain one or more chiral centers, and exist in various optically active forms. When the compounds of formula I contain a single chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers. The enantiomers may be resolved using procedures known to those skilled in the art, for example, by formation of diastereomeric salts which may be separated, for example, by crystallization; forming diastereoisomeric derivatives or complexes which can be separated, for example, by crystallization, gas-liquid or liquid chromatography; selectively reacting one enantiomer with an enantiomer-specific reagent, for example by enzymatic esterification; or by gas-liquid or liquid chromatography in a chiral medium, for example on a chiral support such as silica, with a bound chiral ligand, or in the presence of a chiral solvent. It will be appreciated that when the desired enantiomer is converted to another chemical entity using one of the separation procedures described above, an additional step is required to release the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer to the other enantiomer 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 using procedures known to those skilled in the art, for example

-25 by chromatography or crystallization and the individual enantiomers within each pair may be separated as described higher. The present invention includes all diastereoisomers 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 all tautomers and / or geometric isomers of the compounds of formula I and mixtures thereof.

Certain compounds of formula I may exist in differently stable conformational forms which may be separable. Torsional asymmetry due to limited rotation around an asymmetric single bond, for example due to spherical hindrance or ring tension, may allow separation of different conformers. The present invention encompasses all conformational isomers of the compounds of Formula I and mixtures thereof.

Certain compounds of formula I may exist in the form of zwitterions, and the present invention includes all forms of zwitterions of compounds of formula I and mixtures thereof.

The compounds of the invention are useful as serine / threonine inhibitors and tyrosine kinases. The compounds of the invention are particularly useful as inhibitors of tyrosine kinases which are important in hyperproliferative diseases, in particular in the angiogenesis process. Since these compounds are anti-angiogenic, they are important agents for inhibiting the progression of disease states in which angiogenesis is an important component.

Preferred definitions of substituents are given below.

Preferably R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl, or optionally substituted pyrrolyl.

Particularly preferably R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, di- and tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-26); · ··· ··················································································· Piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy, 2- (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl); yl) propoxy, 3- (pyrrolidin-1-yl) -propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially) phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalogen-lower-alkyl, polyhalogen-lower-alkoxy (especially difluoromethoxy), nitro, cyano, lower alkylthio (especially methylthio), carboxyl, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido), and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl and pyrenylcarbamoyl) wherein the pyridine ring is optionally substituted with one or more of the following groups: trifluoromethyl or nitro.

Most preferably, R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2 aminometyl-4-pyridyl, 2- (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2- methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) phenyl, 4-carbamoyl-methoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 3- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3-carbamoyl -methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl,

4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4- dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbonylcarbonylphenyl, 4-carbamoyl; -cyanophenyl, 4-N-methylcarbamoylphenyl, 4N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-enyloxy) phenyl, 3 - (2-hydroxyethoxy) phenyl,

-27 • ··········································· · ··

3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylamino-ethyl) -carbamoyl) propoxy] phenyl, 2-furyl, 5- [3,5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy- 2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3-N (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3- [3- (N- (2-morpholinoethyl) carbamoyl) propoxyphenyl], 4- (N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 4- (morpholinoacetamido) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl.

Preferably R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2- carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and 2- morpholinoethoxy), amido (especially acetamido and benzamido), optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl and N-phenylcarbamoyl), carboxyl, nitro and amino.

Particularly preferably, R ³ , R ⁴ , R ⁵ and R ⁶ represent the following groups, such as: 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl,

6- (N-methylcarbamoyl), 6- (N-phenylcarbamoyl), (3-morpholino) propoxy and 2-morpholinoethoxy.

The term lower as used herein means a group having 1 to 6 carbon atoms.

Specific compounds of the present invention include:

3- (3,4,5-trimethoxyphenyl) -1,4-dihydro-indeno [1,2-cjpyrazol,

3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenol,

3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole,

····· · · · · · · · · · · · · · · · · · · · · · · · · · ·

3- (2-thienyl) -1H- [1] benzothieno [3,2-c] pyrazole,

3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole 4-oxide,

3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole 4,4-dioxide,

3- (2-thienyl) -1H- [1] benzothieno [3,2-c] pyrazole,

3-phenylindeno [1,2-c] pyrazol-4 (1H) -one oxime,

3- (3,4-dimethoxyphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime,

3- (4-methylphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime,

3- (2-thienyl) indeno [1,2-c] pyrazol-4 (1H) -one,

3-phenyl-1H-benzofuro [3,2-c] pyrazole

1,4-dihydro-3-phenylpyrazolo [4,3-b] indole,

1,4-dihydro-4-methyl-3-phenylpyrazolo [4,3-b] indole;

4,4-dimethyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazole, 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid, 4- (1-methyl-methyl) ester 4-dihydroindeno [1H-pyrazol-5-yl] benzoic acid,

4- (- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide),

4 '- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -3-morfolinopropionanilid,

4 '- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) morfolinoacetanilid.

4 '- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzanilide.

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -acetamide,

3-Morpholino-N- (3-phenyl-1,4-dihydropyrido [1,2-c] pyrazol-6-yl) propionamide, N- (3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol-6-yl) benzanilide.

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

N-methyl-4- (1,4-dihydroindeno [1 H -pyrazol-S-yl] benzamide,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzanilide.

N- (2-diethylaminoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl) -4- (1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) benzamide,

-29 • ···············

9,999 9,999 9 9 9

999 99 99 99 99

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenol,

3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole,

3- (2-thienyl) -1,4-dihydro-indeno [1,2-c] pyrazol-6-ol,

6- (2-morpholinoethoxy) -3- (2-thienyl) -1,4-dihydro-indeno [1,2-c] pyrazole,

3- [3- (2-hydroxyethoxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole, 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetic acid , 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetic acid ethyl ester,

3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide

N- (2-diethylaminoethyl) -3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide, N- (2-morpholinoethyl) -3- (1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) phenoxyacetamide, 4- (3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butanoic acid, ethyl 4- (3- (1) , 4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenoxy} butanoic acid,

4- (3- (1,4-dihydroindeno (1,2-c) pyrazol-3-yl) phenoxy) benzamide,

N- (2-diethylaminoethyl) -4- {3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butyramide ₁ N- (2-morpholinoethyl) -4- (3- ( 1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) phenoxy} butyramide, 3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide,

N-methyl-3- (2-thienyl) -1,4-dihydro-indeno [1,2-c] pyrazole-6-carboxamide,

N- (2-morpholinoethyl) -3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazole-6-carboxamide,

3- (2-thienyl) -1,4-dihydro-indeno [1,2-c] pyrazole-6-carboxanilide;

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -acetamide,

3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-ylamine

3- (4-nitrophenyl) -1,4-dihydroindeno [1,2-c] pyrazole,

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) aniline,

4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) pyridine 1-oxide,

3- (2-chloro-4-pyridyl) -4,5-dihydro-1 H -benzo [g] indazole,

4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridinecarbonitrile,

• · · · · · · · · · · · · ·

4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridinecarboxamide oxime,

4- (4 _L 5-dihydro-1 H-benzo [g] indazole-3-yl) -2-pyridinecarboxamide, {^ - ^. S-dihydro-IH-benzoIglindazol-S ^ YLJ -pyridyljmetylJamóniumchlorid, N - {[ 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridyl] methyl} formamide.

2- (3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenoxy] ethanol,

2-morpholinoethyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoate,

3- (3-nitrophenyl) -1,4-dihydroindeno [1,2-c] pyrazole,

3- (4-tiometoxyfenyl) -1,4-dihydro-indeno [1,2-c] pyrazole,

3- (2-naphthyl) -1,4-dihydroindeno [1,2-c] pyrazole,

3- (4-difluoromethoxy-phenyl) -1,4-dihydro-indeno [1,2-cJpyrazol,

3- (4-acetamidophenyl) -4,5-dihydro-2H-benz [g] indazole,

3- (4-bromo-2-thienyl) -4,5-dihydro-indeno [1,2-cJpyrazol,

3- (4-Benzyloxyphenyl) -4,5-dihydro-2H-benz (g) indazole

6,7-dimethoxy-3- (3-phenoxyphenyl) -1,4-dihydro-indeno [1,2-c] pyrazole,

5 ^ -is-trifluoromethyl--pyridyloxyJfenylJ ^ M ^ dihydroindenoll -cJpyrazol, 6,7,8-trimethoxy-3- (2 _I, 3,4-trimethoxyphenyl) -1,4-dihydro-indeno [1,2-c] pyrazole,

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxymethyl) phenol, 2-methoxy-5- (1,4-dihydroindeno [1,2-c] pyrazol-3) yl) phenol,

2-chloro-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenol,

2-Methoxy-4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol

3-Chloro-4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol

2- (4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] acetamide,

4 '- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) Diethylaminoacetanilide.

4- (1H- [11benzothieno [3,2-c] pyrazol-3-yl) benzamide,

3- (4-aminophenyl) -1H- [1] benzothieno (3,2-c) pyrazole,

3- (4-methoxyphenyl) -1 H -benzo [3,2-c] pyrazole,

-31 y.

3- (4-hydroxyphenyl) -1H- [1] benzothieno [3,2-c] pyrazole,

N- (3-phenyl-1,4-dihydro-indeno [1,2-cJpyrazol-6-yl) benzamide,

N- (2-morpholinoethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile,

7-methoxy-3- (4-methylsulfonylphenyl) -4,5-dihydro-2H-benz [g] indazole,

4-methyl-3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-4-ol,

N-P-In.na-dietylaminoJetylH-im-dihydroindenoíl -cjpyrazol ^ S-yObenzamid,

N- [2- (N, N-dimethylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-p-In.na dipropylaminoJetylH-OAdihydroindenotl -cjpyrazol ^ S-yObenzamid,

N- [2- (N, N-diisopropylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N - ^ - CN.N dietylaminoJpropylH-Il ^ ^ -dihydroindenotl -cJpyrazol-S-yObenzannid,

N- [3- (N, N-dimethylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (N, N-dipropylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N43- (N, N-dHzopiOpylamino) pľOpyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-Piperidinoethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-piperidino-propyl) -4- (1,4-dihydro-indeno [1 _t2-c] pyrazol-3-yl) benzamide,

N- (2-morpholinoethyl) -4- (1 ₁ 4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-morpholino-propyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [2- (piperazin-1-yl) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (piperazin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [2- (pyrrolidin-1-yl) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (pyrrolidin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [2- (4-methylpiperazin-1-yl) ethyl 4- (1,4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) benzamide,

N- [3- (4-methylpiperazin-1-yl) propyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

-32 ··

N-p-L-ítiomorfolin ylJetylH-OAdihydroindenoII -cjpyrazol ^ S-yObenzamid,

N-Ts-L-ítiomorfolin-yOpropylH-OAdihydroindenotl -clpyrazol ^ S-yObenzamid,

N- [2- (homopiperazine-1-yl) ethyl] -4- (1,4-dihydiOindeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (homopiperazine-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-P-L-Íperhydroazepin ylJetylH-im-dihydroindenon -clpyrazol ^ S-yObenzamid,

N- [3- (perhydroazepin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-isopropyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-but-2-yl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-methyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-ethyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-pentyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-bromoethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (3,3,3-trifluoro] uórpiOp-1-yl-4- (1,4-dihydiOÍndeno [1,2-c] pyrazol-3-yl) benzamide,

N- (cyclopropylmethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N-cyclopentyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (cyclohexylmethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-chlórcyklopentyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (N, N-dimethylamino) -2,2-dimethylpropyl] -4- (1H-dihydroindenone-4-pyrazol-1-y) benzamide,

N- [3- (2-methylpiperidin-1-yl) propyl] -4- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) benzamide,

N- (3-methyl-but-2-yl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [2- (pyrrolidin-1-yl) ethyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (N, N-dimethylamino) prop-2-yl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-hexyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

-33 ··

B «· i i i i i i i i

· ·

N-tert-butyl 4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2-methylbut-2-yl) -4- (1,4-dihydroindeno [1,2-c] pyrazole-4-yl) -N-1'-N, N-dimethylamino-4-heptyl-1-adihydroindeno [1,2-c] pyrazol-5-yl 3-yl) benzamide, N- (2-pentyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

N-sec-butyl-4- (1,4-dihydroindeno [l, 4-pyrazol-S-yl] benzamide,

N- (3,3-dimethylbutyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2,2,3,3,3-pentafluoro-propyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide _l

N- (2,5-dichlórpentyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- (2,2-difluoroethyl) -4- (1 _l 4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide _l

N- (2-chloroethyl) -4- ( _1,4 -dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

N-P-In.na-dimetylaminoJpropylH-im-dihydiOindenon -cJpyrazol ^ S-yObenzamid,

N- (3-morpholino-propyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

N- [3- (pyrrolidin-1-yl) propyl] -4- (1,4-dihydiOÍndeno [1,2-c] pyrazol-3-yl) benzamide,

4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) piperidinoacetanilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-methylpiperazin-1-ylacetanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-methylhomopiperazin-1-ylacetanilide

4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) piperazin-1-ylacetanilide,

4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) homopiperazin-1-ylacetanilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) dipropylaminoacetanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) dimethylaminoacetanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) fluoroacetanilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3,5-difluorobenzylanilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-fluorobenzylanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-fluorobenzylanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3-fluorobenzylanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,4-difluorobenzylanilide,

-34 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • · · · · · · · · ·

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,5-difluorobenzylanilide,

4 '(1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) _-2) 3-difluórbenzylanilid,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-nitrobenzylanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3-nitrobenzylanilide

4 '- (1,4-dihydroindeno [1 H -pyrazol-5-yO-S.S.-trifluoropropananilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) isobutananilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) isopentananilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-methylbutananilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-methylpentananilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-ethylbutananilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) neopentylanilide

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4,4-dimethylpentananilide

4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) cyclohexananilide,

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) trifluoroacetanilide,

4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pentafluoropropananilide, fluoro-N- (3-phenyl-1-adihydroindeno [1,2-c] pyrazol-6-yl) acetamide,

3,5-difluoro-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide,

4-fluoro-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide,

2-fluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide,

3-fluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide,

2,4-Difluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide

2,3-difluoro-N- (3-phenyl-1 _l 4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide,

2,5-Difluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide

4-nitro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide; 3-nitro-N- (3-phenyl-1,4-dihydroindeno [1, 2-c] pyrazol-6-yl) benzylamide,

5.5.5-Trifluoro-N-5-phenyl-N-dihydroindeno-4'-pyrazol-e-ylpropanamide,

-35 · 9 9 9 9 9 9 9 9 · · ·

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) izobutanamid.

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) izopentanamid.

2-methyl-N- (3-phenyl- _1,4 -dihydroindeno [ _1,2 -c] pyrazol-6-yl) butanamide,

2-methyl-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) pentanamide,

2-ethyl-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) butanamide,

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) neopentanamid.

4,4-dimethyl-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) pentanamide, N- (3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol-6-yl) cyclohexanecarboxamide, trifluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide, pentafluoro-N- (3-phenyl- 1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) propanamide;

4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide

2-hydroxy-N- (2-morpholinoethyl) -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- (2-morpholino-propyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [2- (pyrrolidin-1-yl) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-Hydroxy-N- [3- (pyridin-1-yl) propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

N- [2- (N, N-diethylamino) ethyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -2-hydroxybenzamide,

N- [3- (N, N-diethylamino) propyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -2-hydroxybenzaldehyde amide,

2-hydroxy-N- [2- (N, N-dimethylamino) ethyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benz amide,

2-hydroxy-N- [3- (N, N-dimethylamino) propyl-5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [2- (N, N-dipropylamino) ethyl-5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

• ·· • · · • ·· • · · · · • · • e • · · · · • · • · ··· 9 99 9 9 9 • t • · ·· ·· · · 99 ·· ·

2-hydroxy-N- [2- (N ₁ N-di-isopropylamino) ethyl] -5- (1,4-dihydroindeno [1,2- c] pyrazol-3-yl) -benzamide,

2-hydroxy-N- [3- (N ₁ N-dipropylamino) propyl] -5- (1,4-dihydroindeno [1,2- c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [3- (N, N-di-isopropylamino) propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -benzamide,

2-hydroxy-N- (2-piperidinoethyl) -5- ( _1,4 -dihydroindeno [ _1,2 -c] pyrazol-3-yl) benzamide ₁

2-hydroxy-N- (2-piperidino-propyl) -5- (1,4-dihydro-indeno [1 2 _{I-cJpyrazol-3-yl)} benzamide,

2-hydroxy-N- [2- (piperazin-1-yl) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [3- (piperazin-1-yl) propyl] -5- ( _1,4 -dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [2- (4-methylpiperazin-1-yl) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [3- (4-methylpiperazin-1-yl) propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -benzamide,

2-Hydroxy-N- [2- (thiomorpholin-1-yl) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [3- (thiomorpholin-1-yl) petroleum] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [2- (homopiperazine-1-yl) ethyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benz amide,

2-hydroxy-N- [3- (homopiperazine-1-yl) propyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -benzamide,

2-hydroxy-N- [2- (perhydroazepin-1-yl) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [3- (perhydroazepin-1-yl) propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -benzamide,

4- (1 _l 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (2-morfilinoetyl) aniline • _I · · · · · • • • · · · · ·

-37 ·· ·· ···························

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (2-morfilinopropyl) aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (2-piperidinoethyl) aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (2-piperidino-propyl) aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (tiomorfilin1-yl) ethyl] aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (tiomorfilin1-yl) propyl] aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (piperazin-1-yl) ethyl] aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (piperazin-1-yl) propyl] aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin-1-yl) ethyl] anilino,

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin-1-yl) propyl] amino,

N- [2- (N, N-diethylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) aniline,

N- [3- (N, N-diethylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (N, N-dipropylamino) ethyl] aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [3- (N, N-dipropylamino) propyl] aniline,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (N, N-dimethylamino) ethyl] aniline,

4- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) -N- [3- (N, N-dimethylamino) propyl] aniline, 4- (6-acetamido-1,4-methyl ester) -dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid,

N- (3-methoxypropyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide,

4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (4-nitrophenyl) benzamide,

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) morpholinoacetamide,

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) morpholinoacetamide,

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) piperidinoacetamide.

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) thiomorpholinoacetamide.

N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -4-methylpiperazin-1-ylacetamide; - (c) pyrazol-6-yl) piperazin-1-ylacetamide, 2- (N) - (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) pyrrolidin-1-ylacetamide; , N-diethylamino) -N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -acetamide,

-38 · 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38 38

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -2- (dimethylamino) acetamide,

N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -2- (dipropylamino) acetamide,

4- (6-amino-1,4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) -N- [2- (N _I, N-diethylamino) ethyl] benzamide,

3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole,

3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole,

3- [3- (3-morpholinopropoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole,

3- [3- (2-piperidino-ethoxy) -phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole,

S-tS-IS-piperidinopropoxyJfenylj-IA-cJpyrazol dihydroindenoíl ^.

3- {3- [2- (piperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole,

3- {3- [3- (piperazin-1-yl) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [3- (4-methylpiperazin-1-yl) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (homopiperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [3- (homopiperazin-1-yl) propoxy] phenyl -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (4-methylhomopiperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [3- (4-methylhomopiperazin-1-yl) -propoxy] -phenyl} -1,4-dihydro-indeno [1,2-c] pyrazole,

S-fS - ^ - In.na-dietylaminoJetoxyjfenylJ-IA-dihydroindenotl ^ clpyrazol,

3- {3- [3- (N, N-diethylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, S-fs-4-N, N-dimethylamino] ethoxy] phenyl} -1H-dihydroindenone-4-pyrazrazole .

S-fS-CI-In.na-dimetylaminoJpropoxyJfenylJ-IA-dihydroindenoIl ^ clpyrazol,

S-fS-p-In.na dipropylaminoJetoxylfenylJ-IA-dihydroindenotl ^ clpyrazol,

S-β-β-N, N-dipropylamino-propoxy-phenyl-1 H -dihydroindenol-4-pyrazole, dihydroxy 4- (4H-indeno- [1,2-c] pyrazol-3-yl) phenylborane,

4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) benzaldehyde,

4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) -N- [3- (imidazol-1-yl) propyl] benzylamine trihydrochloride.

-39 · · 39 39 -39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 39 · 4- (4-oxo-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid methyl ester,

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide oxime,

3- {4 - [(2-diethylaminoethyl) aminomethyl] phenyl} -1,4-dihydroindeno [1,2-c] pyrazole trihydrochloride

N- [4- (1,4-dihydro-indeno [1,2-c] pyrazole-3-yl) phenyl] benzenesulfonamide,

N- (2-morpholinoethyl) -4 ' -dihydroindeno [1,2-c] pyrazol-3-ylaniline dihydrochloride,

N- (1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2-morpholinoacetamide, N- (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ylamine trihydrochloride, 4 '- (1-acetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide, 3- [4- (2-morpholinoethoxy) phenyl] -1, 4-Dihydroindeno [1,2-c] pyrazole, 3- [2- (2H-1,2,3,4-tetraazol-5-yl) -4-pyridyl] -4,5-dihydro-2H-benzo [ g] indazole, 3- (4-isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole,

2- (diethylamino) ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-1) phenyl] carbamic acid ethyl ester,

2-morpholinoethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate;

3- (dibenzylamino) propyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate,

2- [ethyl (2-hydroxyethyl) amino] ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate,

N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate, 2 - [[2- (dimethylamino) ethyl] (methyl) amino] ethyl ester,

1-methyl-2-propoxyethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate,

2- (1-methyltetrahydro-1H-2-pyrrolyl) ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate,

2- [2- (dimethylamino) ethoxy] ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate,

-40 · · 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 40 9 40 9

999 99 99 99 99

2- (diethylamino) -1-methylethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate,

N- [2- (diethylamino) ethyl] -N '- [4- (1,4-dihydiOÍndeno [1,2-c] pyrazol-3-yl) -phenyl] nnočovina,

N- [4- (1,4-dihydro-indeno [1,2-cJpyrazol-3-yl) phenyl] -N '- (2-morpholinoethyl) urea,

N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -1-piperidinekarboxamid,

N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2- (dimethylamino) -1-methylethyl] urea,

N-p'HM dihydroindenoP ^ -clpyrazol yOfenyll-S-N-tetrahydro--furanylmetylmočovina,

N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2-furylmethyl) urea;

N- (1,3-benzodioxol-5-ylmethyl) -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea,

N-cyclobutyl-N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea,

N - ^ - ^ ~ M-dihydroindenotl -cjpyrazol yOfenyll-S-N '- ^ - piperidinoetyOmočovina,

N-benzyl-N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea,

N- [4- (diethylamino) butyl] -N '- [4- (1,4-dihydiOÍndeno [1,2-c] pyrazol-3-yl) phenyl] urea,

N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2- (2-thienyl) ethyl] urea,

N- [3- (diethylamino) propyl-N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea,

N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [(1-ethyltetrahydro-1'-2-pyrrolyl) methyl] urea,

N- (2,5-difluorobenzyl) -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea,

N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2- (2-hydroxyethoxy) ethyl] urea,

N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2-hydroxy-1- (hydroxymethyl) ethyl] -urea,

N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2,3-dihydroxypropyl) urea,

-41 • ································· · · «· · · · · · ·

N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4- (2-pyridyl) -1-piperazinecarboxamide.

N - ^ - ^ -dihydroindenoII.Z clay-cJpyrazol-S-ylJfenylJ-N-P-N-methyl-ídimetylaminoJpropylJ urea,

N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -1-azetánkarboxamid,

N- 1- (4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl) -4- (4-fluorophenyl) -1-piperazinecarboxamide,

N-benzyl-N '- ^ - ^ im-dihydroindenofl -cJpyrazol yOfenylj-S-N-methylurea,

N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N-ethyl-N- (2-hydroxyethyl) urea,

N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4- (2-methoxyphenyl) -1-piperazinecarboxamide.

N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N- [2- (dimethylamino) ethyl] -N-methyl urea,

NI - ^ - ^ CM-dihydroindenotl -cjpyrazol yQfenylH-S-methyl-l-piperazinecarboxamide,

N1 - [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4- (4-hydroxyphenyl) -1-piperazinecarboxamide,

N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4 - [(E) -3-phenyl-2-propenyl] -1piperazínkarboxamid,

N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4-phenyl-1-piperazinecarboxamide.

^N - [4- (1 _l 4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) phenyl] -N, N-di (2-methoxy-ethyl) -urea,

N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N- (2,3-dihydroxypropyl) -Nmetylmočovina.

N, N-dip-CdietylaminoJetylj-N - ^ - ^ OAdihydroindenon -cJpyrazol-S-yOfenyl] -urea,

N- [4- (1,4-dihydroindeno [1H-pyrazol-5-yl] phenyl] -N'-4-pyridylmethyl urea, N- [4- (1,4-dihydroindeno [1H-pyrazol-S-yl] phenyl] -N '- 4-pyridylmethylurea, N- [4- (1,4-dihydroindeno [1H-pyrazol-5-yl] phenyl] -N-N '- ^ - hydroxyetyOmočovina,

-42 ·· ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ·· ·>

N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [7- (dimethylamino) heptyl] urea and pharmaceutically acceptable salts and tautomers thereof.

Other specific compounds of formula I that are represented by the formula are shown in the tables below. The pharmaceutically acceptable salts and tautomers of these compounds are also included within the scope of the present invention.

X = FCH _{2) n}

-43 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ·· ·· ·? ·

Table 1 -

R ³ R ¹ R * ^f R ^o n R H 1 2 - S-. 5-NO at A A 1 3-NCB 6 ₃ 7- (OMe) 2 1 3-OPh H 1 4-SMe H ¹ N-Λ 4—0 — ¾ CFj H 1 3-OMe-OH.4 H 1 4-OH, 3-onie H 1 2-OH 6,7- (OMs) 2 1 4-Me? H 1 '-XJ 6,7,8- (OMe) ₃ 1 2,3,4- (OMe) 3 The 1 4-OCHF 2 H 1 4-OH, 3,5- (But) ₂ The 2 4-NHAc H 2 4-OCH? CH = CH2 H 2 4-NEt 2 H 2 4-NCB H 2 4-OCH 2 Ph H 2 4-CN H 2 2-C1,5-NO2

X = (CH ₂ ) n 'Table 2

-S _G R. R R R n 1 R 6-AcNH 1 A H 1 cf ₃ H 1 z ^Br -V 7-OMe 2 H 2 JA.

t \) ··

-45 ··· · 9 · 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·

R ¹ = Η

R X R ³ . R ⁴ . R '. R ' 4- (Ph) phenyl ch ₂ H 4- (OPh) phenyl ch ₂ H 4- (SO ₂ Me) phenyl (CH ₂ ) ₂ R ⁴ = MeO 3- (CO ₂ H). 4 (0H) phenyl ch ₂ H 3- (NO ₂ ), 4- (OH) phenyl ch ₂ H 3- (OCH ₂ CONH ₂ ) phenyl ch ₂ H 4- (OCH ₂ Ph) phenyl ch ₂ R ⁴ . R '= (MeO) ₂ 4- (OCH ₂ Ph) phenyl ch ₂ R = MeO 4 (0H) phenyl ch ₂ R ^4, R = ^p (MeO) ₂ 3- (CONH (CH ₂ ) ₂ MOR), 4 (OH) phenyl ch ₂ H 3- (CONH (CH ₂ ) ₂ NEt ₂ ), 4 (OH) phenyl ch ₂ H 4- (Br) phenyl ch ₂ H 4 (OH) phenyl ch ₂ R ⁴ = MeO 4- (CONH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ H 4- (CONH (CH _{2) 2} OMe) phenyl ch ₂ H 4- (CONH (4-NO ₂ Ph)) phenyl ch ₂ H 4 (OH) -phenyl ch ₂ ^And R = MeO 4- (CONH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ R ⁴ = NH ₂ 4- (Br) phenyl with H 4 (OH) -phenyl ch ₂ R 0 = ^J _{{CH2) 2} 0me

-46 · · 46 46 46 46 46 46 46 46 46 46 46 · 46 46 46 46 46 46 46 46 · ··· ·· · ··· F

4- (SO ₂ NH (CH ₂ ) ₂ MOR) phenyl ch ₂ H 4- (SO ₂ NH (CH ₂ ) ₂ OMe) phenyl ch ₂ H 3- (CH ₂ NMe ₂₎ 4 (OH) -phenyl ch ₂ H 4 (OH) -phenyl ch ₂ R ^J = O (CH _{2) 2} MOR 4- (SO ₂ NH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ H 4- (OCH ₂ CONH ₂₎ phenyl ch ₂ R ^J = O (CH ₂ ) ₂ OMe 4 (OH) -phenyl ch ₂ Rf = (OH). R ⁵ = O (CH ₂ ) ₂ OMe 4 (OH) -phenyl ch ₂ R-O (CH _{2) 2} OMe 4- (CONH (CH _{2) 2} NHEt) phenyl ch ₂ H 4- (CONHCH ₂ -2-pyr) phenyl ch ₂ H 4- (OCH ₂ CONH ₂₎ phenyl ch ₂ ^RJ = OH 4- (OCH ₂ CO ₂ H) phenyl ch ₂ H

I

X NRR ' CH2 NHN-Ci2H25 CK2 hn— ^OMe CH2 CH2 CH2 •"ABOUT CH2 CH2 ~ jq

-47 ·· • 9 9 9

9,999 9 9 9

998 99 ·· «· *

CH2 M CH2 \ = N CH2 HU H ⁿ VH • w CH2 CH2 0 HN ~ ° ^{? e} 0 H K 'e 0 0 "N-θ ABOUT HN— iMe ₂ ABOUT «U. 0 T; _N 0 WITH \ _y WITH ^HN ^ _eJ WITH ^hn -O with HN- ^ £ with HN- with CH2 NHIS-Pr

-48 »« 48 48 48 48 48 48 48 48 48 48 E

CH2 NHcyc-PR CH2 NHN-Hex CH2 CH2 Ό CH2 f- \ N NMe CH2 / ~ Λ N 0 VJ CH2 ΗΝ - ^ - ΟΜβ CH2 ^ην Ό ^ - ° ^η CH2 ν-ά HM-0 CH2 HN-0 CH2 CH2 k / ^NH CH2 ^HN V 0 about ABOUT HN- ABOUT HN. NMe ₂ 0 \ _t

-49 · · 49 49 49 49 49 49 49 49 49 49 49

X NRR ' CH2 CH2 about CH2 / ~ A N Kl 'e \ _y CH2 CH2 CK2

The present invention further encompasses the use of these compounds in pharmaceutical compositions with a pharmaceutically effective amount of the compounds described above and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions may be administered to individuals to retard or delay the process of angiogenesis in angiogenesis-promoting diseases or to treat edema, effusion, exudates or ascites and other conditions associated with vascular hyperpermeability.

-50 ··· ···································· · ·

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the invention exhibit anti-angiogenic properties. These anti-angiogenic properties are due, at least in part, to the inhibition of protein tyrosine kinases, essential for angiogenic processes. Therefore, these compounds can be used as active agents against such disease states as arthritis, atherosclerosis, psoriasis, hemangioma, myocardial angiogenesis, coronary and cerebral collateral, ischemic limbal angiogenesis, wound healing, peptic ulceration of Helicobacter-related fractures, Helicobacter cat scratch fever, rubeosis, neovascular glaucoma, and retinopathy such as diabetic retinopathy associated with diabetic retinopathy, premature retinopathy or age-related macular degeneration. In addition, some of these compounds may be used as active agents against solid tumors, malignant ascites, hematopoietic malignancies and hyperproliferative diseases such as thyroid hyperplasia (especially Grave's disease), and cysts (such as hypervascular ovarian stroma (polycystic syndrome) Stein-Leventhal syndrome)), such diseases require the proliferation of blood vessel cells for growth and / or metastasis.

In addition, some of these compounds may be used as effective agents against burns, chronic pulmonary diseases, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumors associated with scerebral edema, high altitude, trauma or cerebral hypoxia pulmonary edema, ocular and macular edema, ascites and other diseases in which the disease is manifested by vascular hyperpermeability, effusion, exudates, protein extravasation, or edema. The compounds will also be useful in the treatment of diseases in which protein extravasation results in the deposition of fibrin and extracellular matrix while promoting proliferation by trees (e.g., fibrosis, cirrhosis and carpal canal syndrome).

VEGFs are specific in that they are the only angiogenic growth factors known to contribute to vascular hyperpermeability and edema formation. In fact, vascular hyperpermeability and edema that is associated with the expression or administration of many other growth factors appears to be ···

-51 • ·· ·

• mediated through VEGF production. Inflammatory cytokines stimulate VEGF production. Hypoxia results in a significant upregulation of VEGF in numerous tissues, hence situations involving heart attack, occlusion, ischemia, anemia or impaired circulation typically elicit VEGF / VPF mediated responses. Vascular hyperpermeability, associated edema, altered transendothelial exchange and macromocular extravasation, which are often accompanied by diapedesis, may result in excessive matrix deposition, abnormal stromal proliferation, fibrosis, and the like. Therefore, VEGF-mediated hyperpermeability may significantly contribute to diseases with these ethnological characteristics.

It is expected that the above-mentioned diseases are mediated to a significant extent by the activity of a protein tyrosine kinase comprising KDR / VEGFR-2 and / or Flt-1 / VEGFR-1 tyrosine kinase. By inhibiting the activity of these tyrosine kinases, the progression of these diseases is inhibited since the angiogenic or vascular hyperpermeable component of this disease state is severely occluded. The effect of the compounds of the invention, due to their selectivity for specific tyrosine kinases, results in minimization of the side effects that might occur if less selective tyrosine kinase inhibitors are used.

The compounds of the present invention exhibit protein kinase inhibitory activity. That is, these compounds modulate signal transduction by protein kinases. The compounds of the present invention inhibit protein kinase from the serine / threonine and tyrosine kinase classes. In particular, these compounds selectively inhibit the activity of KDR / FLK-1 / VEGFR-2 tyrosine kinases. Certain compounds of the invention also inhibit the activity of other tyrosine kinases such as Flt1 / VEGFR-1, Src-subfamily kinases such as Lck, Src, fyn, yes, and the like. In addition, some of the compounds of the invention significantly inhibit serine / threonine kinases, such as CDKs, which play an essential role in cell cycle progression. The efficacy and specificity of the generic compounds of the invention against the respective protein kinase can often be varied and optimized by variations in nature, number and arrangement of substituents (ie, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ ) and conformational constraints. In addition, metabolites of certain compounds may also exhibit significant protein kinase inhibitory activity.

· · · · · · · · · · · · · · · · · · · · · · · · · · · ·

-52 ·· • u

The compounds of the present invention, when administered to an individual in need of such compounds, inhibit vascular hyperpermeability and edema formation in such individuals. These compounds act, as predicted, by inhibiting the activity of KDR tyrosine kinase, which is involved in the process of vascular hyperpermeability and edema. KDR tyrosine kinase can 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 (VEGF) or another activating ligand (such as VEGF-C, VEGF-D or HIV Tat protein) binds to the KDR receptor tyrosine kinase, which lies on the surface of vascular endothelial cells. Upon such activation of KDR tyrosine kinase, blood vessel hyperpermeability occurs and fluid moves from the bloodstream beyond the walls of the blood vessels to the interstitial spaces, creating an edema area. Diapedesis is often an accompanying feature of this response. Similarly, excessive vascular hyperpermeability can disrupt normal molecular exchange through the endothelium in critical tissues and organs (e.g., lungs and kidneys), causing macromolecular extravasation and deposition. Following this acute response to KDR stimulation, which is believed to facilitate the subsequent angiogenic process, prolonged KDR tyrosine kinase stimulation results in proliferation and chemotaxis of vascular endothelial cells and formation of new vessels. By inhibiting KDR tyrosine kinase activity, either by blocking the production of the activating ligand, blocking the binding of the activating ligand to the KDR receptor tyrosine kinase, preventing dimerization and transphosphorylation of the receptor, inhibiting the enzymatic activity of KDR tyrosine kinase (inhibiting the phosphorylation function of the enzyme) Mukhopedhyay et al., Cancer Res. 58: 1278-1284 (1998) and references therein), can be inhibited with minimized hyperpermeability, as well as associated extravasation, subsequent edema formation and matrix deposition, and angiogenic responses.

One group of preferred compounds of the present invention exhibits the property of inhibiting KDR tyrosine kinase activity without significantly inhibiting Flt1 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 binding of VEGF to KDR tyrosine kinase receptors and to Fit-1 tyrosine kinase receptors. Because Flt-1 tyrosine kinase activity may mediate significant events in endothelial ···

While maintaining and vascular function, inhibition of this enzymatic activity may lead to toxic or inverse effects. At least, such inhibition is not necessary for blocking the vascular response, inducing vascular hyperpermeability, and producing edema, so that it is unnecessary and of no value to the individual. Certain preferred compounds of the invention are unique in that they inhibit the activity of one VEGF receptor tyrosine kinase (KDR), which is activated by activating ligands, but does not inhibit other receptor tyrosine kinases, such as Flt-1, which are also activated by certain activating ligands. Preferred compounds of the invention are therefore selective with respect to their tyrosine kinase inhibitory activity.

The compounds of the present invention are also useful in the treatment of ulcerative-bacterial, fungal, Mooren's ulcerative and ulcerative colitis.

The compounds of the present invention are also useful in the treatment of conditions in which undesirable angiogenesis, edema or stromal deposition occurs in viral infections such as Herpes simplex, Herpes Zoster, AIDS, Kaposi's sarcoma, protozoal infections and toxoplasmosis, endometriosis, ovarian hyperstimulation syndrome, ovarian hyperstimulation syndrome, lupus erythematosus, sarcoidosis, synovitis, Crohn's disease, sickle cell anemia, Lyme's disease, pemphigoid, Paget's disease, hyperviscosity syndrome, Osler-Weber-Rend's disease, chronic inflammation, chronic occlusive pulmonary disease, asthma, rheumatoid arthritis and rheumatoid arthritis and rheumatoid arthritis trauma, irradiation or stroke.

The compounds of the present invention are also useful in the treatment of ophthalmic conditions such as ocular and macular edema, ocular neovascular disease, scleritis, radial keratotomy, uveitis, vitritis, myopia, papilla ophysiological excision, chronic retinal detachment, post-laser junction, post-laser complications disease and Eales' disease, except macular retinopathy and degeneration.

The compounds of the present invention are also useful in the treatment of cardiovascular conditions such as atherosclerosis, restenosis, vascular occlusion and carotid obstructive disease.

-54 • ··············

• i: ii: i

··· ·· ·· ·· ·

The compounds of the present invention are also useful in the treatment of cancer-related indications such as 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 useful in the treatment of diabetic conditions such as glaucoma, diabetic retinopathy and microangiopathy.

It is believed that the aforementioned diseases are significantly mediated by protein tyrosine kinase activity including VEGF receptors (e.g. KDR and Flt-1). By inhibiting the activity of these receptor tyrosine kinases, the progression of the above-mentioned diseases is inhibited since the angiogenic component of the disease state is severely reduced. The effect of the compounds of the invention, due to their selectivity for specific tyrosine kinases, results in the minimization of side effects that could occur if less selective tyrosine kinase inhibitors were used.

The present invention relates to compounds of formula I as defined above (including limitations) for use as medicaments, in particular as inhibitors of protein kinase activity, for example tyrosine kinase activity, serine kinase activity and threonine kinase activity. Still further, the present invention relates to the use of compounds of formula I as defined in the introduction (including limitations) for the manufacture of a medicament for use in inhibiting protein kinase activity.

The following definitions apply in the present invention:

Pharmaceutically acceptable salts refer to those salts which retain the biological activity and properties of the free bases and which are obtainable by reaction with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or organic acids such as acid. sulfonic acid, carbonic acid, organic phosphoric acid, methanesulfonic acid, ethanesulfonic acid, ptoluenesulfonic acid, salicylic acid, lactic acid, tartaric acid and the like.

Alkyl refers to a saturated aliphatic hydrocarbon, including straight and branched chain groups containing 1 to 4 carbon atoms.

Alkoxy refers to an O-alkyl group wherein alkyl is defined as described above.

Pharmaceutical preparations

The compounds of the present invention may be administered to a human patient alone or in pharmaceutical compositions in which they are mixed with suitable carriers or excipient (s) in doses to treat or ameliorate vascular hyperpermeability, edema, and associated diseases. Mixtures of these compounds may also be administered to the patient in the form of a simple mixture or in suitably formulated pharmaceutical compositions. The therapeutically effective dose further represents an amount of the compound or compounds sufficient to result in prevention or attenuation of inappropriate neovascularization, progression of hyperproliferative diseases, edema, VEGF-related hyperpermeability and / or VEGF-related hypotension. Methods for modifying and administering the compounds of the present application can be found in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, last edition.

Routes of administration

Suitable routes of administration may include, for example, oral administration, ocular instillation, rectal, transmucosal, topical or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal or intraocular injections.

Alternatively, the compound may be administered in a topical rather than systemic manner, for example, by injecting the compound directly into the oedematous site, often in a sustained-release formulation or a sustained release formulation.

In addition, the drug may be administered in the form of a targeted drug delivery system, for example, in a liposome coated form with an endothelial cell-specific antibody.

-56 ··

Composition / Preparation

The pharmaceutical compositions of the present invention may be manufactured in a manner known per se, for example using a conventional process of mixing, dissolving, granulating, dragee-making, finely divided, emulsifying, encapsulating, entrapping or lyophilizing.

Thus, the pharmaceutical compositions for use according to the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers containing excipients and excipients which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Appropriate processing will depend upon the route of administration chosen.

For injection, the agents of the present invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution or physiological buffer. For transmucosal administration, penetrants appropriate to the barrier through which they are to penetrate are used in the formulation. Such penetration agents are generally known in the art.

For oral administration, the compounds can be formulated simply by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers adapt the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, and the like, for oral ingestion for the patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture and processing the mixture of granules, after adding suitable excipients, if necessary, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone (PVP). If desired, disintegrants may be added

Agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid Agents such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate.

Dragee cores are provided with suitable coatings. Concentrated sugar solutions may be used for this purpose, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopole gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings to identify or characterize different combinations of active compound doses.

Pharmaceutical formulations that can be used orally include extrusion capsules made of gelatin as well as soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. The extrusion capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate, and optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

For buccal administration, the compositions may be formulated as tablets or lozenges formulated in conventional manner.

For administration by inhalation, the compounds for use according to the present invention are usually delivered in the form of an aerosol spray form from pressurized packs or a nebulizer using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gases. In the case of pressurized aerosols, the dosage units may be determined by providing a metered delivery valve. Capsules and cartridges, for example gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

-58 • ·

The compounds may be formulated for parenteral administration by injection, for example by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, for example, in vials or in multi-dose containers, with the addition of a preservative. The compositions may be in the form of suspensions, solutions, or emulsions in oil or aqueous compositions, and may contain formulatory agents such as suspending agents, stabilizers and / or dispersing agents.

Pharmaceutical preparations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active compounds in the form of suitable oily injection suspensions may be prepared. Suitable lipophilic solvents or excipients include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleic acid, or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

Alternatively, the active ingredient may be in powder form for use with a suitable excipient, for example sterile, pyrogen-free water, before use.

The compounds may be formulated into rectal compositions such as suppositories or retention enemas containing, for example, conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may also be formulated as sustained-release formulations. Such sustained-release preparations may be administered by implantation (for example, subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or as poorly soluble derivatives, for example, as a poorly soluble salt.

An example of a pharmaceutical carrier for the hydrophobic compounds of the invention is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer, and an aqueous phase. The co-solvent system may be a VPD co-solvent system. VPD is a 3% w / v solution. benzyl alcohol, 8% w / v nonpolar surfactant polysorbate 80 and 65% w / v; polyethylene glycol 300, made up to volume in absolute ethanol. The VPD cosolvent system (VPD: 5W) consists of VPD diluted 1: 1 with 5% dextrose in aqueous solution. This co-solvent system dissolves hydrophobic compounds well and produces low toxicity by systemic administration alone. Naturally, the proportions of the cosolvent system can vary considerably without compromising its solubility and toxicity characteristics. In addition, the identity of the co-solvent components may be varied, for example, other low-toxic non-polar surfactants may be used instead of polysorbate 80; the size fraction of polyethylene glycol may vary; polyethylene glycol can replace other biocompatible polymers such as polyvinylpyrrolidone; and other sugars or polysaccharides may replace dextrose.

Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be used. Liposomes and emulsions are well known examples of excipients or carriers for the administration of hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, may also be used, although usually at the cost of greater toxicity. In addition, the compounds may be administered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained release materials have been formed and are well known to those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for several weeks up to more than 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, other strategies for protein stabilization may be used.

The pharmaceutical compositions may also contain suitable solid carriers 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 such as polyethylene glycols.

Many organic molecular compounds of the present invention may be provided in the form of salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts can be formed with many acids including, but not limited to, hydrochloric acid, sulfuric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid, and the like. The salts tend to have higher solubility in aqueous or other protonic solvents than the corresponding free base forms.

Effective dose

Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredients are contained in an amount effective to achieve the intended purpose. More specifically, a therapeutically effective amount means an amount effective to prevent the development or amelioration of the existing symptoms of the subject being treated. Determination of effective amounts is within the skill of those skilled in the art.

For any compound used in the method of the present invention, the therapeutically effective dose can first be determined from cellular samples. For example, a dose may be formulated in cellular models and animal models to achieve a circulating concentration range that includes IC ₅₀ as determined in cellular samples (ie, the concentration of test compound that achieves half maximal inhibition of said protein kinase activity). In some cases it is appropriate to determine the IC ₅ s presence of 3 to 5% serum albumin since such a determination approximates the binding effects of plasma protein on the compound. Such information may be used to more accurately determine useful doses in humans. In addition, most preferred compounds for systemic administration effectively inhibit signal protein kinase in inactivated cells at levels that can be safely achieved in plasma.

A therapeutically effective dose refers to that amount of the compound that results in amelioration of the symptoms in the patient. The toxicity and therapeutic efficacy of such compounds can be determined using standard pharmaceuticals

-61 procedures in cell cultures or experimental animals, for example to determine the maximum tolerable dose (MTD) and ED ₅₀ (effective dose at 50% of the maximum response). The dose ratio between toxic and therapeutic effects is the therapeutic index and can be expressed as the ratio between MTD and ED ₅₀ . Compounds that exhibit high therapeutic indices are preferred. Data obtained from these cell culture samples and animal studies can be used to formulate a range of dosage for human use. The dose of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized. The exact formulation, route of administration and dose can be selected by the attending physician, taking into account the patient's condition. (See, for example, Fingl et al., 1975, The Pharmacological Basis of Therapeutics, Chapter 1, p. 1). In the treatment of crisis situations, an acute bolus or infusion of impending MTD may be required to achieve a rapid response.

Dosage amounts and intervals can be determined individually to provide plasma levels of the effective fraction that are sufficient to maintain kinase modulating effects or minimally effective concentrations (MECs). MECs will vary for each compound but can be determined from in vitro data; for example, from the concentration required to achieve 50-90% inhibition of protein kinase, using the methods described herein. The dosages required to achieve the MEC will depend on the individual characteristics and route of administration. However, HPLC or bioassays may be used to determine plasma concentrations.

Dosage intervals can also be determined using the MEC value. The compounds should be administered using a regimen that maintains plasma levels above the MEC for 10 to 90% of the time, preferably between 30 and 90%, and particularly preferably between 50 and 90% until the desired symptom improvement is achieved. In cases of local administration or selective absorption, the local drug concentration may not be effective relative to the plasma concentration.

The amount of composition administered will, of course, depend on the subject being treated, the subject's weight, the severity of the disease, the mode of administration, and the judgment of the attending physician.

-62Balenie

The compositions may, if desired, be provided in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. For example, the pack may comprise a metal or plastic foil, such as a blister pack. The pack or dispensing device may be accompanied by instructions for administration. Compositions comprising a compound of the present invention formulated in a compatible pharmaceutical carrier can also be prepared, placed in a suitable container, and labeled, indicating the treatment of the indicated condition.

In some formulations, it may be useful to use the compounds of the present invention in the form of particles of very small size, for example as obtained by fluid grinding.

In the compositions of the present invention, the active compound may, if desired, be associated with other compatible pharmacologically active ingredients. For example, the compounds of the invention may be administered in combination with one or more additional pharmaceutical agents that inhibit or prevent the formation of VEGF, attenuate intracellular responses to VEGF, block intracellular signal transduction, inhibit vascular hyperpermeability, reduce inflammation, or inhibit or prevent formation neovascularization. The compounds of the invention may be administered prior to, sequentially or concurrently with another pharmaceutical agent, any route of administration being appropriate. Other pharmaceutical agents include, but are not limited to, anti-edemic steroids, NSAIDS, Ras inhibitors, anti-TNF agents, anti-IL1 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 such a combination of agents that inhibits angiogenesis, vascular hyperpermeability, and / or inhibits edema formation may provide greater relief of the harmful effects of hyperproliferative disease, angiogenesis, vascular hyperpermeability, or edema than administration of both agents alone. Combinations with antiproliferative or cytotoxic chemotherapy or radiation are contemplated for the treatment of malignant diseases.

-63 ·· ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

The present invention also encompasses the use of compounds of formula I as medicaments.

Both kinases, Src and Syk, play key roles in regulating immune function. The current Src family includes Fyn, Lck, Fgr, Fes, Lyn, Src, Yes, Hck, and Blk. The Syk family is now understood to include only Zap and Syk. The Janus kinase family is involved in the growth factor transduction and pro-inflammatory cytokine signals through a variety of receptors. Although BTK and ITK, members of the Tec kinase family, play a less comprehensible role in immunobiology, their modulation by an inhibitor may prove therapeutically beneficial. RIP, IRAK-1, IRAK-2, NIK, IKK-1, and IKK-2 kinases are involved in signal transduction pathways for key pro-inflammatory cytokines TNF and IL-1. Because of their ability to inhibit one or more of these kinases, the compounds of Formula I may act as immunomodulatory agents useful for the maintenance of allografts and for the treatment of autoimmune diseases. Through their ability to regulate T cell activation or potentiate the inflammatory process, these compounds could be used to treat such autoimmune diseases. Transplants due to the rejection phenomenon, either host versus graft for solid organs or graft versus host for bone marrow, are limited by the toxicity of currently available immunosuppressive agents and would be achieved by obtaining an effective drug with an improved therapeutic index. Genetically directed experiments have demonstrated the essential role of Src in the biology of osteoclasts, the cells responsible for bone resorption. The compounds of formula I, through their ability to regulate Src, may also be useful in the treatment of osteoporosis, osteopetrosis, Paget's disease, tumor-induced hypercalcaemia and bone metastasis.

A variety of protein kinases have been demonstrated to be proto-oncogenes. Chromosome destruction (at the Itk kinase cleavage point on chromosome 5), translocation, as in the case of the Abl gene with BCR (Philadelphia chromosome), truncation in cases such as c-Kit or EGFR, or mutation (e.g., Met) results in the formation dysregulated proteins, being converted from proto-oncogenic to oncogenic products. In other tumors, oncogenesis is driven by autocrine or paracrine ligand / growth factor receptor interactions. Members of the src-kinase family are typically involved in downlink signaling

-64transduction, potentiating oncogenesis and can become oncogenic through overexpression or mutation. By inhibiting the protein kinase activity of these proteins, the disease process can be interrupted. Vascular restenosis may involve a process of FGF and / or PDGF-assisted smooth muscle and endothelial cell proliferation. Inhibition of FGFr or PDGFr kinase activity may be an effective strategy for inhibiting this phenomenon. Thus, compounds of Formula I that inhibit kinase activity of normal or diverse members of c-kit, cmet, c-fms, src-family, EGFr, erbB2, erbB4, BCR-Abl, PDGFr, FGFr, and other receptors or cytosolic tyrosine kinases may be valuable in the treatment of benign and neoplastic proliferative diseases.

In many pathological conditions (such as solid primary tumors and metastases, Kaposi's sarcoma, rheumatoid arthritis, blindness due to inadequate ocular neovascularization, psoriasis and atherosclerosis), disease progression is based on persistent angiogenesis. Polypeptide growth factors often produced by diseased tissues or associated inflammatory cells, and their corresponding endothelial cell specific receptor tyrosine kinases (e.g., KDR / VEGFR-2, Flt-1 / VEGFR-1, Tie-2 / Tek and Tie) are essential for stimulating endothelial growth cells, migration, organization, differentiation and stablization of the need for a new functional vasculature. As a consequence of VEGF “vascular permeability factor” activity in mediating vascular hyperpermeability, VEGF-stimulation of VEGFR kinase is also believed to play a significant role in the formation of tumor ascites, cerebral and pulmonary edema, pleural and pericardial effusions, and hypersensitemia organ dysfunction following trauma, burns, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), post-cardiopulmonary bypass-related hypotension and hyperpermeability, and neural gastrointestinal disease, or eye edema disease . In addition to VEGF, the recently identified VEGF-C and VEGF-D, and the HIV-Tat protein can also cause a vascular hyperpermeability response through VEGFR kinase stimulation. Tie-2 is also expressed in a select population of hematopoietic stem cells, in which it can play a role in their replenishment, adhesion, regulation and

-65 differentiation (Blood 89: 4317-4326 (1997)); this Tie-2 expressing population may serve as a circulating angiogenic endothelial precursor. Certain agents of Formula I capable of blocking the endothelial cell specific kinase kinase activity could therefore inhibit the progression of diseases involving such situations.

The compounds of formula I, or salts thereof, or pharmaceutical compositions containing a therapeutically effective amount thereof, can be used to treat benign and neoplastic proliferative diseases and immune system diseases. Such diseases include autoimmune diseases such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, inflammatory bowel disease, myasthenia gravis and systemic lupus erythematosus; psoriasis, transplanted organ rejection (e.g., kidney rejection, graft versus host disease), benign and neoplastic proliferative diseases, human cancer such as lung, breast, stomach, bladder, colon, pancreas, ovaries, prostate and rectal cancer and malignant tumors (leukemia and lymphoma), and diseases involving inadequate vascularization, for example diabetic retinopathy, retinopathy of prematurity, choroidal neovascularization due to age-related macular degeneration, and infantile hemangioma in man. In addition, such inhibitors may be useful in the treatment of diseases involving VEGF-mediated edema, ascites, effusions and exudates, including, for example, macular edema, cerebral edema, and adult respiratory distress syndrome (ARDS).

The compounds of the present invention may also be useful in the prophylaxis of the above diseases.

The present invention further relates to the use of a compound of formula I or a salt thereof for the manufacture of a medicament for the treatment of vascular hyperpermeability, angiogenesis-dependent diseases, proliferative diseases and / or immune system diseases in mammals, particularly humans.

The present invention also provides a method of treating vascular hyperpermeability, inadequate neovascularization, proliferative diseases and / or immune system diseases, which comprises administering therapeutically.

-66 ··· ···· * · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·. An effective amount of a compound of Formula I to a mammal, particularly a human in need thereof.

The in vitro potency of the compounds in inhibiting these protein kinases can be determined using the procedures detailed below.

The potency of the 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)) using the test compound relative to the control.

Preparation of KDR tyrosine kinase using baculovirus system:

The coding sequences for the human KDR intracellular domain (aa789-1354) were generated by PCR using cDNA isolated from HUVEC cells. The poly-His6 sequence was also introduced at the N-terminus of this protein. This fragment was cloned into the pVL1393 transfection vector at the Xba 1 and Not 1 sites. Recombinant baculovirus (BV) was generated by co-transfection using BaculoGold transfection reagent (PharMingen). Recombinant BV was plaque purified and verified by Western analysis. For protein preparation, SF-9 cells were grown in SF-900-II medium at 2 x 10 ⁶ / ml, and infected at 0.5 plaque-forming units per cell (MOI). Cells were harvested 48 hours after infection.

Purification of the DRC

SF-9 cells expressing (His) ₆ KDR (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 µg / ml aprotin, 1 µg / ml leupeptin) per cell pellet from 1 L cell culture. The lysate was centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 minutes at 4 ° C. The cell lysate was used in a 5 ml NiCb chelating sepharose column, equilibrated with 50 mM HEPES, pH 7.5,

0.3 M NaCl. KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and an ELISA assay (below) to measure kinase activity. The purified KDR was exchanged into 25 mM HEPES, pH 7.5, 25 mM NaCl, 5 mM DTT buffer and stored at 80 ° C.

-67 ································································· · ·· ·

Preparation and purification of human Tie-2 kinase

The coding sequence for the human Tie-2 intracellular domain (aa775-1124) was generated by PCR using cDNAs isolated from the human placenta matrix. A poly-His ₆ sequence was introduced into the N-terminal and this construct was cloned into the pVL 1939 transfection vector at the Xba 1 and Not 1 sites. Recombinant BV was generated by co-transfection using BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and verified by Western analysis. For protein preparation, SF-9 insect cells were grown in SF-900-II medium at 2 x β / ml, and infected at an MOI of 0.5. Purification of His-recipient kinase used in screening was analogous to that described for KDR.

Preparation 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-Hise was located 5 'to the nucleotide region encoding the total intracellular kinase domain of human Flt-1 (amino acids 786-1338). The nucleotide sequence encoding the kinase domain was generated by PCR using cDNA standards isolated from HUVEC cells. Histidine residues allowed affinity purification of the protein in a manner analogous to that for KDR (Part B.) and ZAP70 (Part

F.) SF-9 insect cells were infected at 0.5 abundance and harvested 48 hours after infection.

Sources of Lck and EGFR tyrosine kinases

EGFR was purchased from Sigma (Cat # E-3641; 500 units / 50 μΙ) and EGF ligands were purchased from Oncogene Research Products / Calbiochem (Cat # PF011-100).

ZAP70 Expression

The baculovirus expression vector used was pVL1393 (Pharmingen, Los

Angeles, CA.). The nucleotide sequence encoding amino acids M (H) 6 of LVPR9S was located 5 'to the nucleotide region of total ZAP70 (amino acids 1 to 619).

-68 • ····························· · ··· ·· ·· ·· ·· ·

The nucleotide sequence encoding the ZAP70 coding region was generated by PCR using cDNA standards isolated from Jurkat immortalized T cells. Histidine residues allowed affinity purification of the protein (see below). The LVPR9S bridge constitutes the recognition of the sequence for proteolytic cleavage by thrombin, allowing the removal of affinity labeling from the enzyme. SF-9 insect cells were infected at a frequency of 0.5 and harvested 48 hours after infection.

Extraction and purification of ZAP70

SF-9 cells were lysed in buffer containing 20 nM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 µg / ml leupeptin, 10 µg / ml aprotin, and 1 mM ortovanadate. solution. The soluble lysate was applied to a chelating sepharose Hi Trap column (Pharmacia) equilibrated in 50 mM HEPES, pH 7.5, 0.3 M NaCl. The fusion protein was eluted with 250 mM imidazole. The captured enzyme was stored in a buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.

Source Lck

Lck or truncated forms of Lck can be obtained commercially (e.g., from Upstate Biotechnology Inc. (Saranac Lake, NY) and Santa Cruz Biotechnology Inc. (Santa Cruz, Ca.)) or purified from known natural or recombinant sources using conventional methods. .

Enzyme-linked immunosorbent assay (ELISA) for RTK

Enzyme-linked immunosorbent assays (ELISA) were used to detect and measure the presence of tyrosine kinase activity. ELISAs were performed according to known protocols as described, for example, in Volier, et al., 1980, Enzyme-Linked Immunosorbent Assay, V: Manual of Clinical Immunology, 2d ed., Ed. Rose and Friedman, p. 359-371 Am. Soc. of Microbiology, Washington, D.C.

The published protocol was modified to determine activity with respect to specific

RTK. For example, a preferred protocol for performing ELISA experiments for DRC is shown below. Adaptation of this protocol to determine compound activity

-69 BB B BB

BB B B B B B B B B B B B

BB BB BB BB for other members of the RTK family as well as non-receptor tyrosine kinases are within the capabilities of their prior art. For the determination of inhibitor selectivity, a universal substrate (for example, a random copolymer of poly (Glu ₄ Tyr), with a molecular weight of 20,000 to 50,000) was used together with ATP (typically 5 μΜ) at concentrations approximately approximately twice the apparent Km in the sample.

The following procedures were used to evaluate the inhibitory effect of the compounds of the present invention on KDR, Flt-1, Tie-2, EGFR and ZAP70 tyrosine kinase activity:

Buffers and solutions:

PGT: Poly (Glu, Tyr) 4: 1

Store powder at -20 ° C. Dissolve the powder in phosphate buffered saline (PBS) to a 50 mg / ml solution. Store 1 ml aliquot at -20 ° C. Dilute to 250 μg / ml in Gibco PBS to form plates.

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 aliquots of 100 mM at -20 ° C. Dilute to 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 9: 1 TMB substrate and peroxide solutions immediately prior to use or use Neogen K-Blue substrate

Stop solution: 1 M phosphoric acid

Workflow

1. Preparation of plates

-70 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Dilute PGT stock solution (50 mg / ml, frozen) in PBS to 250 µg / ml. Add 125 μΙ per well of Corning modified high-affinity flat bottom ELISA plates (Corning # 25805-96). Add 125 μΙ PBS to empty wells. Cover with sealing tape and incubate overnight at 37 ° C. Wash 1x with 250 μΙ wash solution and dry for approximately 2 hours in a dry incubator at 37 ° C. Store coated plates in sealed bags at 4 ° C until use.

2. Tyrosine kinase reaction:

- Prepare inhibitor solution at 4x concentration in 20% DMSO in water.

- Prepare reaction buffer

- Prepare the enzyme solution so that the required units are at 50 μΙ, for example for KDR n adjust to 1 ng / μΙ for a total of 50 ng per well in reactions. Store on ice.

- Prepare 4 x ATP solution at 20 μΜ from 100 mM stock solution in water. Store on ice.

- Add 50 μΙ of enzyme solution per well (typically 5 to 50 ng enzyme / well depending on specific kinase activity)

-. Add 25 μΙ 4 x inhibitor

Add 25 μΙ 4 x ATP per inhibitor sample

Incubate for 10 minutes at room temperature

-71 • ································ · ··· ·· ·· ·· ·· ·

- Stop the reaction by adding 50 μΙ 0.05 N HCl per well

- Wash plate ** Final concentrations for reaction; ATP; 5 μΜ, 5% DMSO

3. Antibody binding

- Dilute 1 mg / ml aliquot of PY20-HPR (Pierce) antibody (phosphotyrosine antibody) to 50 ng / ml in 0.1% BSA in PBS by dilution in 2 steps (100 x then 200 x)

- Add 100 μΙ Ab per well. Incubate for one hour at room temperature. Incubate for one hour at 4 ° C.

- Wash 4 plates

4. Color reaction

- Prepare the TMB substrate and add 100 μΙ per well

- Monitor OD at 650 nm until 0.6.

- Stop with 1 M phosphoric acid, Shake on a plate reader.

- Immediately read OD at 450 nm.

Optimal incubation times and enzymatic reaction conditions slightly vary according to enzyme preparations and are determined empirically for each group.

For Lck, a reaction buffer consisting of 100 mM MOPSO, pH 6.5, mM MnCl _2, 20 mM MgCl _2, 5 mM DTT, 0.2% BSA, 200 mM NaVO _{4 was used} under analogous experimental conditions.

Compounds of formula I may have therapeutic utility in the treatment of diseases including, but not limited to, as yet identified as well as previously unidentified protein tyrosine kinases that are inhibited using compounds of formula I. All of the compounds exemplified herein are significantly inhibit KDR kinase at concentrations of 50 micromoles or less. Some of the compounds of the present invention also significantly inhibit other PTKs such as Ick at concentrations of 50 micromoles or less.

-72 • ······································· · ·· ···

Source Cdc2

Human recombinant enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly, MA. USA) or purified from known natural or recombinant sources using conventional methods. Cdc2 test

The protocol used was a protocol that provided the reagents purchased with slight modifications. Briefly, the reaction was performed in a buffer consisting of 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 with fresh 300 μΜ ATP (31 pCi / ml) and 30 pg / ml of lllss-type histone to final concentrations. A reaction volume of 80 µl containing enzyme units was processed for 20 minutes at 25 ° C in the presence or absence of inhibitor. The reaction was terminated by the addition of 120 µL of 10% acetic acid. The substrate was separated from the unincorporated label by applying the mixture to phosphocellulose paper, followed by washing three times for 5 minutes each with 75 mM phosphoric acid. Counts were measured using a beta counter in the presence of a liquid scintillation counter.

Certain compounds of the present invention significantly inhibit cdc2 at concentrations of less than 50 pM.

Source of PKC kinase

The catalytic PKC subunit can be obtained commercially (Calbiochem).

PKC Kinase Assay

The radioactive kinase assay was performed using the following published procedure (Yasuda, I., Kirshimoto, A., Tanaka, S., Tominaga, M., Sakurai, A., Nishizuka, Y. Biochemical and Biophysical Research Communication 3, 166, 1220. 1227 (1990)). Briefly, all reactions were performed in a kinase buffer consisting of 50 mM Tris-HCl pH7.5, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 100 μΜ ATP, 8 μΜ peptide, 5% DMSO and ³³ P ATP ( 8 (Ci / mM). Compounds and enzyme were mixed in a reaction vessel and the reaction was initiated by addition of ATP and substrate mixture. After completion of the reaction by adding 10 μ 10 of stop buffer (5 mM ATP in 75 mM phosphoric acid), a portion of the mixture was applied

-73 • ··················································· · Phosphocellulose filters. The loaded samples were washed three times in 75 mM phosphoric acid at room temperature for 5 to 15 minutes. Incorporation of radiolabeled isotopes was quantified using a liquid scintillation counter. Source of Erk2 enzyme

Recombinant mouse enzyme and assay buffer can be obtained commercially (New England Biolabs, Beverly MA, USA) or purified from known natural or recombinant sources using conventional methods. Assay of Erk2 enzyme

Briefly, the reaction was performed 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 2 (commercial buffer) supplemented with fresh 100 µΜ ATP (31 pCi / ml) and 30 μΜ of myelin base protein under conditions recommended by the supplier. Reaction volumes and methods for assessing incorporated radioactivity were as described for PKC assays (see above).

In vitro models for T-cell activation

Upon activation with mitogen or antigen, T cells were induced to induce the secretion of IL-2, a growth factor that supports their subsequent proliferation phase. Therefore, either IL-2 production or cell proliferation, from primary T-cells or suitable T-cell lines, can be measured to replace T-cell activation. Both of these assays are described in detail in the literature and their parameters well documented (in Current Protocols in Immunology, Vol 2, 7.10.1 - 7.11.2).

Briefly, T cells can be activated by co-culture with allogeneic stimulatory cells, a process defined by a unidirectional mixed lymphocyte response. The responder and the peripheral blood mononuclear cell stimulator are purified using a Ficoll-Hypaque gradient (Pharmacia), in accordance with the manufacturer's instructions. Stimulator cells are mitotically inactivated by treatment with mitomycin C (Sigma) or gamma-irradiation. Responder and stimulator cells are co-cultured at a ratio of two to one in the presence or absence of the test compound. Typically, 10 ⁵ responders are mixed with 5 x 10 ⁴ stimulators and plated on 200 µl plates 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 harvested human AB

-74 ··· ···························· (· · Serum from male donors, 5 x 10 ^-5 M 2-mercaptoethanol and 0.5% DMSO.

The cultures are pulsed with 0.5 µCi of ³ H thymidine (Amersham) one day before harvesting (typically three days). Cultures are harvested (Betaplate, Wallac collector) and isotope absorption is evaluated by liquid scintillation (Betaplate, Wallac).

The same culture system can be used to evaluate T-cell activation by measuring IL-2 production. Eighteen to twenty-four hours after the start of the culture, supernatants are removed and IL-2 concentrations are measured by ELISA (R and D Systems), according to the manufacturer's instructions.

In vivo models of T-cell activation

The in vivo efficacy of the compounds can be tested in animal models known to directly measure T-cell activation or for which T-cells have been shown to be effectors. T cells can be activated in vivo by ligation of a constant portion of the T cell receptor with a monoclonal anti-CD3 antibody (Ab). In this model, BALB / c mice were given 10 µg of anti-CD3 Ab intraperitoneally two hours before they were bled. Animals receiving the test drug were pre-treated with a single dose of the compound one hour prior to anti-CD3 Ab administration. Serum levels of proinflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α ((TNF-α), indicators of T-cell activation, were measured by ELISA. A similar model is used in vivo to initiate T-cells with specific an antigen, such as keyhole limpet hemocyanine (KLH) followed by secondary in vitro immunization of draining lymph node cells with the same antigen, as mentioned previously, measurement of cytokine production is used to assess the activation status of cultured cells In brief, C57BL / 6 mice were immunized subcutaneously with 100 µg of KLH emulsified in Complex Freund's Adjuvant (CFA) at day 0. Animals were pretreated with the compound one day before immunization and then on day one, two, and three after immunization. cultured at 6 x 10 ⁶ per ml in tissue culture medium (RPMI 1640 supplemented with heat-inactivated bovine fetal serum). bead (Hyclone Laboratories) 5 x 10 ^-5 M 2-mercaptoethanol and 0.5% DMSO) for 24 and 48 hours. Culture supernatants were then evaluated for interleukin-2 (IL-2) autocrine T-cell growth factor and / or IFN-γ levels by ELISA.

-75 9 9 9 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20

Lead compounds can also be tested in animal models for human diseases. These were exemplified using experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models that mimic aspects of multiple sclerosis in humans have been described in both rats and mice (reviewed in FASEB J. 5, 2560-2566, 1991; mouse model: Lab. Invest. 4, (3), 278, 1981). rodent model: J. Immunol 146, (4): 1163-1168, 1991). Briefly, mice or 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 such as Bordetella pertussis. Recurrent / remitting disease is induced by adoptive T-cell transfer from MBP / peptide-immunized animals.

CIA can be induced in DBA / 1 mice by immunization with type II collagen (J. Immunol: 142, (7): 2237-2243). Mice develop symptoms of arthritis within 10 days of antigen immunization and can score for up to 9 days after immunization.

In both models, the EAE model and the CIA model, the compound may be administered either prophylactically or at the time of disease onset. Effective drugs could reduce severity and / or incidence.

Certain compounds of the present invention that inhibit one or more angiogenic PTK receptors and / or a protein kinase such as lck involved in mediating inflammatory responses may reduce the severity and incidence of arthritis in these models.

Compounds can also be tested in graft models in mice, either skin (reviewed in Ann. Rev. Immunol., 10, 333-358, 1992; Transplantation: 57, (12): 1701-17D6, 1994) or heart (Am). J. Ann., 113, 273 (1963). Briefly, complex thickness skin grafts were transplanted from C57BL / 6 mice into BALB / c mice. The grafts were examined daily, starting on day six, to demonstrate rejection. In mouse models of neonatal heart transplantation, neonatal hearts were ectopically transplanted from C57BL / 6 mice into the ears of an adult CBA / J mouse. Hearts began to beat four to seven days after transplantation, and rejection could be assessed visually using a dissecting microscope to observe pulmonary disruption.

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Cellular receptor PTK assays

The following cellular assays were used to determine the level of activity and effect of various compounds of the present invention on KDR / VEGFR2. Similar PTK receptor assays using a specific ligand stimulus can be designed for the same lines of other tyrosine kinases using methods well known in the art.

VEGF-induced KDR phosphorylation in Human Umbilical Vein Endothelial Celis (HUVEC) as measured by Western Blot assays.

1. HUVEC cells (from pooled donors) were purchased from Clonetics (San Diego, CA) and cultured according to the manufacturer's instructions. Only the primary flow rates (3 to 8) were used in this test. Cells were cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using complex EBM medium (Clonetics).

2. To evaluate the inhibitory activity of the compound, cells were trypsinized and seeded at 0.5 to 1.0 x 10 ⁵ cells / well in each of the 6-well cluster plates (Costar; Cambridge, MA).

3. Three to four days after seeding, the plates were run down to 90-100%. Medium was removed from all wells, cells were washed with 5-10 ml PBS and incubated for 18-24 hours with 5 ml EBM basic medium without the addition of additives (i.e. serum fasting).

4. Sequential dilution of inhibitors was added in 1ml EBM medium (25 μΜ, 5 μΜ or 1 μΜ final concentration) to the cells and incubated for one hour at 37 ° C. Human recombinant VEGF ₍₁₆ 5) (R&D systems) was then added to all wells in 2 ml EBM medium at final concentrations of 50 ng / ml and incubated at 37 ° C for 10 minutes. Control cells untreated or treated with VEGF were used only to assess background phosphorylation and VEGF-induced phosphorylation.

-77 • ····················································· · ··· ·· ·· ·· ·· ·

All wells were then rinsed with 5-10 ml of cold PBS containing 1 mM sodium orthovanadate (Sigma) and cells were lysed and scraped into 200 μΙ RIPA 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, aprotin 1 µg / ml, pepstatin 1 µg / ml, leupeptin 1 µg / ml, sodium vanadate 1 mM, sodium fluoride 1 mM) and 1 µg / ml ml Dnase (all chemicals from Sigma Chemical Company, St. Louis, MO). The lysate was centrifuged at 14,000 rpm for 30 minutes to eliminate the core.

Equal amounts of proteins were then precipitated by the addition of cold (20 ° C) ethanol (2 volumes) for a minimum of one hour or a maximum of overnight. The granules were reconstituted in Laemli sample buffer containing 5% β-mercaptoethanol (BioRad; Hercules, CA) and boiled for 5 minutes. Proteins were resolved by polyacrylamide gel electrophoresis (6%, 1.5 mm Novex,

San Diego, CA) and transferred to a nitrocellulose membrane using a Novex system. After blocking with bovine serum albumin (3%), proteins were tested overnight with anti-KDR polyclonal antibody (C20, Santa Cruz Biotechnology; Santa Cruz, CA) or with anti-phosphotyrosine monocional antibody (4G10, Upstate Biotechnology, Lake Placid, NY) ) at 4 ° C. After washing and incubating for one hour with HRP-conjugated F (ab) 2 goat anti-rabbit or goat anti-mouse IgG, the bands were visualized using an emission chemiluminescence (ECL) system (Amersham Life Sciences, Arlington Height,

IL).

Certain examples of the present invention significantly inhibit cellular VEGF-induced KDR tyrosine kinase phosphorylation at concentrations of less than 50 µΜ.

In vivo model of uterine edema

This assay determined the capacity of the compounds to inhibit the acute increase in uterine weight in mice in the first few hours after estrogen stimulation. It is known that this early onset of uterine weight increase is due to edema due to the increased permeability of the uterine vasculature. Cullinan-Bove and Koss (Endocrinology (1993), 133, 829-837) demonstrated narrow

-78 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Temporal correlation of estrogen-stimulated uterine edema with increased expression of VEGF mRNA in the uterus. These results were confirmed by the use of a neutralizing monoclonal antibody to VEGF, which significantly reduced the acute increase in uterine weight after estrogen stimulation (WO 97/42187). Therefore, this system can serve as an in vivo model for the inhibition of VEGF-mediated hyperpermeability and edema.

Materials: All hormones were purchased from Sigma (St. Louis, MO) or Cal Biochem (La Jolla, CA) in the form of lyophilized powders and prepared according to the supplier's instructions.

Excipient ingredients (DMSO, Cremaphor EL) were obtained from Sigma (St. Louis, MO).

Mice (Balb / c, 8-12 weeks of age) were obtained from Taconic (Germantown, NY) and housed in pathogen-free animal husbandry facilities, in accordance with the institutional guidelines of the Committee for Animal Breeding and Use.

methods:

Day 1: Balb / c mice were injected intraperitoneally with 12.5 units of pregnant mares serum gonadotropin (PMSG).

Day 3: Mice received 15 units of human chorionic gonadotropin (hCG) intraperitoneally.

Day 4: Mice were randomized into groups of 5 to 10. Test compounds were administered by the intraperitoneal, intravenous or oral route, depending on solubility and excipient at doses ranging from 1 to 100 mg / kg. The excipient control group received only the excipient and the two groups were left untreated.

Thirty minutes later, experimental groups, excipient groups and one of the untreated groups were injected intraperitoneally with 17βestradiol (500 µg / kg). After two to three hours, the animals were sacrificed by inhalation

-79 ························································

C0 ₂ . After cutting the midline, each uterus was isolated and removed by cutting just below the cervix and the uterine junction and the fallopian tubes. The fat and connective tissue were carefully removed so as not to compromise the integrity of the uterus before weighing. Mean weights in the treatment groups were compared to the untreated or excipient treated groups. Significance was determined using the Student's test. Unstimulated control groups were used to monitor the estradiol response.

The results demonstrate that certain compounds of the present invention inhibit edema formation when administered systemically by different routes.

Certain compounds of the invention that are angiogenic receptor tyrosine kinase inhibitors may also prove effective in the Matrigel implant model of neovascularization. The Matrigel model of neovascularization involves the formation of new blood vessels within the clear marble of an extracellular matrix implanted subcutaneously, which is induced by the presence of a pro-angiogenic tumor cell-producing factor (see Passaniti, A., et al., Lab. Investig. (1992), 67, 4), 519-528, Anat Rec (1997),

249. (1), 63-73; Int. J. Cancer (1995), 63, (5), 694-701; Vasc. Biol. (1995), 15, (11), 1857-6. The model is preferably processed within 3 to 4 days and the endpoint includes macroscopic visual / depicted neovascularization scoring, microscopic microvessel density determinations and quantitative hemoglobin determination (Drabkin method) after implant removal as compared to controls with animals not treated with inhibitors. Alternatively, the model may be used as a bFGF or HGF stimulus.

Certain compounds of the present invention that inhibit one or more oncogenic, proto-oncogenic or proliferation-dependent protein kinases or the angiogenic PTK receptor also inhibit the growth of primary mouse, rat, or human xenograft tumors in mice or inhibit metastasis in mouse models.

1. Synthesis

There are two general approaches to the synthesis of ring systems of compounds of formula I, which have been disclosed in US Patents 3,843,665 and 3,843,666.

U.S. Pat. No. 3,843,665 discloses cyclizing a pyrazole ring by heating compounds of formula Ii with an aromatic sulfonylhydrazide of formula III in an inert solvent and a catalytic amount of acid. The reaction is carried out for a period of 5 to 30 hours, preferably at a temperature of from 75 ° C to 100 ° C, to give compounds of formula I wherein R ¹ is hydrogen, e. · ··· · ···············································

where:

p is 0, 1, 2; W represents lower alkyl; and R ^2, R ^3, R ^4, R ^5, R ⁶ and X are as defined above. Compounds of formula II are prepared by reacting suitably functionalized compounds of formula IV with an aldehyde of formula V in the presence of an acidic or basic catalyst (Braun, RA; Mosher, WAJ Amer.

A second method for preparing ring systems of compounds of formula I wherein R ¹ is hydrogen is disclosed in US Patent 3,843,666, wherein compounds of formula VI are heated to a temperature of 75 ° C to 175 ° C with a catalytic amount of organic carboxylic acid or organic sulfonic acid in an inert solvent such as an aromatic hydrocarbon for a period of from 6 to 24 hours,

W

9 • IN • IN • • •  « • * · • · • a · · • • • • * · • • • · • aaa • · · • · · · '«· aa aa aa

wherein: R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are as defined above.

Compounds of formula VI are prepared by reacting compounds of formula VII with hydrazine in an inert solvent. The reaction is carried out at a temperature of 15 ° C to 20 ° C for a period of up to 24 hours.

Alternatively, compounds of Formula I may be prepared directly by reacting a compound of Formula VII with hydrazine without isolating a compound of Formula VI, for example by heating a compound of Formula VII with hydrazine in an inert solvent such as methanol in the presence of an acid catalyst such as acetic acid at in the range of from 60 ° C to the boiling point of the inert solvent used.

Compounds of formula I may also be prepared by reacting a compound of formula XVI

where:

R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and X are as defined above, with hydrazine in an inert solvent such as methanol at a temperature ranging from 15 ° C to the boiling point of the inert solvent used.

Compounds of formula VII are prepared by reacting a compound of formula VIII with an aldehyde of formula V under basic conditions. The reaction is carried out in an inert solvent at a temperature between 5 ° C and 10 ° C for a period of 3 to 6 hours,

ÍVIIU ··· ·········································· Where:

Y is any leaving group such as chloro, bromo, iodo, tosylate or mesylate and R ^3, R ^4, R ^{5, R} and X are as defined above.

Compounds of formula VII may also be prepared by reacting a compound of formula II with an epoxidizing agent, such as hydrogen peroxide, in an inert solvent such as methanol, dichloromethane, water or mixtures thereof, at a temperature between 0 ^and C up to 100, optionally in the presence of a base such as sodium hydroxide.

The cyclization of the compound of formula VI can also be carried out by reaction with a mineral acid such as hydrochloric acid, sulfuric acid or phosphoric acid. The reaction is carried out in a lower alkanol at a temperature between 15 ° C and 20 ° C for a period of 12 to 48 hours. The reaction product, a compound of formula IX, can then be aromatized to a compound of formula I by heating at a temperature of from 50 ° C to 150 ° C with an organic carboxylic acid or organic sulfonic acid in a linear chain ether or cyclic ether for a period of 8 to 30 hours. .

Compounds of formula IX can be diacetylated by reaction with an acid anhydride of formula (R _X CO) 2 O (X) in which R ^x represents a C 1-4 alkyl group in an inert solvent such as an aromatic hydrocarbon at a temperature between 35 ° C and 200 ° C over a period of 5 to 8 hours to obtain a compound of formula XI.

-83 • ················································· ·· ··· ·· ·· ·· ·· ·

(XI /

The compounds of formula XI can then be aromatized to the compound of formula XII by heating at a temperature of from 35 ° C to 200 ° C with a mineral acid or an organic acid, in an inert solvent for a period of 4 to 8 hours. Finally, the compound of formula XII can be converted to the compound of formula I by heating to a temperature of 50 ° C to 150 ° C in an inert solvent such as water or a lower alcohol in the presence of an alkali metal or alkali metal hydroxide for a period of 8 to 30 hours.

(X »/

Compounds of formula II may be cyclized to compounds of formula XIII by reaction with hydrazine in an inert solvent such as methanol at a temperature in the range of from 35 to 150 ° C.

Compounds of formula I may be prepared by reacting a compound of formula XIII with a dehydrogenating agent such as sulfur, oxygen, palladium, magnesium oxide or lead oxide, optionally in the presence of an inert solvent such as a hydrocarbon at a temperature ranging from 15 to 250 ° C. .

Specific examples of the above transformations can be found in U.S. Patents 3,843,665 and 3,843,666.

-84 ······································· · ·

The bridged carbonyl can be transformed into a methylene group by Wolf-Kishner reduction of the corresponding hydrazone (Mosher, W.A., Tawfik, E.-Z., Lipp, D. W. J. Org. Chem. 1971, 36, 3890).

Other methods for functionalizing a bridged carbonyl and specific examples can be found in Japanese Patent Application JP 60 130521 A2 and in B. Loev, US Patent 3,004,983 (1960).

Compounds of formula I may be prepared by reacting a compound of formula XIV

nh ₂

With a strong base such as n-butyllithium at a temperature ranging from -78 ° C to 25 ° C, followed by reaction with a compound of formula R ² COG (XV), wherein R ² is as defined above and G is Cve an alkoxy group.

Compounds of formula IV, VIII, XIV, XV and XVI are commercially available or can be prepared in a manner well known to those skilled in the art.

Compounds of formula I in which X represents SO or SO ₂ can be prepared by oxidizing a compound of formula I in which X represents S, using procedures well known to those skilled in the art, for example using an appropriate number of molar equivalents of 3- chloroperbenzoic.

Compounds of formula I in which X represents a group of formula -C = NOR ⁷ can be prepared by reacting a compound of formula I in which X represents carbonyl with a compound of formula H ₂ NOR7 using a procedure well known to those skilled in the art.

Compounds of formula I in which R ² = 4-pyridyl can be further functionalized at the 2-position of the pyridine ring using procedures well known to those skilled in the art, for example by pyridine-N-oxide mediated rearrangement.

-85 • ························ · 9 · · · ··· ·· ·· ·· ·· ·

Certain substituents in the compounds of formula (i) may be interconverted using procedures well known to those skilled in the art. For example, alkoxy substituents can be reacted with a suitable ether cleavage reagent such as hydrobromic acid, boron tribromide or pyridine hydrochloride to give a compound of formula I with a hydroxyl substituent. Alternatively, compounds of Formula I with an alkoxy substituent may be prepared using alkylating compounds of Formula I that contain a hydroxyl substituent. Carboxylic acid ester substituents can be converted to carboxylic or amide substituents, and carboxylic acid substituents can be converted to carboxylic acid ester substituents or amide substituents. Nitro substituents can be reduced to amines and the amines can be acylated using procedures well known to those skilled in the art.

It will be appreciated by those skilled in the art that certain substituents may react with some of the reagents described in the above procedures.

In such cases, an alternative procedure is required or the reactive substituent must be protected for the reaction and the protecting group removed after the reaction.

The invention is illustrated by the following examples, which are given by way of illustration only. The final product of each of these examples was characterized using one or more of the following methods: high performance liquid chromatography; elemental analysis, nuclear magnetic resonance spectroscopy, infrared spectroscopy and high resolution mass spectroscopy. The following abbreviations were used

IMS = industrially methylated spirit

LCMS = liquid chromatography / mass spectroscopy.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

a) A mixture of indan-1-one (10.0 g), ethanol (35 mL), hydrazine hydrate (10.0 mL) and glacial acetic acid (2.0 mL) was heated under reflux under nitrogen for one hour. The mixture was cooled to 20 ° C and the mixture was concentrated under reduced pressure to give a solid,

-86 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Which was collected by filtration to give indan-1-one hydrazone, mp 84-86 ° C.

b) A solution of n-butyllithium (15.0 mL of a 2.5 M solution in hexane) was added dropwise to a mixture of hydrazone at (1.82 g) in tetrahydrofuran (40 mL) at 0 ° C under nitrogen with stirring . The mixture was stirred at 0 ° C for 0.5 hours and then 3,4,5-trimethoxybenzoic acid methyl ester (1.41 g) was added dropwise over 10 minutes and the mixture was stirred at 0 ° C for 20 minutes. . Dilute hydrochloric acid (40 mL, 3 M) was added and the mixture was heated under reflux for one hour. The mixture was then cooled to room temperature and separated. The aqueous layer was neutralized with sodium bicarbonate and extracted with ether to give a brown oil. The oil was purified by flash column chromatography on silica using ethyl acetate / petroleum ether (1: 4) as the mobile phase to give 3- (3,4,5-trimethoxyphenyl) -1,4-dihydro-indeno [1, 2, 3, 4, 5, 6, 7, 8, 9, 9, 9]. 2-cis-pyrazole, m.p. 185-187 ° C.

Example 2

a) In a similar manner to Example 1, indan-1-one hydrazone (3.55g) was dissolved in tetrahydrofuran (80ml) at 0 ° C under a nitrogen atmosphere with stirring. To the solution was added n-butyllithium (28.8 mL of a 2.5 M solution in hexane) and the mixture was stirred at 0 ° C for 0.5 hours. Ethyl 3-methoxybenzoate (2.16g) was added followed by 3M hydrochloric acid (80ml) and the mixture was worked up as described in Example 1 to give 3- (3-methoxyphenyl) -1,4-dihydroindeno [1]. 2-c] pyrazole, m.p. 172-174 ° C.

b) A solution of boron tribromide in dichloromethane (4.58 mL of a 1 M solution) was added with stirring to a suspension of the product of a) (0.30g) in dichloromethane (30 mL) at -40 ° C with stirring under a nitrogen atmosphere. The mixture was stirred at -40 ° C to -20 ° C for 0.5 hours and then warmed to room temperature. The mixture was further stirred at room temperature for 0.5 hours and then poured into 100 mL of methanol. Silica was added and the mixture was pre-absorbed onto silica and then purified by

-87 ··· ························································ Flash column chromatography using ethyl acetate / petroleum ether (1: 2.5 with increasing ethyl acetate until 100% ethyl acetate was achieved) and finally using ethyl acetate / methanol (1: 1). )). Appropriate fractions were collected, combined and recrystallized from ethanol to give 3 (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol, mp 302-304 ° C.

Example 3

A mixture of 2-benzoylbenzo [b] thiophen-3 (2H) -one (1.50 g, available from Maybridge Chemical Company, Tintagel, England), hydrazine hydrate (0.3 mL) and butan-1-ol (50 mL) was added. was allowed to reflux under a nitrogen atmosphere during

7.5 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried and evaporated to give a solid which was purified by flash column chromatography on silica using toluene / ethyl acetate (7.5: 1) as a mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether and filtered to give 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole, mp 236-62. 238 [deg.] C.

Example 4

A solution of 3-chloroperoxybenzoic acid (450 mg, 60% purity) in dichloromethane (30 mL) was added dropwise with stirring over 15 minutes to a solution of 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole ( 400 mg) in dichloromethane (50 mL) at 0-5 ° C. The mixture was stirred at 5-15 ° C for 4 hours, then washed with water, dried and evaporated to give a solid which was purified by chromatography on silica using petroleum ether / ethyl acetate (1: 3). as a mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with ether and filtered to give 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole 4-oxide, temperature mp 222-224 ° C.

Example 5

A solution of 3-chloroperoxybenzoic acid (440 mg, 60% purity) in dichloromethane (30 mL) was added dropwise with stirring over 15 minutes to a solution of 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole ( 190 mg) in dichloromethane (30 mL) at 0-5 ° C. The mixture was stirred at 5-15 ° C for 4 hours

-88 with another 3-chloroperoxybenzoic acid (220 mg), which was added after 2 hours. The reaction mixture was washed with water, dried, filtered and evaporated to give a solid which was dissolved in ethyl acetate (100 mL), washed with 1 M sodium hydroxide solution (50 mL), then with water and then dried , filtered and evaporated to give a solid which was triturated with ether and filtered to give 3-phenyl-1H- (1) benzothieno [3,2-c] pyrazole 4,4-dioxide, mp 266 m.p. to 268 ° C.

Example 6

A mixture of 3-phenylindeno [1,2-c] pyrazol-4 (1H) -one (1.28 g, prepared as described in Japanese document JP60-130521), hydroxylamine hydrochloride (0.5 g), sodium acetate (0) (8 g), water (10 mL) and methanol (100 mL) were heated to reflux for 66 hours. Additional hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g) and water (10 mL) were added and the mixture was heated under reflux for an additional 16 hours. Additional hydroxylamine hydrochloride (0.5 g) and sodium acetate (0.8 g) were added and the mixture was heated under reflux for an additional 20 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure until crystallization began. The mixture was cooled and filtered to give a solid which was washed with water and dried to give 3-phenylindeno [1,2-c] pyrazol-4 (1H) -one oxime, mp 280 ° C (s) decomposition).

Example 7

a) A mixture of indan-1-one (3.3 g), methyl 4-formylbenzoate (5.0 g), piperidine (0.6 ml) and glacial acetic acid (0.5 ml) was heated in a steam bath for 3 hours. hours. The obtained solid was boiled in industrial methylated spirits (200 ml) and then filtered hot. The obtained solid residue was washed with industrial methylated spirits and dried to give methyl 4- (1-oxoindan-2-ylidenemethyl) benzoate, mp 194-198 ° C.

b) The product of step a) (1.5 g) was suspended in methanol (10 ml) and dichloromethane (15 ml) and stirred at 0-5 ° C while 2 M sodium hydroxide solution (2.7 ml) was added. ) followed by 30% hydrogen peroxide (100 vol. 1.1 ml). The mixture was stirred at 0-5 ° C for 5 minutes and then at room temperature for 24 hours. Dichloromethane was added to the mixture

-89 • ······························ (100 mL) and the mixture was then washed with brine (2 x 50 mL), dried, filtered and evaporated to give 4- (1-oxospiro [indan-2,2 (-oxirane) -3] methyl ester 160 DEG-163 DEG C. The aqueous phase was acidified with 5 M hydrochloric acid and extracted with dichloromethane to give 4- (1-oxospiro [indan-2,2 (-oxiranine) (-). yl) benzo, mp 220 ° C, dec.

c) A mixture of 4- (1-oxospiro [indan-2,2 (-oxirane) -3 (-yl) benzoic acid (750 mg), methanol (30 ml) and hydrazine hydrate (0.16 ml) was stirred at glacial acetic acid (6 drops) was added and the mixture was heated to reflux for 24 hours and then allowed to stand at room temperature for 24 hours, then cooled to 0 ° C and filtered to give the methyl ester. 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid, m.p. 224-226 ° C.

Example 8

4- (1-Oxospiro [indan-2,2 (-oxirane) -3 (-yl) benzoic acid from Example 7b (780 mg), methanol (50 mL), hydrazine hydrate (0.18 mL) and glacial acetic acid ( 6 drops) were heated under reflux for 24 hours The mixture was cooled in ice and filtered to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid, mp> 320 ° C.

Example 9

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid (1.05 g) and dry tetrahydrofuran (30 mL) was stirred at room temperature while triethylamine (1.1 mL) was added. ). The mixture was stirred at room temperature for 0.5 hours, then cooled to 3 ° C and methyl chloroformate (1.2 ml) was added dropwise over 5-10 minutes at 3 to 9 ° C. was added to concentrated aqueous ammonia solution (70 mL, SG 0.880) with rapid stirring. The mixture was stirred for 2 hours at 5 ° C and allowed to warm to room temperature. The mixture was concentrated under reduced pressure and then treated with 1 M sodium hydroxide solution (200 mL). The mixture was stirred for 0.5 hours and then filtered. The obtained solid was stirred with 2M sodium hydroxide solution (50 ml) for 6 hours and then allowed to stand at room temperature for 18 hours.

-90 · · · t t 90 t t t 90 90 90 t t t t t t t t The mixture was filtered to give a solid, which was washed with water and dried. This solid was purified by flash column chromatography on silica using dichloromethane / industrial methylated spirit / triethylamine (25: 2.5: 1.5) as the mobile phase. Appropriate fractions were combined and concentrated to give a residue which was washed with water and dried under vacuum at 40 ° C to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl). benzamide, m.p. 290-293 ° C.

Examples 10 and 11

a) A mixture of N- (1-oxoindan-5-yl) acetamide (10.0 g, obtained from Maybridge Chemical Co. Ltd), benzaldehyde (6.73 g), glacial acetic acid (1.06 g) and piperidine (10.8 g) was heated at 90 ° C under a nitrogen atmosphere. Methanol (200 mL) was added and the mixture was cooled and then filtered to give N- (2-benzylidene-1-oxoindan-5-yl) acetamide (13.47 g).

b) The product from step a) above (9.20 g), dichloromethane (30 ml) and methanol (30 ml) were stirred at 20 ° C and then 2M sodium hydroxide solution (15 ml) and hydrogen peroxide were added. (6.6 mL, 100 volumes) with stirring at 20 ° C. The mixture was stirred at 20 ° C for 24 hours. Additional hydrogen peroxide (3 mL, 100 volumes) was added and the mixture was stirred for 24 hours. The mixture was neutralized with glacial acetic acid and the resulting solid was collected by filtration to give N- (1-oxo-3 (-phenylspiro [indan-2,2 (-oxiran) -5-yl) acetamide), m.p. 195-197 °. C.

c) The product of step b) (2.0 g) was dissolved in ethanol (30 ml) and then hydrazine hydrate (0.34 g) was added followed by glacial acetic acid (30 drops). The mixture was heated under reflux for 5 hours, then cooled. The solid was collected by filtration and purified by flash column chromatography on silica using dichloromethane / methanol (95: 5) as the mobile phase to give N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide, m.p. 275-276 ° C, as in Example 10.

Certain fractions from the chromatography contained another compound except the example

10. These fractions were combined and evaporated under reduced pressure. The residue obtained was dissolved

-91 • ····························· In ethyl acetate and extracted with 2 M hydrochloric acid. The combined acidic extracts were basified with 2M sodium hydroxide solution and filtered to give 3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ylamine, mp 228-230 ° C, as an example 11th

Example 12

a) A mixture of indan-1-one (20.0 g), 4-nitrobenzaldehyde (27.0 g), glacial acetic acid (3.0 g) and piperidine (3.06 g) was heated at 95 ° C under under nitrogen for 3.5 hours. The mixture was cooled to 20 ° C and filtered to give a solid which was recrystallized from industrial methylated spirit to give 2- (4-nitrobenzylidene) indan-1-one.

b) The product of step a) (28.0 g) was stirred with dichloromethane (100 ml) and methanol (100 ml) at 20 ° C and then 2M sodium hydroxide solution (50 ml) was added followed by hydrogen peroxide ( 20 ml, 100 volumes). The mixture was stirred at 20 ° C for 24 hours. Additional hydrogen peroxide (10.0 mL, 100 volumes) was added and the mixture was stirred for an additional 24 hours. Additional hydrogen peroxide (10 mL, 100 volumes) was added and the mixture was stirred for 64 hours. The reaction mixture was neutralized with glacial acetic acid and the solid that formed was collected by filtration and dried to give 3 (- (4-nitrophenyl) -1-oxospiro [indan-2,2 (oxirane)].

c) The product of step b) (10.0 g) was dissolved in ethanol (180 ml) and to the obtained solution was added hyrazine hydrate (1.78 g) followed by glacial acetic acid (30 drops). The mixture was heated under reflux for 5 hours and then cooled to 20 ° C and allowed to stand at this temperature for 18 hours. The solid was collected by filtration and recrystallized from acetone to give 3- (4-nitrophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, mp 267-270 ° C.

Example 13

The product of Example 12 (3.0 g) was suspended in industrial methylated spirit (200 mL) and 5% palladium on charcoal (250 mg) was added followed by

-92 • 99 ·· ··· 9 9 · 99 9999 · 9 9 ·······

9 * Ammonium formate (2.05 g) was added. The mixture was stirred and heated at 70 ° C for 3 hours and then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and triturated with dichloromethane to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) aniline, mp 253-254 ° C.

Example 14

3- (4-Pyridyl) -4,5-dihydro-1 H -benzo [g] indazole (100 mg, a compound commercially available from Aldrich) was dissolved in tetrahydrofuran (5-10 ml) with heating and then acid 3 was added. -chloroperoxybenzoic acid (1.25 molar equivalents of 70-75% pure material). The mixture was heated at 55-60 ° C for 4 hours. The precipitate was collected by filtration, washed with tetrahydrofuran and then ether to give 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) pyridine oxide.

Example 15

The N-oxide product of Example 14 (150 mg) was dissolved in phosphorus oxychloride (6 mL). The mixture was heated under reflux for 4 hours. Excess phosphorus oxychloride was removed under reduced pressure and the residue was washed with saturated sodium carbonate solution and the product was extracted into chloroform, washed, dried and evaporated to give 3- (2-chloro-4-pyridyl) -4,5- dihydro-1H-benzo [g] indazole.

Example 16

The N-oxide product of Example 14 (25 mg) was suspended in dimethylformamide (200 μΙ) and trimethylsilyl cyanide (5 molar equivalents) and triethylamine (3 molar equivalents) were added. The mixture was heated at 110 ° C for 12 hours and then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried, filtered and evaporated to give, after flash column chromatography using 20-40% acetonitrile in dichloromethane as the mobile phase, 4- (4,5-dihydro-1H-benzo [g] -indazole-3- yl) -2-pyridinecarbonitrile.

Example 17

The product of Example 16 (50 mg) was suspended in a mixture of ethanol (1 mL) and water (0.5 mL) containing sodium carbonate (1 molar equivalent) and hydroxylamine.

-93 · Hydrochloride (2 molar equivalents). The mixture was heated under reflux for 4 hours, then cooled. The precipitate formed was collected by filtration to give 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridinecarboxamide oxime.

Example 18

Potassium carbonate (1 molar equivalent) was added to a mixture of the product of Example 16 (50 mg), DMSO (600 µL) was added, followed by hydrogen peroxide (250 μΐ 30% solution), which was added dropwise. Within a few minutes after the addition was complete, a precipitate formed. The mixture was stirred for one hour and then water was added. The precipitate was collected by filtration to give 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridinecarboxamide.

Example 19

Palladium on charcoal (spatula tip 10% material) was added to a suspension of the product of Example 16 (50 mg) in a mixture of trifluoroacetic acid in methanol (5 mL of a 5% v / v solution of trifluoroacetic acid in methanol) and stirring under hydrogen atmosphere for 24 hours. The mixture was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure (about 0.5 mL). Ethereal hydrogen chloride (20 ml) was added and the precipitate formed was collected by filtration and dried to give {[4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridyl] methyl] ammonium chloride.

Example 20

The product of Example 19 (100 mg) was suspended in propyl formate (10 mL) and ethanol (1.5 mL). This mixture was heated to reflux and after 2 minutes triethylamine (0.5 mL) was added. The mixture was heated at reflux for 4 hours and then cooled and diluted with dichloromethane (50 mL). The mixture was washed with water, then dried, filtered and evaporated to give a residue which was triturated with ether and dichloromethane to give N - {[4- (4,5-dihydro-1H-benzo [g] indazole-3). yl) -2-pyridyl] methyl} formamide.

Examples 21 to 24

The following compounds are commercially available or can be prepared using analogous procedures to those described in Examples 1 to 6.

Example 21

3- (3,4-Dimethoxyphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime.

Example 22

3- (4-Methylphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime (available from Menai).

Example 23

3- (2-Thienyl) indeno [1,2-c] pyrazol-4 (1H) -one (was commercially available or can be prepared using analogous procedures as described in Japanese Patent Document JP60-130521).

Example 24

3-phenyl-1H-benzofuro [3,2-c] pyrazole.

Example 25

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid (0.8 g), methylamine in ethanol (0.27 mL of a 33% w / w solution), 4 -pyrrolidinopyridine (0.47 g), diisopropylcarbodiimide (0.5 mL) and dichloromethane (30 mL) was stirred at room temperature for 20 hours. Additional methylamine in ethanol (0.3 mL of 33% w / w solution), 4-pyrrolidinopyridine (0.5 g) and diisopropylcarbodiimide (1 mL) were added and the mixture was stirred for 3 hours at room temperature. The solvent was removed under reduced pressure at 50 ° C. The mixture was kept under vacuum for 2 hours and then dichloromethane (50 mL) was added. The mixture was stirred at room temperature for 20 hours and then allowed to stand for 72 hours. The solid was removed by filtration and purified by flash column chromatography on silica using toluene / acetic acid (10: 1) and then ethyl acetate as the mobile phase to give N-methyl-4- (1,4-dihydroindeno [1]). 2-c] pyrazol-3-yl) benzamide, m.p. 182-188 ° C.

Example 26

a) Lithium diisopropylamide (27.2 mL of a 2.0 M solution in heptane / THF / ethylbenzene) was added dropwise with stirring to a solution of 5-methoxyindan-1-one tert-butyloxycarbonylhydrazone (5.0 g) in tetrahydrofuran (150 mL) at -78 ° C under a nitrogen atmosphere. After the addition was complete, the mixture was stirred for 1.5 hours at -78 ° C and then stirred

a solution of thiophene-2-carboxylic acid ethyl ester (3.39 g) in tetrahydrofuran (25 mL) was added dropwise. The mixture was stirred at -78 ° C for 1.5 hours and then allowed to warm to room temperature. After 30 minutes, the reaction mixture was quickly diluted by addition of saturated ammonium chloride solution and the layers were separated. The aqueous phase was extracted with ether. The combined organic phases were washed with 2 M hydrochloric acid, dried and evaporated to give a residue which was dissolved in dichloromethane (100 ml) and trifluoroacetic acid (0.35 ml) was added. The mixture was stirred under a nitrogen atmosphere at room temperature and then purified by flash column chromatography using ethyl acetate / petroleum ether t. in. 60-80 ° C (4: 1) as the mobile phase to yield

6-methoxy-2-tert-butyloxycarbonyl-3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazole.

b) A solution of boron tribromide in dichloromethane (1.35 ml of a 1M solution) was added with stirring to a solution of the product of step a) (100 mg) in dichloromethane (5 ml) at -78 ° C under a nitrogen atmosphere. The mixture was stirred for 2 hours at -78 ° C and the mixture was then allowed to warm slowly to room temperature and stirred at this temperature for 18 hours. The mixture was rapidly diluted with water and the organic layer was separated. The aqueous layer was extracted with dichloromethane and the combined organic extracts were washed with brine, dried, filtered and evaporated to give 3- (2-thienyl) -1,4-dihydro-indeno [1,2-c] pyrazol-6-ol, mp> 300 ° C.

Example 27

a) Triethylamine (0.48 ml) was added to a solution of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) aniline (400 mg) in dichloromethane (20 ml) with stirring under a nitrogen atmosphere at room temperature temperature and then benzoyl chloride (0.4 mL) was added. The mixture was stirred for 3 hours and then allowed to stand for 18 hours. The mixture was filtered to give 4 (- (1-benzoyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide, mp 241 ° C.

b) The product of step a) (0.35 g) was dissolved in methanol (20 ml) and 2M sodium hydroxide solution (3.85 ml) was added. The mixture was stirred at 20 ° C for 2 hours and the solid was then collected by filtration and dried in vacuo

-96 • ·· ·· ··

j · .. ·: i:

H under vacuum at 60 ° C for 2 hours to give 4 (- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide hydrate, m.p.

274 ° C.

Example 28

a) Thiosalicylic acid methyl ester (2.0 g) was added dropwise with stirring at room temperature to a solution of sodium methoxide (1.28 g) in methanol (50 ml). The mixture was stirred at room temperature for 15 minutes, and then a solution of 2- (bromoacetyl) thiophene (2.26 g) in methanol (50 mL) was added dropwise. After the addition was complete, the mixture was heated under reflux for 3 hours, then cooled and 10% aqueous hydrochloric acid (100 mL) was added. The solid was collected by filtration, dried and then recrystallized from ethanol to give 2-thioylbenzo [b] thiophen-3-ol.

b) A mixture of the product of step a) (500 mg), hydrazine hydrate (106 mg) and n-butanol (5 ml) was heated under reflux under a nitrogen atmosphere for 7 hours. The mixture was concentrated in vacuo to give a gum which was crystallized from ethyl acetate / petroleum ether, m.p. in. 60-80 ° C to give a solid which was purified by flash column chromatography on silica using ethyl acetate / petroleum ether, m.p. at 60 to 80 ° C (3: 7) as the mobile phase. Appropriate fractions were collected and evaporated to give 3- (2-thienyl) -1H-benzothieno [3,2-c] pyrazole, mp 236-238 ° C.

Example 29

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid methyl ester (0.3 g) and Ν, Ν-diethylethylenediamine (1 mL) was heated at 150 ° C for 3.5 hours and then at 180 ° C for 2 hours. The mixture was cooled and dissolved in industrial methylated spirit, and this solution was pre-absorbed onto silica which was applied to the top of the flash chromatography column. The column was eluted with dichloromethane / industrial methylated spirit / triethylamine (25: 2: 1) to give a solid which was stirred with water for one hour, filtered and dried under vacuum at 60 ° C while

·· ·· <

(· «· · · · I <

N- (2-diethylaminoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, m.p. 172-174 ° C, was obtained.

Example 30

A mixture of 4- (1-oxoindan-2-ylidenemethyl) phenol (1.67 g, Chem. Ber. 1901, 34, 413), p-toluenesulfonylhydrazine (1.95 g), p-toluenesulfonic acid (0.27 g) and ethanol (15 mL) was heated under reflux for 72 hours. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica using petroleum ether, m.p. in. 60-80 ° C / ethyl acetate (1: 1) as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a residue which was triturated with petroleum ether, m.p. in. 60-80 ° C to give a solid which was crystallized from ethanol to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol, mp 266-268 ° C.

Example 31

Mixture of 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol (0.29 g), ethylene carbonate (0.11 g), traces of solid sodium hydroxide (spatula tip, beads 20 to 20) 40 mesh) and dry dimethylformamide (3 mL) was stirred under a nitrogen atmosphere and heated at 100 ° C for 45 minutes. The outside temperature was allowed to rise to 140 ° C and the mixture was heated at this temperature for 3.5 hours. The reaction mixture was cooled and diluted with ethyl acetate and the mixture was washed with dilute aqueous sodium hydroxide solution and then with water. The organic phase was dried, filtered and evaporated to give a residue which was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with diethyl ether and filtered to give 2- (3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl). (phenoxy) ethanol, m.p. 203-205 ° C.

Example 32

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid (0.37 g), dichloromethane (20 mL) and oxalyl chloride (0.26 mL) was stirred at 15 to 20 ° C. 20 ° C and then dimethylformamide (3 drops) was added dropwise. The mixture was stirred at 15 to 20 ° C for 30 minutes and then heated at 40 ° C for one hour. The solvent was removed under reduced pressure to give a solid

-98 ·· ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · A substance that was dissolved in dichloromethane (20 ml) and then aniline (0.13 ml) and triethylamine (0.38 ml) were added. The mixture was stirred at room temperature under a nitrogen atmosphere for 2 hours and then washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica to afford 4- (1, 1, 2). 186 DEG-190 DEG C. 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide.

Example 33

A mixture of 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol (2.4 g), anhydrous potassium carbonate (1.2 g), 2-bromoacetic acid ethyl ester (1.2 ml) and dry dimethylformamide (20 ml) were stirred at room temperature for 24 hours. The mixture was diluted with dichloromethane (200 mL), washed with water, then with 1 N sodium hydroxide solution. The organic layer was separated, dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using ethyl acetate / petroleum ether t. in. 60-80 ° C (1: 2 as mobile phase). Appropriate fractions were combined and evaporated to give 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetic acid ethyl ester, mp 134-136 ° C.

Example 34

A mixture of 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetic acid ethyl ester (0.66 g), 1 M sodium hydroxide solution (4 ml) and ethanol (20 ml) was heated on a steam bath. for 30 minutes. The solvent was removed under reduced pressure and the residue was stirred with 1 M hydrochloric acid (20 mL) at room temperature for one hour. The mixture was filtered to give 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetic acid, mp 246-248 ° C.

Example 35

In a similar manner to Example 33, a mixture of 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol (0.20 g) was treated with ethyl 4-bromobutyrate (0.16 g), to give 4- (3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] butyric acid ethyl ester, m.p. 142-148 ° C.

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 36

In a similar manner to Example 34, 4- (3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -phenoxy] -butyric acid ethyl ester (0.36 g) was treated with 1 M sodium hydroxide solution. (5 mL) in ethanol (10 mL) to give 4- [3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] butyric acid, m.p. 216-217 ° C.

Example 37

A mixture of 4- (3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] butyric acid (0.24 g) was stirred in dry tetrahydrofuran (5 mL) at room temperature and then stirred at room temperature. triethylamine (0.20 ml) was added and the mixture was stirred at room temperature for 15 minutes, then cooled in an ice bath, and methyl chloroformate (0.2 ml) was added. Concentrated ammonia solution (SG 0.880, 5 mL) was added dropwise using a pipette, the mixture was stirred at 0 ° C for 5 minutes and then evaporated to dryness under reduced pressure. The residue was purified by flash column chromatography on silica using dichloromethane / IMS / triethylamine (8: 1: 1) as the mobile phase The appropriate fractions were combined and evaporated to give 4- (3- (1,4-dihydroindeno [1,2-c] pyrazol-3yl)) phenoxy] butyramide, m.p. 200-202 ° C.

Example 38

a) Chloroacetyl chloride (0.3 g) was added to a mixture of 4- (1,4-dihydroindeno [1,2c] pyrazol-3-yl) aniline (0.6 g), dichloromethane (20 ml) and triethylamine (0, 27 g) at 0 ° C with stirring under a nitrogen atmosphere. Additional triethylamine (0.37 mL) and chloroacetyl chloride (0.21 ° mL) were added and the mixture was stirred for an additional hour. The mixture was filtered and washed with water to give 4 (- (1-chloroacetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) chloroacetanilide).

b) A mixture of 4 (- (1-chloroacetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) chloroacetanilide (0.7 g), tetrahydrofuran (40 mL) and morpholine (0.61 g) sodium carbonate (0.97 g) was added and the mixture was heated at reflux for an additional hour. The mixture was poured into water and extracted with ethyl acetate to give 4 (- (1 , 4-100-

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

dihydroindeno [1,2-c] pyrazol-3-yl) morpholinoacetanilide, m.p. 291-292 ° C.

Example 39

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-yl) benzoyl chloride [(500 mg), which was prepared by reacting the product of Example 8 (1.45 g) with oxalyl chloride (1.5 mL) in dichloromethane (100 mL) and DMF (8 drops) followed by solvent evaporation], dichloromethane (50 mL), 2-morpholinoethanol (0.22 mL) and triethylamine (0.5 mL) were stirred at room temperature for 3.5 hours . The reaction mixture was washed with water, then with saturated sodium bicarbonate solution, then dried, filtered and evaporated to give an oil which was purified by flash column chromatography on silica using dichloromethane / IMS (10: 1) as mobile phase. phase to give an oil which was purified again using flash column chromatography using dichloromethane / IMS (25: 1) as the mobile phase to give the product 2-morpholinoethyl 4- (1,4-dihydroindeno [1,2c] m.p. 168 DEG-172 DEG C. pyrazol-3-yl) benzoate, as a solid.

Example 40

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzoic acid methyl ester (2.2 g, Example 7) and N, N-diethylethylenediamine (7 mL) was heated under reflux for 5 hours. The mixture was cooled and allowed to stand for 16 hours at room temperature, petroleum ether was added at 60-80 ° C (50 mL) and the mixture was then decanted off to give a gum which was further treated with petroleum ether as above, and the remaining gum was dissolved in dichloromethane and purified by flash column chromatography on silica using dichloromethane / IMS / triethylamine (25: 2: 1) as the mobile phase to give a solid which was dissolved in ethanol (70 mL). ) and then dry hydrogen chloride gas was introduced into the solution and the precipitated solid was collected by filtration, washed with ethanol and dried to give N- (2-diethylaminoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -benzamide dihydrochloride, m.p. 230 DEG.

Examples 41 to 50

Step 1

-101 • ································ · ··· ·· ·· ·· ·· ·

A 1: 1 (v / v) dichloromethane: methanol (1 mL) mixture was added via Gilson 215 liquid handler to the starting enone (approximately 50 mg, see Table A) in a sealed tube with a baffle followed by aqueous 2 M sodium hydroxide solution. (1 molar equivalent, see Table A) and 100 volumes of aqueous hydrogen peroxide (1.8 molar equivalents). The resulting solutions / suspensions were then shaken at room temperature for 20 hours. After LCMS analysis, an additional 100 volumes of aqueous hydrogen peroxide (1.8 molar equivalents) was added to each reaction tube, this time manually using a plastic tip pipette. To these tubes containing a significant amount of insoluble material was also added another mixture, in a ratio of 1: 1 (v / v) dichloromethane: methanol (1 mL). Shaking was then continued for an additional 24 hours.

All reactions were analyzed by thin-layer chromatography and in those reactions judged to be incomplete, an additional 100 volumes of aqueous hydrogen peroxide (1.8 molar equivalents) was added, again using a plastic tip pipette (see those reactions which are designated as x3 in Table A). These reaction mixtures were stirred at room temperature for 3 days.

The reaction solutions / suspensions were equilibrated between dichloromethane (about 5 mL) and water (about 2 mL), with the organic phase filtered through an Empore® filter cartridge and washed with dichloromethane (about 2 mL). The dichloromethane phases were evaporated and the residues were further dried under vacuum.

Table A

Starting enon 2 N aqueous NaOH (ΜΙ) 100 volumes aqueous H2O2 (μΙ) 41 2- (3-Nitrobenzylidene) -1-indanone (49.7 mg) 93.7 38,3 x 3 42 2- (4-Thiomethoxybenzylidene) -1- indanone (50.2 mg) 94.2 38.5 x 2 43 2- (2-Naphthylmethylene) -1-indanone (51.3 mg) 94.9 38.8 x 2

-102 • II II II II II II II II II II II ·· ·· ·

44 2- (4-Difluoromethoxybenzylidene) -1- indanone (51.3 mg) 89.6 36.7 x 2 45 2- (4-Acetamidobenzylidene) -1- tetralone (50.5 mg) 86.7 35.5 x 3 46 2- (4-Bromo-2-thienylmethylene) -1- indanone (50.9 mg) 83.4 34.1 x 2 47 - (4-Benzyloxybenzylidene) -1- tetralone (50.7 mg) 74.5 30.5 x 2 48 5,6-Dimethoxy-2- (3-phenoxy benzylidene) -1-indanone (50.2 mg) 67.4 27.6 x 3 49 2- [4- (5-trifluoromethyl-2-pyridyloxy) - benzylidene] -1-indanone (50.2 mg) 65.8 26.9 x 2 50 5,6,7-trimethoxy-2- (2,3,4-trimethoxy- benzylidene) -1-indanone (50.0 mg) 62.4 25,5x3

The products of Step 1 were obtained based on the corresponding 2,3-epoxy ketones.

Step 2

To the products of Step 1 in a sealed tube with a septum, n-butanol (2 mL) was added, using a Gilson 215 liquid manipulator, followed by hydrazine hydrate (2 molar equivalents based on the amount of starting enone used in Step 1) as a 10% solution (v / v). in n-butanol (see Table B). Finally, glacial acetic acid (2 drops) was added manually to each tube using a syringe. The reaction mixtures were heated at 100 ° C with shaking for the period shown in Table B based on monitoring by thin layer chromatography analysis. The reaction mixtures were evaporated to dryness and the residue purified by chromatography on silica eluting with ethyl acetate, where dilution with petroleum ether, m.p. in. 40-60 ° C. The appropriate fractions were evaporated and dried in vacuo. If necessary, the products were further purified by preparative HPLC (see Table B) to give the final pyrazoles. The products were analyzed by LCMS and the conditions will be set forth below.

-103 ·····································. ·· ·· ·· ···

Table B

Detailed description of reactions

Example Volume 10% NH2NH2.H2O μΙ Warm-up time at 100 ° C Further cleaning product using preparative HPLC 41 182.5 6 hours Yes 42 183.6 6 hours Not 43 184.8 22 hours Not 44 174.5 6 hours Not 45 168.8 38 hours Yes 46 162.4 22 hours Not 47 145.1 38 hours Not 48 131.3 22 hours Not 49 128.2 6 hours Not 50 121.6 22 hours Not

Yields / LCMS

Example MF Molecular mass M + found HPLC RT (Min.) Final mass 41 C16H11N3O2 277 Yes 4.67 3.5 mg 42 C17H14N2S 278 Yes 4.94 5.3 mg 43 C20H14N3 282 Yes 5.29 21.9 mg 44 C17H12F2N2O 298 Yes 4.82 21.2 mg 45 C19H17N3 303 Yes 3.67 5.0 mg 46 C ₄ HgBrN32S 317 Yes 5.16 10.2 mg 47 C24H20N2O 352 Yes 5.93 2.7 mg 48 C24H20N2O3 384 Yes 5.16 16.3 mg 49 C22H14N3O3O 393 Yes 5.56 20.1 mg 50 C22H24N2O6 412 Yes 4.25 11.9 mg

Example 41

3- (3-Nitrophenyl) -1,4-dihydro-indeno [1,2-c] pyrazole

-104 ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 42

3- (4-Tiometoxyfenyl) -1,4-dihydro-indeno [1,2-c] pyrazole

Example 43

3- (2-Naphthyl) -1,4-dihydroindeno [1,2-c] pyrazole

Example 44

3- (4-difluoromethoxy-phenyl) -1,4-dihydro-indeno [1,2-c] pyrazole

Example 45

3- (4-Acetamidophenyl) -4,5-dihydro-2H-benz [g] indazole

Example 46

3- (4-Bromo-2-thienyl) -4,5-dihydro-indeno [1,2-cJpyrazol

Example 47

3- (4-Benzyloxy-phenyl) -4,5-dihydro-2H-benz [g] indazole

Example 48

6,7-Dimethoxy-3- (3-phenoxyphenyl) -1,4-dihydro-indeno [1,2-c] pyrazole

Example 49

3- [4- (5-Trifluoromethyl-2-pyridyloxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole Example 50

6,7,8-trimethoxy-3- ₍₂ '3,4-trimethoxyphenyl) -1,4-dihydro-indeno [1 _l2-c] pyrazole

LC

column:

Mobile phase

Conditions:

(Gradient)

HYPERSIL BDS C18 (100 X 2.1mm)

0.1% formic acid: MeCN (gradient see below) to 100% MeCN over 8 minutes

100% MeCN for 1 minute

100 to 10% MeCN in 2 minutes (total analysis time 11 minutes)

Flow rate ml / min

-105 - • · · • • • ·· ·· ·· • · · · · · ·· · · · · • · · · ··· · • · · · ft Wavelength range: 206-320 nm ·· ·· ·· Injected volume: 10 μΙ MS ionization APcI + ve / -ve Weight range: 150-500 m / z Conical voltage: 20 Example 51 a) A mixture of 4-hydroxy-3- (hydroxymethyl) benzaldehyde (1.08 g), indan-1-one (0.94 g), ethanol (30 mL) and 5 M aqueous sodium hydroxide (1.6 mL) were added ml) was heated under reflux for 6.5 hours. The mixture was cooled to

at room temperature and allowed to stand at this temperature for 16 hours. The mixture was diluted with water (45 mL) and then with 5 M hydrochloric acid (1.6 mL), which was added with cooling. The precipitate formed was collected by filtration, washed with water and dried to give 2- (4-hydroxy-3- (hydroxymethyl) -benzylidene) -1-indan-one, mp 194-195 ° C.

b). A mixture of the product of step a) (0.85 g), p-toluenesulfonylhydrazine (0.9 g), p-toluenesulfonic acid (0.12 g) and ethanol (15 ml) was heated under reflux for 4.5 hours. The solvent was removed under reduced pressure at room temperature and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate solution. The organic layer was separated, washed with water and dichloromethane was removed from the gum using a pipette. The gum was purified by flash column chromatography on silica using 10% and 20% IMS in dichloromethane as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a solid which was triturated with diethyl ether to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxymethyl) phenol, m.p. &Gt; 300 ° C.

Examples 52 to 55

The following examples were carried out in a similar manner to Example 51 by reacting indan-1-one with a suitable aldehyde.

-106 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Example 52

2-Methoxy-5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol, m.p. 189-199 ° C, prepared from 3-hydroxy-4-methoxybenzaldehyde.

Example 53

2-Chloro-4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol, m.p. 235-236 ° C, prepared from 3-chloro-4-hydroxybenzaldehyde.

Example 54

2-Methoxy-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -phenol _I, m.p. 243-244 DEG C., prepared from 4-hydroxy-3-methoxybenzaldehyde.

Example 55

3-Chloro-4- (1,4-dihydroindeno [1,2-clpyrazol-3-yl) phenol, mp 231-233 ° C, prepared from 2-chloro-4-hydroxybenzaldehyde.

Example 56

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol (0.28 g, Example 30), potassium carbonate (0.16 g) and 2-bromoacetamide (0.16 g) ) was stirred together at room temperature in dry dimethylformamide (5 ml) for 4 days and then allowed to stand at room temperature for 9 days. The mixture was diluted with dichloromethane (50 mL) and washed with 1 M aqueous sodium hydroxide solution and then water. Part of the insoluble material remaining during the extractions was collected by filtration. The solid was purified by flash column chromatography on silica using ethyl acetate as the mobile phase. Appropriate fractions were collected, combined and evaporated to give 2- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] acetamide, mp 247-248 ° C.

Example 57

A mixture of 4 (- (1-chloroacetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) chloroacetanilide (1.0 g) in THF (40 mL), diethylamine (0.73 g) and carbonate Potassium (1.38 g) was heated at reflux for 6 hours and then cooled to 20 ° C and allowed to stand at this temperature for 16 hours. The mixture was poured into water / ethyl acetate (50 ml each) and the organic layer was evaporated. separated, dried and evaporated to give an oily solid which was purified by flash column

-107 9 99 99 99 silica chromatography using 5 % methanol in dichloromethane as the mobile phase and then re-chromatographed using ethyl acetate as the mobile phase followed by 5% methanol in dichloromethane. Appropriate fractions were collected, combined and evaporated to give 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) diethylaminoacetanilide, mp 99-100 ° C.

Example 58

a) A mixture of 4-cyanophenacyl bromide (3.0 g), thiosalicylic acid methyl ester (2.25 g), sodium methoxide (1.52 g) and ethanol (100 mL) was heated under reflux for 3.5 hours. The mixture was cooled and diluted with 2 M hydrochloric acid (100 mL). The precipitate was collected by filtration and recrystallized from ethanol to give 2- (4-cyanobenzoyl) -3-hydroxybenzo [b] thiophene.

b) Hydrazine hydrate (5 ml) was added to a solution of the product of step a) (2.0) in ethanol (100 ml) containing glacial acetic acid (1 drop) through 4A molecular sieves (5 g). The mixture was heated under reflux for 24 hours and then filtered. The filtrate was concentrated under reduced pressure and the residue obtained was purified by flash column chromatography on silica using diethyl ether / petroleum ether, m.p. in . 60-80 ° C (1: 1) as the mobile phase to give a solid which was recrystallized from ethanol / water to give 4- (1H- [1] benzothieno [3,2-c] pyrazole- 290 DEG-292 DEG C. (with decomposition).

Example 59

In a similar manner to Example 58, a mixture of methyl thiosalicyl ester (2.76 g), 4-nitrophenacyl bromide (4.0 g), sodium methoxide (1.94 g) and ethanol (200 mL) afforded 2- (4-nitrobenzoyl) -3-hydroxybenzo [b] thiophene, of which 2.25 g was reacted with hydrazine hydrate (6 mL) in a similar manner to Example 58 to give 3- (4-aminophenyl) -1H- [1] benzothieno [3] 2-c] pyrazole, mp 113-115 ° C.

Example 60

In a similar manner to Example 58, 4-methoxyphenacyl bromide (0.81 g) was reacted with thiosalicylic acid methyl ester (5.0 g) in sodium methoxide and

-10899 9 · • ·· · · ·

9 9 ··· 99 methanol to give 2- (4-methoxybenzoyl) -3-hydroxy [b] thiophene, which was reacted with hydrazine hydrate to give 3- (4-methoxyphenyl) -1H-benzothieno [3] M.p. 185-287 ° C.

Example 61

Boron tribromide (3.0 mL of a 1.0 M solution in dichloromethane) was added with stirring to a solution of the product of Example 60 (210 mg) in dichloromethane (10 mL) at -78 ° C under a nitrogen atmosphere. The mixture was allowed to warm slowly to room temperature and after stirring at this temperature for 2 days, the mixture was quickly diluted by addition of aqueous ammonium chloride solution. The organic layer was separated, dried and evaporated to give a residue which was purified by flash column chromatography on silica using dichloromethane and then increasing amounts of methanol, up to 15% methanol, in dichloromethane as mobile phase. Appropriate fractions were collected, combined and evaporated to give 3- (4-hydroxyphenyl) -1H [1] benzothieno [3,2-c] pyrazole, mp 137-139 ° C.

Example 62

5-Aminoindan-1-one (2.5 g) was treated with benzoyl chloride (2.63 g) in dichloromethane and triethylamine to give 5-benzamidoindan-1-one, which was treated with benzaldehyde in a similar manner to Example 7a), to obtain N- (2-benzylidene-1-oxoindan-5-yl) benzamide, which was reacted with hydrogen peroxide in a similar manner to Example 7 b), to obtain an intermediate which was reacted with a hydrazine hydrate similar to by the method of Example 7 c) to give - (3 N-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzamide, m.p. 271 ° C, after chromatography of the reaction mixture.

Example 63

4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenol was stirred with water (20 mL) containing 2M aqueous sodium hydroxide solution (0.41 mL). The suspension was warmed gently and then stirred at room temperature for 1.5 hours and then ethanol (20 mL) was added to give an almost complete solution. The solvent was removed under reduced pressure and the residue was dried under vacuum. The solid was triturated with diethyl ether (10 mL) and filtered to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol sodium salt, mp> 300 ° C.

9 9 9 9 9 9 9 9 9 99 99 9

-109 • ·

The compounds listed in Tables 1, 2 and 3 were prepared in a similar manner to Examples 7b and 7c. Alternatively, these compounds were prepared in a similar manner to Example 30.

Example 64

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid methyl ester (100 mg) and N- (2-aminoethyl) morpholine (0.5 mL) was stirred and heated at 150 ° C. C for 5 hours. The mixture was cooled and washed with petroleum ether, m.p. in. 40-60 ° C (20 mL). The mixture was dissolved in dichloromethane / IMS / triethylamine (25: 2: 1) and purified by flash column chromatography on silica using the same solvent mixture as the mobile phase. Appropriate fractions were collected, combined and evaporated to give a gum which was dissolved in dichloromethane, washed with water, then dried, filtered and evaporated to give a solid which was triturated with ether and filtered to yield a gum. N- (2-morpholinoethyl) -4- (1,4-dihydroindeno [1,2c] pyrazol-3-yl) benzamide monohydrate, m.p. 210-214 ° C.

Example 65

In a similar manner to Example 7a, indan-1-one was reacted with 4-cyanobenzaldehyde and the obtained intermediate was reacted with hydrogen peroxide in a manner similar to Example 7b to give an intermediate of the spiro compound which was reacted with hydrazine hydrate in a similar manner to in Example 7c, to give 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile, mp 245 ° C.

Example 66

6-Methoxy-2- (4-thiomethoxybenzylidene) -1-tetralone was reacted with hydrogen peroxide followed by hydrazine hydrate according to the general procedure described for Examples 41 to 50 to give 7-methoxy-3- (4-methylsulfonylphenyl) -4 5-dihydro-2H-benz [g] indazole (C 18 H 16 N 2 O 2 S, molecular weight 354, M + found, percent purity, 66% by HPLC).

Example 67

3-Phenylindeno [1,2-c] pyrazol-4- (1H) -one (2.4g) was suspended in toluene (40ml) under nitrogen and added at 20 ° C with stirring.

-110-

• ·· • · · • ·· • · · · · · • · • · • · • t • · • · ··· · · · • · · • · • · ·· ·· • · · · ·· ·

trimethylaluminium (2.2 ml of a 2 M solution in heptane). The mixture was heated at 90 ° C for 16 hours, then cooled to room temperature and poured into crushed ice (approximately 600 mL) containing concentrated hydrochloric acid (30 mL). The precipitated solid was collected by filtration and recrystallized from ethyl acetate by hot filtration to give 4-methyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-4-ol, mp 154-155 ° C.

Example 68

Dihydroxy 4- (4H-indeno- [1,2-c] pyrazol-3-yl) phenylborane

A solution of 3- (4-bromenyl) -4H-indeno [1,2-c] pyrazole (2.0 g, 6.43 mmol) in dry THF (50 mL) was added to a suspension of potassium hydride (35 wt%) with stirring. dispersion in mineral oil (0.365g, 6.75mmol) in dry THF (50ml) under nitrogen. After 10 minutes, the mixture was cooled to about -78 ° C and tert-butyllithium (1.5M solution in pentane, 8.78 mL, 13.18 mmol) was added and the mixture was stirred for about 15 minutes. To the red solution was added a solution of triisopropylborate in THF (1.56m, 6.75mmol) and the mixture was allowed to warm to room temperature and stirred overnight. Hydrochloric acid (1 M, 150 mL) was added and the solution was stirred for approximately 30 minutes and then extracted with ether (3 x 200 mL). The combined ether extracts were then extracted with sodium hydroxide (3 x 100 mL). The combined alkaline extracts were acidified with hydrochloric acid (2 M) and the solid precipitate was filtered and dried by pump to give dihydroxy-4- (4H-indeno- [1,2-c] pyrazol-3-yl) phenylborane ( 602 mg, 34%). Mpt> 300 ’C.

Example 69

4- (1H- [1] Benzothieno [3,2-c] pyrazol-3-yl) benzaldehyde

-111 ············································

A solution of 3- (4-bromophenyl) -1H- [1] benzothieno [3,2-c] pyrazole (4.0 g, 12.2 mmol) in dry THF (200 mL) was added dropwise with stirring to the hydride suspension potassium (35% w / w dispersion in mineral oil, 1.53g 13.4mmol) under a nitrogen atmosphere while maintaining the temperature at about 0 ° C. After the addition was complete, the reaction mixture was stirred for about 15 minutes at about 0 ° C, then cooled to -78 ° C. Tert-Butyllithium (1.5 M solution in pentane, 17 mL, 25.62 mmol) was added dropwise and the mixture was stirred for about 45 minutes. Dry DMF (61 mmol) was then added dropwise while maintaining the temperature at about -78 ° C. The resulting mixture was stirred at this temperature for about one hour, allowed to warm to room temperature and stirred overnight. The reaction mixture was quickly diluted by careful addition of hydrochloric acid (1 M, 200 mL) and the two layers were separated. The aqueous layer was extracted with ether (2 x 200 mL). The combined extracts and the organic layer were washed with saturated sodium bicarbonate (1 x 200 mL), water (3 x 200 mL), dried (MgSO ₄ ), filtered and the solvent was evaporated. was removed to give a waxy red solid (1.3 g) which was purified by flash chromatography (eluting with 20% ethyl acetate / 80% 60 to 80 petroleum ether) to afford 4- (1H [1] benzotierio [3]). 2-c] pyrazol-3-yl) benzaldehyde (200 mg, 6%). Mp 261-263 ° C.

Example 70

4- (1H- [1] Benzothieno [3,2-c] pyrazol-3-yl) -N- [3- (imidazol-1-yl) propyl] benzylamine trihydrochloride

A solution of 4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) benzaidehyde (0.1 g 0.36 mmol), 3- (imidazol-1-yl) propylamine (0.058 g, 0 , 47 mmol) and glacial acetic acid (0.03 mL, 0.47 mmol) in 1,2-dichloroethane were stirred at room temperature for about one hour. Solid sodium triacetoxyborohydride (0.084 g, 0.4 mmol) was then added in one portion and the resulting mixture was stirred for about 16 hours at room temperature. Another portion of sodium triacetoxyborohydride (0.084 g, 0.4 mmol) was added and the mixture was stirred for

-112 ·· next 24 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (20 mL) and stirred for approximately 30 minutes, the layers were separated and the aqueous layer was extracted with dichloromethane (2 x 50 mL). The combined extracts and the organic layer were washed with water (1 x 25 mL), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a waxy solid which was taken up in ethanol. Two drops of hydrochloric acid (conc.) Were added, the solution was cooled and evaporated to give a solid which was removed by filtration, dried under vacuum to give 4- (1H- [1-benzothieno [3,2-c] pyrazole-). 3-yl) -N- [3 (imidazol-1-yl) propyl] -benzylamine trihydrochloride (0.09 g, 50%) Mpt 206-208 ° C.

Example 71

4- (4-Oxo-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid methyl ester

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid methyl ester (6.3g, Example 7), sodium bismuthate (31g), glacial acetic acid (180ml) and water (60ml). ml) was heated under reflux for about 3.5 hours. An additional amount of sodium bismuthate (33 g) was added and the mixture was heated under reflux for about 24 hours, then cooled. The pH of the reaction mixture was adjusted to 8-9 by addition of saturated sodium bicarbonate solution. The reaction mixture was filtered through a pad of celite and the solid residue was washed with ethyl acetate. The organic layer was separated, dried, filtered and evaporated to give a brown solid. The solid was boiled in methanol (50ml), cooled and the solid filtered off, then dried to give 4- (4-oxo-1,4-dihydroindeno [1,2c] pyrazol-3-yl methyl ester). Melting point (decomposition) 235 ° C.

Example 72

4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide oxime

-113-

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile (730 mg, Example 65), hydroxylamine hydrochloride (0.4 g), sodium carbonate (0.8 g) and ethanol (30 mL) was heated to reflux for about 16 hours. The solvent was removed under reduced pressure at about 50 ° C and the residue was stirred with water (70 mL). The mixture was extracted with ethyl acetate and the combined organic phases were dried, filtered and evaporated to give a solid. The solid was purified by flash column chromatography on silica using ethyl acetate as eluent to give a solid which was washed with diethyl ether and dried to afford 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide oxime, m.p. > 300 ° C.

Example 73

3- {4 - [(2-diethylaminoethyl) aminomethyl] phenyl} -1,4-dihydroindeno [1,2-c] pyrazole trihydrochloride

A mixture of N- (2-diethylaminoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide (2.75 g, Example 29) and dry tetrahydrofuran (100 mL) was stirred at Lithium aluminum hydride (3.4 g) was added portionwise. The reaction mixture was then heated under reflux for about 2.5 hours, then cooled in an ice / water bath. Ethyl acetate (100 mL) and water (100 mL) were added. The organic layer was then separated, washed with brine (25 mL), dried, filtered and evaporated to give a yellow oil. The oil was purified by flash column chromatography on silica using a mixture

- 114 114 114 114 114 - 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 114 Ethyl acetate / ethanol / triethylamine (7: 2: 1) as eluent to give a pale yellow gum. The gum was dissolved in hot ethanol (5 mL), hydrochloric acid (horses, 0.6 mL) was added and the solvent was then removed under reduced pressure. The gummy solid residue was boiled with ethanol (10 mL) and cooled in ice. The precipitated solid was collected by filtration, washed with ethanol and dried to give 3- {4 - [(2-diethylaminoethyl) aminomethyllphenyl} -1,4-dihydroindeno [1,2-c] pyrazole trihydrochloride, mp 225 ° C.

Example 74

N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) fenyljbenzénsulfónamid

a) 4 '- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) aniline (1 g) was dissolved in dichloromethane (30 mL) and triethylamine (0.62 mL) was added. The reaction mixture was then cooled to about 0 ° C and benzenesulfonyl chloride (0.57 mL) was added dropwise over 5 minutes. The reaction mixture was then warmed to room temperature and stirred for about 2 hours. Further addition of benzenesulfonyl chloride (0.57 mL) and triethylamine (0.62 mL) was performed and stirring was continued for about another 4 hours at room temperature. Then diethyl ether (80 mL) and water (40 mL) were added. A solid precipitated, which was filtered and washed with aqueous sodium bicarbonate solution (40 mL) and diethyl ether (40 mL). The solid was further purified by flash chromatography on silica using dichloromethane as eluent. The first fractions were combined and the solvent removed in vacuo to give N- [4- (1-benzenesulfonyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] benzenesulfonamide as a brown solid (0, 35 g), mp 251-252 ° C, later fractions gave a brown solid (0.76 g) mp 267-268 ° C.

-115 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· ·· ·

b) N- [4- (1-Benzenesulfonyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -phenyl] -benzenesulfonamide (0.56 g) was suspended in methanol (40 ml) and at room temperature 2 N aqueous sodium hydroxide solution (5.3 mL) was added. A clear solution was obtained. The reaction mixture was stirred at room temperature for approximately 20 minutes and then poured into a 2 N aqueous hydrochloric acid solution (75 mL). A colorless solid precipitated and was collected by filtration (0.42 g). The solid was partitioned between aqueous sodium bicarbonate (25 mL) and ethyl acetate (25 mL), and stirred for about 30 minutes at room temperature. It was then collected by filtration and dried under vacuum at about 60 ° C to give N [4- (1'-dihydro-indenophenyl-6'-pyrazol-5-yl) -phenyl] -benzenesulfonamide as a colorless solid (0.14 g), temperature mp 286-288 ° C.

Example 75

N- (2-Morpholinoethyl) -4'-dihydroindeno [1,2-c] pyrazol-3-yaniline dihydrochloride

^4, - (1,4-dihydro-indeno [1 _l 2-cjpyrazol-3-yl) morpholinoacetamide (1.5 g, Example 38) was dissolved in tetrahydrofuran (80 ml) at room temperature under nitrogen in portions over a period of Lithium aluminum hydride (0.6 g) was added for 10 minutes. The mixture was stirred at room temperature for about 6 hours, then poured into saturated aqueous sodium sulfate (75 mL) and extracted with diethyl ether (2 x 75 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a yellow oil (2.24 g) which was purified by flash chromatography on silica using a gradient of 1:20 to 1: 4 methanol: dichloromethane as eluent. The appropriate fractions were combined and evaporated in vacuo to give a yellow solid (0.83 g). The solid was dissolved in ethanol (10 mL) and concentrated hydrochloric acid (0.5 mL) was added. A colorless solid precipitated and was collected by filtration to give N (2-morpholinoethyl) -4'-dihydroindeno [1,2-c] pyrazol-3-ylaniline dihydrochloride (0.94 g), mp 284-285 C.

-116-

•: ι ··

Example 76

N- (1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -2-morpholinoacetamide

H

H

a) 3-Phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ylamine (2.0 g) was dissolved in dichloromethane (70 ml) and triethylamine (2.3 ml) was added. The resulting mixture was cooled to about 0 ° C and chloroacetyl chloride (1.3 mL) was added. The reaction mixture was then stirred at room temperature for 10 hours under a nitrogen atmosphere. A colorless solid precipitated which was collected by filtration and dried under vacuum at about 60 ° C to give N (1-chloroacetyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazole-6- yl) -2-chloroacetamide (2.04 g), which was used in the next step without further purification.

b) N- (1-Chloroacetyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2-chloroacetamide (1.0 g) was dissolved in tetrahydrofuran (30 mL); and morpholine (0.87 mL) was added. The mixture was then heated to reflux for approximately 90 minutes, cooled to room temperature and poured into water (100 mL). A solid precipitated which was collected by filtration and dried under vacuum at about 60 ° C to give N- (1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2-morpholino- acetamide, as a brown solid (0.87 g), m.p. 141-148 ° C.

Example 77

N- (2-Morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ylamine trihydrochloride

H

N- (3-Phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2-morpholinoacetamide (0.6 g) was dissolved in tetrahydrofuran (40 mL) at room temperature under an atmosphere

The lithium aluminum hydride was added portionwise over 10 minutes to the nitrogen in portions over 10 minutes. (0.24 g). The mixture was stirred at room temperature for about 24 hours. Additional lithium aluminum hydride (0.24 g) was added and the mixture was stirred at room temperature for approximately another 24 hours. It was then poured into a saturated aqueous solution of sodium sulfate (30 mL) and extracted with diethyl ether (2 x 30 mL). The combined organic extracts were dried (Na ₂ SO ₄ ) and evaporated in vacuo to give a yellow oil which was purified by flash chromatography over silica using a 1:20 methanol: dichloromethane mixture as eluent. Appropriate fractions were combined and evaporated in vacuo to give a yellow solid. The solid was dissolved in ethanol (5 mL) and concentrated hydrochloric acid (10 drops) was added. The precipitated colorless solid was collected by filtration to give the trihydrochloride salt of N (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ylamine (0.18 g), mp 180 to 182 ° C.

Example 78

4 '- (1-Acetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide

a) ^4, - (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) aniline (1 g) was dissolved in dichloromethane (40 ml) and triethylamine (1.14 mL) followed by anhydride acetic acid (0.85 mL). The reaction mixture was then stirred at room temperature for 2 hours under a nitrogen atmosphere. A colorless solid precipitated, which was collected by filtration and washed with water and dried under vacuum at about 60 ° C to give 4 '- (1-acetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl). acetanilide, as a colorless solid (0.84 g), mp 245-246 ° C.

b) 4 '- (1-acetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide (1.0 g) was suspended in methanol (40 mL) and a 2 N aqueous solution was added sodium hydroxide (15 mL). The mixture was stirred at room temperature for about 20 minutes and then poured into an aqueous solution of 2 N acid

118 hydrochloric acid (75 ml), a colorless solid precipitated, which was collected by filtration and dried under vacuum at about 60 ° C to give 4 '- (1,4-dihydroindeno [1,2-c] pyrazole). -3-yl) acetanilide dihydrochloride (0.96 g), mp 295-304 ° C.

Example 79

3- [4- (2-morpholinoethoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole

A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol (0.76 g, Example 30), 4- (2-hydroxyethyl) morpholine (0.85 g), triphenylphosphine (1). , 77 g) and dichloromethane (20 ml) were stirred together with cooling in an ice / water bath and diethyl azodicarboxylate (1.16g) was added dropwise. The resulting mixture was allowed to warm to room temperature and stirred for about 24 hours. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography on silica using ethyl acetate / ethanol (25%) to give a solid. The solid was triturated with diethyl ether (10 mL) and the solid was filtered off, washed with diethyl ether and dried at about 65 ° C to give 3- [4- (2-morpholinoethoxy) phenyl] -1,4- dihydroindeno [1,2-c] pyrazole, m.p. 175-176 ° C.

R3

Exp. R ^z X R ^3, R ^4, R ^b, R ^b Preparation Explanatory Notes Melting point ° C 80 4- (Ph) phenyl ch ₂ H Prepared as in an experiment. 51 245-6 81 4- (OPh) phenyl ch ₂ H Prepared as in Experiment 7 195-6 82 4- (SO ₂ Ph) phenyl (ch ₂ ) ₂ R '= MeO Prepared as in Experiment 66 83 3- (CO ₂ ), 4- (OH) phenyl ch ₂ H Prepared as in Experiment 51 283-4

- 119 · fl fl 119 119 119 119 119 fl fl 119 fl fl fl fl fl fl fl fl

84 3- (NO ₂ ), 4- (OH) phenyl ch ₂ H Prepared as in Experiment 51 250-2 85 3- (OCH ₂ CONH ₂ ) phenyl ch ₂ H Prepared as in Experiment 56 246-8 86 4- (OCH ₂ Ph) phenyl ch ₂ R ^4, R D = (MeO) ₂ Prepared as in Experiment 51 110-4 87 4- (OCH ₂ Ph) phenyl ch ₂ R ^{@ 1} = MeO Prepared as in Experiment 51 228-31 88 4 (OH) -phenyl ch ₂ R ^4, R = ^p (MeO) ₂ Prepared as in Experiment 13 250-4 89 3- (CONH (CH ₂ ) ₂ MOR), 4 (OH) phenyl ch ₂ H Prepared as in Experiment 40 160 (dec.) 90 3- (CONH (CH ₂ ) ₂ NEt ₂ ), 4 (OH) phenyl ch ₂ H Prepared as in Experiment 40 210 (dec.) 91 4- (Br) phenyl ch ₂ H Prepared as in Experiment 7 277-9 92 4 (OH) -phenyl ch ₂ R '= MeO Prepared as in Experiment 13 256-60 93 4- (CONH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ H Prepared as in Experiment 39 M-388 94 4- (CONH (CH _{2) 2} OMe) phenyl ch ₂ H Prepared as in Experiment 39 M-333 95 4- (CONH (4-NO ₂ Ph)) phenyl ch ₂ H Prepared as in Experiment 39 M-396 96 4 (OH) -phenyl ch ₂ R (R) = MeO Prepared as in Experiment 51 237-40 97 4- (CONH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ R ⁴ = NH _Z Prepared as in experiment 29 212-4 98 4- (Br) phenyl with H Prepared as in Experiment 1-6 287-9 99 4 (OH) -phenyl ch ₂ R ^d = O (CH ₂ ) ₂ OMe Prepared as in Experiment 51 197-8 100 4- (SO ₂ NH (CH ₂ ) ₂ MOR) phenyl ch ₂ H Prepared as in Experiment 7 218-20 101 4- (SO ₂ NH (CH ₂ ) ₂ OMe) phenyl ch ₂ H Prepared as in Experiment 7 184-6 102 3- (CH ₂ NMe ₂₎ 4 (OH) -phenyl ch ₂ H Prepared as in Experiment 51 183-7 103 4 (OH) -phenyl ch ₂ R ^d = H _{(CH2) 2} MOR Prepared as in Experiment 51 280 (dec.) 104 4- (SO ₂ NH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ H Prepared as in Experiment 7 192-6 105 4- (OCH ₂ CONH ₂₎ phenyl ch ₂ R ^J = O (CH ₂ ) ₂ OMe Prepared as in Experiment 56 234-6 106 4 (OH) -phenyl ch ₂ R = J0H), O (CH _{2) 2} OMe Prepared as in Experiment 51 96-100 107 4 (OH) -phenyl ch ₂ R-O (CH _{2) 2} OMe Prepared as in Experiment 51 75-81 108 4- (CONH (CH _{2) 2} NHEt) phenyl ch ₂ H Prepared as in Experiment 40 230 109 4- (CONHCH ₂ -2-pyr) phenyl ch ₂ H Prepared as in Experiment 40 222-6 110 - (OCH ₂ CONH ₂ ) phenyl ch ₂ R @ ^d = OH Prepared as in Experiment 51 220 111 4- (OCH ₂ CO ₂ H) phenyl ch ₂ H Prepared as in Experiment 34 250-3

-120 • ·

Example 112

3- [2- (2H-1,2,3, tetraaza-4 _I-5-yl) -4-pyridinyl] -4,5-dihydro-2H-benzo [g] indazole

4- (4 _{L of} 5-Dihydro-2H-benzo [g] indazol-3-yl) -2-pyridinecarbonitrile (50 mg,

0.184 mmol) was dissolved in 5 mL THF. To this solution was added 900 mg (15 eq) of tributyltin azide. The reaction mixture was heated for about 24 hours and the progress of the reaction was monitored by HPLC. At this time, some of the starting material was still present; the reaction mixture was allowed to cool to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL) and to this was added an excess of 1 N HCl. A precipitate formed, which was filtered off and dried, yielding 33 mg of a white solid. HPLC / MS confirmed product formation: MH + 316.2, retention time: 1.73 minutes.

Experimental Conditions for Examples 113-159

Tricyclic pyrazoles, ureas and carbamates.

LC conditions (analytical measurement):

Column: PECOSPHERE, C18, 3 µm, 33 x 4.6 mm

Gradient: From 100% pH 4.5, 50 mM NH ₄ OAc / H ₂ O to 100% CH ₃ CN in 4.5 minutes

Flow rate: 3.5 ml / min

LC / MS, purification conditions:

Column: Hypersil® BDS, C18, 5 °, 100 x 21.2 mm

Gradient: Generally from 100% pH 4.5, 50 mM NH ₄ OAc / H ₂ O to 100%

CH3CN over 8.5 minutes, but varies depending on the desired separation.

Flow rate: 25 ml / min

Melting points

They were recorded on an Electrothermal 9100 microscope to measure the melting point in an open capillary tube and were not corrected.

-121 • ·

IR:

································

IR spectra were recorded on a Hewlett Packard Nicolete Impact 400 FT-IR spectrophotometer using KBr granules. Only the strongest and most significant bands were recorded.

3- (4-Isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 2:

to a solution of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid 1 (5.8 g, 20.99 mmol) in DMF (200 mL) was added diphenylphosphoryl azide (5.22) mL, 23.09 mmol) and Et ₃ N (3.35 mL, 23.09 mmol). The reaction mixture was heated at about 80 ° C for about 4 hours until no further evolution of N ₂ gas was observed. The off-white precipitate was filtered off and washed with EtOAc (3 x 5 mL) and Et ₂ O (3 x 5 mL). The solid was dried under vacuum to give a quantitative yield of 2, which was used in the next step without further purification. Mp 338-339 ^{& C.} IR (KBr) 2132, 1723,1582,1520.

Examples 113 to 121

General procedure for O-substituted N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamates:

To a solution of the appropriate alcohol in THF was added NaH (12 eq) and the reaction mixture was stirred for about 45 minutes at about 20 ° C. Solid 3 (4-isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 2 was added. The reaction mixture was stirred for about 3 hours at about 45 ° C. Then, 2 M HCl was added to

PH = 7 and the crude material was extracted into EtOAc. Purification by flash chromatography (CH ₂ Cl ₂ / MeOH) gave pure carbamate 3.

Example 113:

2- (Diethylamino) ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate

To a solution of N, N-diethylethanolamine (0.368 mL, 2.75 mmol) in THF (5 mL) was added NaH (60% in mineral oil, 113 mg, 2.75 mmol). The reaction mixture was stirred at about 20 ° C for about one hour, then solid was added

3- (4-Isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 2 (58 mg, 0.22 mmol). The reaction mixture was heated at about 45 ° C for about 3 hours. The reaction mixture was quickly diluted by adding H ₂ O and the product was extracted into EtOAc. The crude material was purified by flash chromatography on SiO ₂ (MeOH / CH ₂ Cl ₂ , 10/90) to give 51 mg (62%) of pure product. LC / MS 391 (M + 1); LC retention time

2.68 minutes.

Example 114:

2- Morpholinoethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate: 56 mg (66%) of pure product was isolated. LC / MS 405 (M + 1); LC retention time

2.69 minutes. .

Example 115:

3- (Dibenzylamino) propyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate: 34 mg (35%) of pure product was isolated. LC / MS 530 (M + 1); LC retention time 4.18 minutes.

Example 116:

2- [ethyl (2-hydroxyethyl) amino] ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate acetate salt: 19 mg (26%) of pure was isolated product. LC / MS 407 (M + 1); LC retention time 2.65 minutes ..

Example 117:

2 - [[2- (dimethylamino) ethyl] (methyl) amino] ethyl-N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate acetate salt: Isolated to 32 mg (42%) of pure product. LC / MS 420 (M + 1); LC retention time 2.80 minutes.

-123Example 118:

1-Methyl-2-propoxyethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazo [-3-yl) phenyl] carbamate: 42 mg (59%) of pure product was isolated. LC / MS 392 (M + 1); LC retention time 3.60 minutes.

Example 119:

2- (1-Methyltetrahydro-1H-2-pyrrolyl) ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate: 4 mg (7%) was isolated ) of the pure product. LC / MS 403 (M + 1); LC retention time 2.81 minutes.

Example 120:

2- [2- (dimethylamino) ethoxy] ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate acetate salt: 32 mg (43%) was isolated pure product. LC / MS 407 (M + 1); LC retention time 2.62 minutes.

Example 121:

2- (Diethylamino) -1-methylethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate acetate salt: 7 mg (9%) of pure product was isolated. LC / MS 405 (M + 1); LC retention time 2.84 minutes.

Examples 122 to 159

General procedures for N '-substituted N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea 4:

To a suspension of 3- (4-isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 2, in toluene was added Et ₃ N (5 eq) and a suitable amine (5 eq). The reaction mixture was stirred at about 95 ° C for 0.5 to 5 hours. The solid was filtered off and washed with EtOAc and Et ₂ O and dried in vacuo to give the desired urea 4.

-124 · · · · · · · · · · · · · · · · · ·

Example 122:

N- [2- (Diethylamino) ethyl] -N '- [4- (1-adihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea

Suspension of 3- (4-isocyanatophenyl) -1,4-dihydroindeno (1,2-c) pyrazole, 2 (75 mg, 0.274 mmol), Et ₃ N (0.191 mL, 1.37 mmol), N, N-diethylethylenediamine (0.112 mL, 1.37 mmol) in toluene (3 mL) was heated at about 95 ° C for about 3 hours The white solid was filtered off and washed with EtOAc and dried in vacuo to afford 61 mg (57%). LC / MS 390 (M + 1), LC retention time 2.76 minutes.

Example 123:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2-morpholinoethyl) urea 84 mg (76%) of pure product was isolated. LC / MS 404 (M + 1); LC retention time 2.50 minutes.

Example 124:

N1- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -1-piperidinecarboxamide 32 mg (49%) of pure product was isolated. LC / MS 359 (M + 1); LC retention time 3.36 minutes.

Example 125:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2- (dimethylamino) methylethyl urea: 57 mg (55%) of pure product was isolated. LC / MS 376 (M + 1); LC retention time 2.72 minutes.

Example 126:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N'-tetrahydro-2-furanylmethyl-urea: 57 mg (56%) of pure product was isolated. LC / MS 375 (M + 1); LC retention time 2.98 minutes.

Example 127:

N- [4- _(1-I, 4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] ^-N, - (2-furylmethyl) urea:

66 mg (65%) of pure product was isolated. LC / MS 371 (M + 1); LC retention time

3.34 minutes.

-125 • ·

Example 128:

N- (1,3-Benzodioxol-5-ylmethyl) -N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea: 75 mg (64%) was isolated. ) of the pure product. LC / MS 425 (M + 1); LC retention time 3.45 minutes.

Example 129:

N-Cyclobutyl-N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl]: 60 mg (64%) of pure product was isolated. LC / MS 345 (M + 1); LC retention time 3.28 minutes.

Example 130:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N ^, - (2-piperidinoethyl) urea: 64 mg (58%) of pure product was isolated. LC / MS 402 (M + 1); LC retention time 2.84 minutes.

Example 131:

N-Benzyl-N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea:

47 mg (45%) of pure product was isolated. LC / MS 381 (M + 1); LC retention time 3.40 minutes.

Example 132:

N- [4- (Diethylamino) butyl] -N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea: 62 mg (54%) of pure product was isolated . LC / MS 418 (M + 1); LC retention time 2.76 minutes.

Example 133:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2- (2-thienyl) ethyl] urea: 65 mg (59%) was isolated pure product. LC / MS 401 (M + 1); LC retention time 3.44 minutes.

Example 134:

N- [3- (Diethylamino) propyl] -N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea: 50 mg (45%) of pure product was isolated . LC / MS 404 (M + 1); LC retention time 2.73 minutes.

-126Example 135:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [(1-ethyltetrahydro-1H-2-pyrrolyl) methyl] urea: 53 mg ( 48%) of pure product. LC / MS 402 (M + 1); LC retention time 2.89 minutes.

Example 136:

N- (2,5-Difluorobenzyl) -N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea: 15 mg (13%) of pure product was isolated. LC / MS 417 (M + 1); LC retention time 3.50 minutes.

Example 137:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2- (2-hydroxyethoxy) ethyl] urea: 34 mg (33%) was isolated pure product. LC / MS 379 (M + 1); LC retention time 2.66 minutes.

Example 138:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [2-hydroxy-1- (hydroxymethyl) ethyl] urea: 4 mg was isolated ( 1%) of the pure product. LC / MS 365 (M + 1); LC retention time 2.48 minutes.

Example 139:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2,3-dihydroxypropyl) urea: 8 mg (8%) of pure product was isolated. LC / MS 365 (M + 1); LC retention time 2.54 minutes.

Example 140:

N1- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4- (2-pyridyl) -1-piperazinecarboxamide: 68 mg (71%) of pure product was isolated. LC / MS 437 (M + 1); LC retention time 3.13 minutes.

Example 141:

N '- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N- [3- (dimethylamino) propyl] N-methyl urea: 54 mg (63%) was isolated pure product. LC / MS 390 (M + 1);

LC retention time 2.60 minutes.

-127Example 142:

N1- [4- (1,4-Dihydroindeno (1,2-c) pyrazol-3-yl) phenyl] -1-azetanecarboxamide: 48 mg (66%) of pure product was isolated LC / MS 331 (M + 1) LC retention time

2.86 minutes.

Example 143:

N1- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4- (4-fluorophenyl) -1-piperazine-carboxamide: 63 mg (63%) of pure product was isolated . LC / MS 454 (M + 1); LC retention time 3.53 minutes.

Example 144:

N-Benzyl-N ' -I-4-dihydro-indenol-4-pyrazol-5-yl-phenyl-N-methylurea: 60 mg (69%) of pure product was isolated. LC / MS 395 (M + 1); LC retention time 3.41 minutes.

Example 145:

N '- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N-ethyl-N- (2-hydroxyelyl) urea: 50 mg (63%) of pure was isolated product. LC / MS 363 (M + 1); LC retention time 2.78 minutes.

Example 146:

N1- (4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4- (2-methoxyphenyl) -1-piperazinecarboxamide: 49 mg (48%) of pure product was isolated. LC / MS 464 (M-1), LC retention time 3.45 minutes.

Example 147:

^N - [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N- [2- (dimethylamino) ethyl] -Nmetylmočovina: was isolated 55 mg (67%) of pure product. LC / MS 376 (M + 1); LC retention time 2.48 minutes.

Example 148:

N 1- (4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4-methyl-1-piperazinecarboxamide: 16 mg (20%) of pure product was isolated. / MS 374 (M + 1), LC retention time 2.48 minutes.

-128 ·· ·································

Example 149:

N 1- (4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4- (4-hydroxyphenyl) -1-piperazinecarboxamide: 11 mg (11%) of pure product was isolated LC / MS 452 (M + 1), LC retention time 3.04 minutes

Example 150:

N1- (4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl) -4 - [(E) -3-phenyl-2-propenyl] 1-piperazinecarboxamide: 47 mg was isolated (45%) pure product LC / MS 476 (M + 1), LC retention time 3.26 minutes.

Example 151:

N1- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4-phenyl-1-piperazinecarboxamide: 46 mg (48%) of pure product was isolated. LC / MS 436 (M + 1); LC retention time 3.58 minutes.

Example 152:

N ^, [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N, N-di (2-methoxyethyl) urea: 31 mg (37%) of pure was isolated product. LC / MS 407 (M + 1); LC retention time 3.25 minutes.

Example 153:

^N - (4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N- (2,3-dihydroxypropyl) -Nmetylmočovina: Isolated 36 mg (43%) of pure product LC / MS 379 (M + 1), LC retention time 2.62 minutes.

Example 154:

N, N-di [2- (Diethylamino) ethyl] -N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea: 50 mg (47%) was isolated ) of the pure product. LC / MS 489 (M + 1); LC retention time 2.61 minutes.

Example 155:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2-pyridylmethyl) urea: 38 mg (45%) of pure product was isolated. LC / MS 382 (M + 1); LC retention time 2.85 minutes.

-129Example 156:

· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

N - [(4-N-Dihydroindeno [3,4-d] pyrazol-5-yl) phenyl] -N- (5-pyridylmethyl) urea: 26 mg (31%) of pure product was isolated. LC / MS 382 (M + 1); LC retention time 2.70 minutes.

Example 157:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N ^, - (4-pyridylmethyl) urea: 43 mg (51%) of pure product was isolated. LC / MS 382 (M + 1); LC retention time 2.69 minutes.

Example 158:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2-hydroxyethyl) urea: 7 mg (8%) of pure product was isolated. LC / MS 335 (M + 1); LC retention time 2.57 minutes.

Example 159:

N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N ^, - [7- (dimethylamino) heptyl] urea: 57 mg (48%) of pure product was isolated . LC / MS 432 (M + 1); LC retention time 2.85 minutes.

Examples 160 to 209

Synthesis of compound

'X

-130-

• · • t • · • · · · • · · · • · • · • · • · • · · ··· · • · • · · · · · • · • ·

(X = CH ₂ or O) test: approx. 85% * state A: in EtOH, room temperature: (for all aliphatic primary amines) state B: p-TSA (cat.) In toluene, reflux (for all secondary or aromatic amines)

ents X NRR » Conditional Yisld 160 CH2 NKN-C12H25 A 44% (360 mg) 161 CH2 HN- A 78% (480 mg) 162 CH2 * A 74% (430 mg) 163 CH2 A 33% 130 mg 164 CH2 . "- Q A 73% (480 mg) 165 CH2 A 82% (350 mg) 166 CK2 0 A 87% (370 mg) 167 ' CH2 '’N B 21% (80 mg)

-131 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

168 CH2 HM— & ~ \ \ = N B- 77% (300 mg) 169 CH2 w B 21% (SO mg) 170 CH2 (B)  52% (210 mg) 171 CH2 B 62% (250 mg) 172 0 _H N ~ ° ^e A • 52% (190 mg) 173 0 Z ^- Λ N Nf / e B 73% (400 mg) 174 0 HN ^ Q 3 60% (390 mg) 175 0 B 68% (440 mg) 176 0 HN ^ NMe B 62% (440 mg) 177 0 ^H V Γ ^ ΝΗ (HCl, B 33% (210 mg) 178 0 ^N 'n B 52% (330 mg) 179 0 ΗΝ ^<Ζχ ^ ~ B 47% (320 mg) 180 WITH in_/ A 61% (430 mg) 181 WITH ^ΗΜ - _(Λ ; _ΟΙ) A 30% 130 mg 182 with hn-HQ B 58% (370 mg) 183 with HN ^ J> 3 66% (420 mg) 184 with HN- B 60% (240 mg) 185 with MtX 'N' = / B 60% (380 mg) 186 CH2 NHIS-Pr A 62% (360 mg)

-132 ······················ · ·· B B B B B

BBB BB BB · BBB BBB

1S7 CH2 - NHcyc-PR A 50% · · (290 mg) 1SS CH2 NHN-Hex . A 52% (320 mg) 189 CH2 A 53% (350 mg) 190 CH2 Ό B 30% (190 mg) 191 CH2 N NMe \_IN B 76% (500 mg) 192 CH2 / A N 0 \ _y B 56% · (360 mg) 193 CH2 OMe B 22% 140 mg 194 CH2 hn - ^^ - OH B 53% (360 mg) 195 CH2 N x B 71% (460 mg) 196 CH2 yí “ ^{N HN} v? B 54% (350 mg) 197 CH2 «UJ A 64% of (430 mg) 193 CH2 ™ N Y'nh N ^ / ' B 48% (300 mg) 199 CH2 ^H 'V 3 51% (340 mg)

-133 ······· · t ························· · ·

200 ABOUT Ό B 73% (460 mg)  201 ABOUT HN- B 5%. (430 mg) 202 0 A 5% (350 mg) 203 0 q (2HCL) A 82% (700 mg)

Entry X NRR ' condition yield 204 CH2 / 'k O (2HCrj A 69% (600 mg) 205 CH2 ABOUT B 65% (400 mg) 206 CH2 / "Λ N Nf / .e \ _y 3 53% (260 mg) 207 CH2 «-0 B 35% (180 mg) 208 CH2 B 73% (380 mg) 209 CH2 B 63% (340 mg)

Example A

The use of the compounds of the present invention in the manufacture of pharmaceutical compositions is illustrated by the following description. As used herein, the term "active compound" refers to any compound of the present invention,

- 134 · · predovšetkým predovšetkým predovšetkým predovšetkým avšak predovšetkým avšak predovšetkým predovšetkým predovšetkým predovšetkým predovšetkým predovšetkým avšak predovšetkým predovšetkým predovšetkým predovšetkým avšak predovšetkým predovšetkým predovšetkým predovšetkým avšak predovšetkým predovšetkým predovšetkým predovšetkým predovšetkým predovšetkým predovšetkým avšak predovšetkým predovšetkým avšak is the final product of one of the preceding examples.

(a) Capsules

In the preparation of capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are deagregated and mixed. The mixture is filled into hard gelatin capsules, each capsule containing a unit dose or part of a unit dose of the active compound.

(b) Tablets

Tablets are prepared from the following ingredients.

weight parts

Active compound 10

Lactose 190

Corn starch

Polyvinylpyrrolidone 10

Magnesium stearate

The active compound, lactose and a portion of the starch are deagregated, mixed and the resulting mixture is granulated with a solution of polyvinylpyrrolidone in ethanol. The dry granulate is mixed with the magnesium stearate and the rest of the starch. The mixture is then compressed in a tabletting machine to give tablets each containing a unit dose or part of a unit dose of the active compound.

c) Enteric-coated tablets

Tablets are prepared as described above under (b). The tablets are enteric coated in a conventional manner using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) Lace

In the preparation of suppositories, 100 parts by weight of the active compound are incorporated into

1300 parts by weight of the triglyceride lace base and the mixture is formed into suppositories each containing a therapeutically effective amount of the active ingredient.

-135 ·· · · · ··· · ·············· · · · · ·· ·

Although the present invention has been illustrated and described in particular with reference to preferred embodiments thereof, those skilled in the art will recognize that various changes in form and details may be made without departing from the spirit and scope of the invention as defined in the appended claims. claims. Those skilled in the art will recognize or be able to ascertain, using no more than routine experimentation, many equivalents to specific embodiments of the invention described herein. It is understood that such equivalents fall within the scope of the claims.

Claims (6)

1) when X is carbonyl or substituted methylene, R ¹ is hydrogen and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not 2-pyrrolyl, pyridyl, 2-thienyl, 3-thienyl, phenyl or phenyl substituted with a substituent such as: a C 1-2 -alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; 1) when R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen and X represents SO ₂ , then R ² does not represent phenyl, and N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamic acid 1-methyl-2-propoxyethyl ester 1,4-dihydro-4-methyl-3-phenylpyrazolo [4,3-b] indole; 1,4-dihydro-3-phenylpyrazolo [4,3-b] indole, 1) when X is carbonyl or substituted methylene, R ¹ is hydrogen and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not 2-pyrrolyl, pyridyl, 2-thienyl, 3-thienyl, phenyl or phenyl substituted with a substituent such as: a C 1-2 -alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; 1) when R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen and X represents SO 2, then R ² does not represent phenyl, and 1) when X is carbonyl or substituted methylene, R ¹ is hydrogen and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not pyridyl, phenyl or phenyl substituted with a substituent such as C 1-6. ₂ -138 · · · -1 <-1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 An alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; and A method of inhibiting protein kinase activity comprising administering a compound of Formula I, comprising: and pharmaceutically acceptable salts thereof, wherein: X is a) substituted methylene, b) carbonyl, c) oxygen, d) -C = NOR ⁷ wherein R ⁷ is H or C 1-4 alkyl, e) NR ⁸ wherein R ⁸ is H, optionally substituted C 1-6 alkyl or optionally substituted phenyl, f) a group of formula (CH ₂ ) n in which n is 1, 2 or 3, or g) a group of formula S (O) _P in which p is 0, 1 or 2; R ¹ represents H; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; R ³ , R ⁴ , R ⁵ and R ® independently of one another are a) H, b) halogen, c) C 1-6 alkyl optionally substituted by one or more of the following groups, such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R 'are as defined below, d) a C 1-4 alkoxy group optionally substituted by one or more of the following groups, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R', wherein R ^h and R ^j have the meanings defined below, provided that these groups are not attached to the carbon that is attached to the oxygen of the alkoxy group; e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a , wherein R ^a represents a hydroxyl group, a C 1-4 -alkoxy group or R a ^and represents a group of the formula NR ^b R ^c in which R ^b and R ^c , -137 denotes hydrogen, C 1-6 -alkyl or, independently of one another, phenyl, wherein the alkyl group and the phenyl are optionally substituted with one or more of the following groups, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 alkyl or wherein R ^h and R x, together with the nitrogen atom to which they are attached, represent a five- or seven-membered saturated heterocyclic ring which optionally contains an additional heteroatom selected from O, S or N and is optionally substituted with C 1-4 -alkyl , h) a group of the formula NR ^d R ^e , wherein R ^d and R ^e are independently selected from the group consisting of hydrogen, C 1-8 -alkyl, C 3-12 -cycloalkyl or phenyl or a group of formula COR ^f , wherein R ^f represents hydrogen , C 1-12 alkyl, C 3-12 -cycloal alkyl, phenyl-C 1-4 -alkyl or phenyl, in each case alkyl, cycloalkyl and phenyl being optionally substituted by one or more of the following substituents, such as: halogen, hydroxy, nitro or amino of the formula NR ^h R ^j , where R ^h and R ^j are as defined above i) a group of formula O (CH 2) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of formula NR ^d R ^e in which R ^d and R ^e are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above and m is 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 -alkyl, I) optionally substituted phenyl-C 1-6 ^ alkoxy m) cyano or o) _C2 ^ -alkenyl, or C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents, such as: C-alkyl a group, a C 1-4 -alkoxy group or a halogen, provided that: 2) when X is methylene, R ¹ is hydrogen and two of R ³ , R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, halogen having an atomic mass of from about 19 to 36, C 1-6 -alkyl, C 1-6 -alkyl alkoxy or trifluoromethyl and the other two are hydrogen, then R ^{2 is} not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl containing two or less substituents, wherein the substituents are halogen having an atomic mass of from about 19 to 36, C 14- alkyl, C1-4-alkoxy or trifluoromethyl; and 2) when X represents S and R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not 2,4-dichlorophenyl. 72. Compounds of Formula I and pharmaceutically acceptable salts thereof in which: X represents oxygen; R ¹ represents hydrogen; R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, b) a C 1-6 alkyl group optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ¹ , wherein R ^h and R 'are as defined below, c) a C 1-6 -alkoxy group optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ^j , wherein R ^h and R ^j are as defined below, with the proviso that these groups are not bound to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, -189 ·· ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · f) a group formula COR ^a or SO 2 R ^a wherein R ^a is hydroxy, (C, -C) alkyl, (C, -C6) alkoxy or R ^a is a group of formula NR ^b R ^c; wherein R ^b and R ^c are each, independently of one another, hydrogen, CI.I ₂ alkyl, C ₃ .i ₂ -cycloalkyl, phenyl _(Co-C6) alkyl or heterocyclyl- (Co-C6) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl and thiophenyl), wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl group is optionally substituted with one or more of the following substituents such as: hydroxyl, ( _Ci-C6) -alcohol, halo, nitro, _(Ci-C6) alkyl, (C _-C 6) alkoxy, -O- _(Ci-C6) alkyl hydroxy, C 3 and ₂ -cycloalkyl or amino of the formula NR ^h R '; wherein R ^h and R ^j are independently from each other hydrogen, (C 1 -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpholine and piperazine), (C 1 -C ₆ alkenyl, (C 1 -C ₆ ) -alkynyl, (C 3 -C ₆ ) cycloalkenyl (C ₀ -C 6) alkyl, hydroxy (C ₁ -C ₆ ) -alkyl, amino (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy (C 1 -C ₆ ) alkyl, mono- or di- (C 1 -C 6) alkylamino (C 1 -C 6) alkyl, morpholinyl (C 1 -C 6) alkyl, pyrrolidinyl (C 1) -C 6) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, amino, mono- or di- (C 1 -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl and (C 1 -C ₆ ) alkoxy, or R ^h and R ^j together with the nitrogen atom to which they are attached represent a four-, five-, six- or seven-membered heterocyclic ring optionally containing one or more other heteroatoms selected from O, S and N a is optionally substituted with a C 1-6 alkyl or heterocycle, or R ^b and R ^c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered ring, said ring optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted with a substituent such as (C 1 -C 6) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, wherein the phenyl moiety is optionally substituted with one or two -190 ·················· Multiple substituents selected from the group consisting of Br, Cl, F, J, hydroxy, nitro, amino, mono- or di- (C 1 -C 6 alkylamino), (C 1 -C ₆ ) alkyl and (C 1 -C 6) alkoxy; g) a group of the formula NR ^d R ® in which R ^d and R ® are, independently of one another, selected from the group consisting of hydrogen, C 1-12 -alkyl, C 3-12 -cycloalkyl, S (O) 2-phenyl, phenyl , heterocycloalkyl- (C 1 -C 6) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N, or R ^d and R ® each, independently, is R COR ^f wherein R ^f represents hydrogen, NR ^b R ^c, _(Ci-C6) alkoxy, amino-íCrCeJalkoxy CCiC6) alkoxy, mono (Ci-6) alkyl-amino- (C6 ) alkoxy- (C 1 -C 6) alkoxy, N, N-di- (C 1 -C 6) alkyl-amino- (C 1 -C 6) alkoxy- (C 1 -C 6) alkoxy, C 1-12 -alkyl, C 3-12 cycloalkyl, phenyl-C 1-6 -alkyl or phenyl, wherein in each case the alkoxy, alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents, such as: halogen, hydroxy a group, nitro, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy, di- (C 1 -C 6) alkylamino- (C 1 -C 6) alkoxy, pyrrolidine which is optionally substituted with (C 1 -C 6) alkyl, or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, h) a group of the formula O (CH 2) m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above ^and m is 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-4 -alkyl, k) optionally substituted phenyl-C 1-6 -alkoxy, (l) cyano; m) C ₃ ^ alkenyloxy, -191 • 99 99 99 9 9 9 9 9 9 9 9 9 9,999,999,999 • 9,999 9,999 99 9 9 9 9 9 9 999 99 99 99 99 n) a pyridyloxy or pyridylthio group, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, q) formamidomethyl group, r) C1-β alkyl group, s) phenyl group, t) a C 2-4 -alkenyl group or a C 2-4 -alkynyl group, each of which is optionally substituted with a phenyl which is optionally substituted with one or more of the following substituents, such as: C 1-6 -alkyl, C 1-6- alkoxy or halogen, u) CHO, v) dihydroxyborane w) tetrazolyl; and R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) and C 1-4 alkyl optionally substituted by one or more of the following substituents such as: hydroxyl, halo or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below; d) C 1-6 alkoxy optionally substituted by one or more of the following substituents such as: hydroxyl, C 1-4 alkoxy, halogen or amino of formula NR ^h R ^j , where R ^h and R ^j are as defined below, provided that these groups are not attached to a carbon that is attached to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxyl, g) a group of the formula COR ^a in which R ^a represents a hydroxyl group, a C 1-6 -alkoxy group or R ^a represents a group of the formula NR ^b R ^c , in which R ^b and R ^c , independently of one another, represent hydrogen, C 1-6 -alkyl or phenyl, rung m alkyl group and -192 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Phenyl is optionally substituted with one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ¹ , independently of one another, are hydrogen or C 1-6 A 6-alkyl group, (C 3 -C 6) -heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R 'together with the nitrogen atom to which they are attached, represent a five-, six- or seven-membered saturated heterocyclic ring which optionally contains an additional heteroatom selected from O, S or N and is optionally substituted with a C 1-4 alkyl group; h) a group of the formula NR ^d R ® in which R ^d and R ® they are, independently of one another hydrogen, Ci.i2-alkyl, C _{3. 12-} cycloalkyl or phenyl or a group of formula COR ^f , wherein R ^f represents hydrogen, C 1-6 -alkyl, C 3-12 -cycloalkyl, phenyl-C 1-6 -alkyl or phenyl, in each case alkyl, cycloalkyl and phenyl is optionally substituted with one or more of the following substituents such as: halogen, hydroxyl, nitro or amino of the formula NR ^h R ^j , wherein R ^h and R 'are as defined above i) a group of formula O (CH 2) _m R ⁹ wherein m is 2, 3, 4 or 5 and R ⁹ is a hydroxyl group or a group of the formula NR ^d R ®, wherein R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ^a , wherein R ^a is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 -alkyl, I) optionally substituted phenyl-C 1-6. ₆ alkoxy m) cyano or o) C ^ ₂ -alkenyl or C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents such as: alkyl-CI6 , C 1-6 -alkoxy or halogen, provided that when each of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ represents hydrogen, then R ^{2 is} not phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl . 73. The compounds of formula I and their pharmaceutically acceptable salts in which: X is NR ⁸ ; R ¹ represents hydrogen; -193 ·· ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, b) a C 1-8 -alkyl group optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , where R ^h and R * are as defined below, c) a C 1-6 -alkoxy group optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ^j , wherein R ^h and R * are as defined below provided that these groups are not bonded to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, f) a group of formula COR ^a or SO ₂ R ^a , wherein R ^a represents a hydroxyl group, (C 1 -C 6 alkyl, (C 1 -C 6) alkoxy or R ^a represents a group of the formula NR ^b R ^c ; wherein R ^b and R ^c are, independently of one another, hydrogen, C 1-6. ₁₂ alkyl, C _{3. 12-} cycloalkyl, phenyl (C 0 -C 6) alkyl or heterocyclyl- (C ₀ -C ₆ ) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl and thiophenyl), wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- ( C ₀ -C ₆ ) alkyl is optionally substituted with one or more of the following substituents, such as: hydroxyl, (C 1 -C ₆ ) -hydroxyl, halogen, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) _C6) alkoxy, -O-fCrCeJalkylhydroxylová group C3.i ₂ -cycloalkyl, or an amino group of formula NR ^h R ^j; wherein R ^h and R ^j are independently from each other hydrogen, (C ₁ -C ₁₂ ) alkyl, (C 3 -C ₆ ) cycloalkyl, (C 3 -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpholine and piperazine), -194 · · Ci ₆ Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci Ci (Ci-C ₆ ) alkenyl, (C 1 -C ₆ ) -alkynyl, (C ₃ -C 6) cycloalkenyl (C ₀ -C ₆ ) alkyl, hydroxyC 1 -C ₆ ) -alkyl, amino (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy (C 1 -C 6) ₆ ) alkyl, mono- or di- (C 1 -C 6) alkylamino (C 1 -C ₆ ) alkyl, morpholinyl (C 1 -C ₆ ) alkyl, pyrrolidinyl (C 1 -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl is optionally substituted with one or more substituents selected from halogen, hydroxy, nitro, amino, mono- or di- (CiCejalkylamino, (C, -C6) alkyl and (C, -C6) alkoxy, or R ^h and R together with the nitrogen atom to which they are attached, represent a four-, five-, six- or seven-membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from O, S and N and is optionally substituted with a C 1-4 alkyl group or a heterocycle or R ^b and R ^c together with the nitrogen atom form to which they are attached an optionally substituted 4-, 5-, 6- or 7-membered ring, said ring optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring optionally substituted with a substituent, such as (C 1 -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of Br, Cl, F J, hydroxy, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, (C 1 -C 6) alkyl and (C 1 -C 6) alkoxy; g) a group of formula NR ^d R ^e in which R ^d and R ^e are, independently, selected from hydrogen, CI.I ₂ -alkyl, C ₃ .i ₂ cycloalkyl, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- (C 1 -C ₆ ) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N, or R ^d and R 8 each, independently of one another, represents a group of the formula COR ^f wherein R ^f represents hydrogen, NR ^b R ^c , (C 1 -C ₆ ) alkoxy, amino- (C 1 -C ₆ ) alkoxy- (C ₁ -C ₆ ) alkoxy, mono- _(Ci-C6) alkyl-amino- (C, -C6) alkoxy- (C, -C6) alkoxy, N, N-di _(Ci-C6) alkyl-amino- (C, -C6) alkoxy- (C 6) alkoxy, and C ₂ -alkyl, C ₃ .i ₂ is cycloalkyl, phenyl-C ^ alkyl group or phenyl wherein in each case alkoxy, alkyl, cycloalkyl, -195 ·· ······························ And phenyl is optionally substituted with one or more of the following substituents, such as: halogen, hydroxy, nitro, (C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, di- (C 1 -C 6) alkylamino - (C 1 -C ₆ ) alkoxy, pyrrolidine which is optionally substituted with (C 1 -C ₆ ) alkyl, or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, h) a group of the formula O (CH 2) _m R ⁹ wherein m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ^e , wherein R ^d and R ^e are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above ^and m is 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-6 -alkyl, k) optionally substituted phenyl-C 1-6 -alkoxy, (l) cyano; m) C ₃ ^ alkenyloxy, n) pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted by one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, q) formamidomethyl group, r) C 1-6 alkyl, s) phenyl group, t) a C 2-4 -alkenyl group or a C 2-4 -alkynyl group, each of which is optionally substituted with a phenyl which is optionally substituted with one or more of the following substituents, such as: C 1-4 -alkyl, C 1-8 -alkoxy or halogen, -196 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· ·· ·· ·· · u) CHO, v) dihydroxyborane w) tetrazolyl; and R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) and C 1-4 alkyl optionally substituted by one or more of the following substituents such as: hydroxyl, halo or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below; d) C 1-6 alkoxy optionally substituted by one or more of the following substituents such as: hydroxyl, C 1-4 alkoxy, halogen or amino NR ^h R ^j , wherein R ^h and R ^j are as defined below, provided that these groups are not attached to a carbon that is attached to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a , wherein R ^a represents a hydroxyl group, a C 1-6 alkoxy group or R ^a represents a group of the formula NR ^b R ^c , wherein R ^b and R ^c , independently of one another, represent hydrogen, a C 1-6 alkyl group or a phenyl group; m alkyl and phenyl are optionally substituted with one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-4 alkyl, C 6) -heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered saturated a heterocyclic ring which optionally contains another heteroatom selected from O, S or N and is optionally substituted with a C 1-4 alkyl group; h) a group of the formula NR ^d R ^e in which R ^d and R ^e are independently selected from the group hydrogen, Ci.i2-alkyl, C ₃ .i ₂ cycloalkyl group or phenyl or a group of formula COR ^f wherein R ^f is hydrogen, C _i-2 alkyl group, a C ₃ .i ₂ -cycloalkyl, phenyl -C 1-6 -alkyl group or phenyl, in each case the alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents such as: halogen, hydroxyl, nitro or amino of the formula NR b R ¹ , wherein R ^h and R ^j are as defined above; ) a group of formula -197 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · O (CH ₂ ) _m R ⁹ wherein m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ^a , wherein R ® is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1. 6-alkyl, l) optionally substituted phenyl-CM-alkoxy m) cyano or o) C ^ ₂ -alkenyl or C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted with one or more from the following substituents such as: Ct. 6-alkyl, C 1-4 -alkoxy or halogen. 74. Compounds of Formula I and pharmaceutically acceptable salts thereof in which: X is -C = NOR ⁷ wherein R ⁷ is H or C 1. A 4-alkyl group; R ¹ represents hydrogen; R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, b) C 1-6 -alkyl optionally substituted by one or more of the following substituents, such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below, c) C 1-6 -alkoxy optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ^j , wherein R ^h and R ^j are as defined below provided that these groups are not bonded to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, f) a group of formula COR ^a or SO ₂ R ^a , wherein R ^a represents a hydroxyl group, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy or R ^a represents a group of the formula NR ^b R ^c ; -198 where R ^b and R ^c represent, independently of each other. -198 · · · · · φ · φ · «φ pričom φ φ φ pričom pričom , hydrogen, Ci. ₁₂ alkyl, C 3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C 0 -C 6) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl and thiophenyl), wherein the alkyl group, cycloalkyl group , phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl are optionally substituted with one or more of the following substituents such as: hydroxyl, (C 1 -C 6) -hydroxy, halogen, nitro, (C 1 -C 6) alkyl, (C 1 -C 6) C ₆ ) alkoxy, -O-C ₁ -C ₆ alkylhydroxyl, C 3 -C ₁₂ -cycloalkyl or amino of the formula NR ^h R ^j ; wherein R ^h and R ^j are each independently hydrogen, (C 1 -C 12) alkyl, (C 3 -C 6) cycloalkyl, (C 3 -C 6) heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl tetrazole, pyridine, piperidine, pyrazine) , imidazole, triazole, morpholine and piperazine), (C 1 -C 6) alkenyl, (C 1 -C 6) -alkynyl, (C 3 -C 6) cycloalkenyl (C 0 -C 6) alkyl, hydroxy (C 1 -C 6) -alkyl, amino (C 1 -C 6) ) alkyl, (C 1 -C 6) alkoxy (C 1 -C 6) alkyl, mono- or di- (C 1 -C 6) alkylamino (C 1 -C 6) alkyl, morpholinyl (C 1 -C 6) alkyl, pyrrolidinyl (C 1 -C 6) alkyl, pyridinyl, phenyl (C 0 -C 6) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C 6) alkyl and (C 1 -C 6) alkyl 6) alkoxy; or R ^h and R ^j together with the nitrogen atom to which they are attached represent a four, five, six or seven membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from O, s and N, and is optionally substi or C 1-6 alkyl or heterocycle, or R ^b and R ^c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered ring, said ring optionally containing one or more additional rings heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted with a substituent such as (C 1 -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C 6) alkenyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of Br, Cl, F, J, -1999 9 · hydroxy, nitro, amino, mono- or di- (C 1 -C 6 alkylamino, (C 1 -C 6) alkyl) and (C ₁ -C ₆ ) alkoxy; g) a group of the formula NR ^d R R, in which R ^d and R ^e are, independently of one another, selected from hydrogen; _12- alkyl, C 3-12 cycloalkyl, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- (C 1 -C 6) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N, or R ^d and R ® each, independently of each other, represent a group of formula COR ^f wherein R ^f represents hydrogen, NR ^b R ^c , (C ₁ -C ₆ ) alkoxy, amino- (C 1 -C ₆ ) _C6) alkoxy- _(Ci-C6) alkoxy, mono- (C6) -alkyl-amino- (C, -C6) alkoxy- (C, -C6) alkoxy, N, N-di- (C, -C6) alkyl-amino- (C _C6) alkoxy- (C, -C6) alkoxy, m ₂ -alkyl, C3.12cykloalkylovú group, a phenyl-C ^ alkyl group or phenyl wherein in each case the alkoxy, alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents such as: halogen, hydroxy, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy, di-C 1 -C ₆ alkyl-amino-C 1 -C 6 alkoxy, pyrrolidine, optionally e substituted with (C 1 -C ₆ ) alkyl, or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, h) a group of the formula O (CH ₂ ) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ represents a group of the formula COR ®, wherein R ® is as defined above and m is 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-4 -alkyl, k) optionally substituted phenyl-C 1-4 -alkoxy, (l) cyano; m) a C 3-6 alkenyloxy group, - 200 - • BB • · · · · • • BB • · B · • B • · • ·· • • • B B B • · · • · • B · · • · B ·· ·· · · · · · · B B n) a pyridyloxy or pyridylthio group, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, q) formamidomethyl group, (r) alkyloxy; s) phenyl group, t) C 2-4 -alkenyl or C 2-4 -alkynyl, each of which is optionally substituted with phenyl, which is optionally substituted with one or more of the following substituents, such as: C 1-4 -alkyl, C 1-6 -alkoxy a group or halogen, u) CHO, v) dihydroxyborane w) tetrazolyl; and R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) and C 1-4 alkyl optionally substituted by one or more of the following substituents such as: hydroxyl, halo or amino of the formula NR ^h R ', wherein R ^h and R ^j are as defined below; _An alkoxy group optionally substituted by one or more of the following substituents, such as: hydroxyl, C 1-6 -alkoxy, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R 'are defined below, provided that these groups e) an optionally substituted phenoxy group, f) a hydroxyl group, g) a group of the formula COR ^a , wherein R ^a represents a hydroxyl group, a C 1-6 alkoxy group or R ^a represents a group of formula NR ^b R ^c , wherein R ^b and R ^c , independently of one another, represent hydrogen, C 1-6 -alkyl or phenyl, wherein the alkyl group; -201 phenyl is optionally substituted with one or more of the following substituents, such as: a hydroxyl group or a phenyl group; an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 -alkyl, (C 3 -C 6) -heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R 'together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered saturated heterocyclic ring optionally containing an additional heteroatom selected from O, S or N and optionally substituted with C 1 h) an alkyl group, h) a group of the formula NR ^d R ^e , wherein R ^d and R ^e are independently selected from the group consisting of hydrogen, C 1-12 -alkyl, C 3-12 -cycloalkyl or phenyl or a group of formula COR ^f , wherein R ^f represents hydrogen, C 1-12 -alkyl, C 1-6 alkyl, 3.12-cycloalkyl, phenyl-C 1-8 -alkyl or phenyl, in each case alkyl, cycloalkyl and phenyl being optionally substituted by one or more of the following substituents, such as: halogen, hydroxyl, nitro or amino of formula NR ^h R, wherein R ^h and R ^j are as defined above i) a group of formula O (CH 2) _m R ^9, wherein m is 2, 3, 4 or 5, and R ⁹ is hydroxy or a group of formula NR ^d R ® wherein R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ®, wherein R ® is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1. e-alkyl, l) optionally substituted phenyl CVE-alkoxy m) cyano or o) C ^ ₂ -alkenyl or C _{2 R} alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents such as: Cv 6-alkyl, C 1-4 -alkoxy or halogen, provided that when each of R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ is hydrogen, and X is C = NOH, then R ^{2 is} not 4- methylphenyl or 3,4-dimethoxyphenyl. 75. The compounds of formula I and their pharmaceutically acceptable salts in which: X represents a substituted methylene or carbonyl group; R ¹ represents hydrogen; -202 ·· ·· ·· ························· R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, b) a C 1-6 -alkyl group optionally substituted with one or more of the following substituents, such as; a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below, c) a C 1-6 -alkoxy group optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ', wherein R ^h and R ^j are as defined below with the proviso that these groups are not bonded to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, f) a group of formula COR ^a or SO 2 R ³ , wherein R ^a represents a hydroxyl group, (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy or R ^a represents a group of the formula NR ^b R ^c ; wherein R ^b and R ^c are, independently of each other, hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, phenyl (C 0 -C 6) alkyl or heterocyclyl- (C 0 -C 6) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3benzodioxole, pyridinyl and thiophenyl) wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl group are optionally substituted with one or more of the following substituents such as: hydroxyl group, (C 1 -C ₆ ) -hydroxyl, halogen, nitro, (C 1 -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy, -O- (C 1 -C 6) alkylhydroxyl, C3. ₁₂ -cycloalkyl or amino of the formula NR ^h R ^j ; wherein R ^h and R ^j are independently from each other hydrogen, (C 1 -C ₁₂ ) alkyl, (C 3 -C 6) cycloalkyl, (C ₃ -C 6) heterocycloalkyl- (C ₀ -C 6) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpholine and piperazine), -203 (C 1 -C 6 alkenyl, (C 1 -C 6) -alkynyl, (-203) C ₃ -C 6) cycloalkenyl (C ₀ -C 6) alkyl, hydroxy (C 1 -C 6) -alkyl, amino (C 1 -C 6) alkyl, (C 1 -C ₆ ) alkoxy (C 1 -C ₆ ) alkyl, mono- or di- (C 1 -C 6) alkylamino (C 1 -C 6) alkyl, morpholinyl (C 1 -C 6) alkyl, pyrrolidinyl (C 1 -C 6) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen , hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C 6) alkyl and (C 1 -C 6) alkoxy, or R ^h and R ^j together with the nitrogen atom to which they are attached, , a five-, six- or seven-membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from O, S and N and is optionally substituted with a C 1-4 alkyl or heterocycle, or R ^b and R ^c together with the nitrogen atom form to which they are bound, pr optionally substituted 4-, 5-, 6-, or 7-membered ring, said ring optionally containing one or more additional heteroatoms selected from O, N and S, and said ring optionally substituted with a substituent such as (C 1 -C 4) ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C 6) alkenyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of Br, Cl, F, J, hydroxy, nitro, amino, mono- or di- (C 1 -C ₆ ) alkylamino, (C ₁ -C ₆ alkyl and (C ₁ -C ₆ ) alkoxy; g) a group of formula NR ^d R ^e in which R ^d and R® are, independently, selected from hydrogen, and C ₂ -alkyl, C ₃ .i ₂ cycloalkyl, S (O) ₂ -phenyl, phenyl, heterocycloalkyl-C 1 -C 6 alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N, or R ^d and R ® each, each other independently of one another, denotes a group of formula COR ^f where R ^f represents hydrogen, NR ^b R ^c , (C ₁ -C ₆ ) alkoxy, amino- (C 1 -C ₆ ) alkoxy- (C ₁ -C ₆ ) alkoxy, mono-C 1 -C ₆ alkyl-amino- ICI-CeJalkoxy-ICI-CeJalkoxy, N, N-di · ^? C 6) alkyl-amino _(Ci-C6) alkoxy- (C, -C6) alkoxy, and C ₂ -alkyl, C ₃ .i ₂ cycloalkyl, phenyl-C 1-4 -alkyl or phenyl, in each case alkoxy, alkyl, cycloalkyl -204 ································ · · · · a phenyl group optionally substituted by one or more of the following substituents: halogen, hydroxy, nitro, (C, ₆₎ alkyl, (C _-C 6) alkoxy, di _(Ci-C6) alkyl -amino- (C 1 -C 6) alkoxy, pyrrolidine, which is optionally substituted with (C 1 -C 6 alkyl), or an amino group of the formula NR ^h R ', wherein R ^h and R ^j are as defined above, h) O (CH 2) _m R ⁹ . wherein m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ^e , wherein R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ®, wherein R ^a is as defined above ^and m represents 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-4 -alkyl, k) optionally substituted phenyl-C 1-6 -alkoxy, (l) cyano; m) C 1-4 alkenyloxy group, n) pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, q) formamidomethyl group, (r) C1-6 alkyl; s) phenyl group, t) 4-C ₂ to alkenyl group or a C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: C ^ -alkyl, Ci_6-alkoxy or halogen, -205 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · u) CHO, v) dihydroxyborane w) tetrazolyl; and R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) and C 1-8 -alkyl, optionally substituted by one or more of the following substituents, such as: hydroxyl , halo or amino of the formula NR ^h R 1 wherein R ^h and R ^j are as defined below, d) C 1-6 alkoxy optionally substituted by one or more of the following substituents such as: hydroxyl, C 1-4 alkoxy, halo or amino NR ^h R ^j , where R ^h and R ^j are as defined below, provided that these groups are not attached to a carbon that is attached to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a , wherein R ^a represents a hydroxyl group, a C 1-6 alkoxy group or R ^a represents a group of the formula NR ^b R ^c , wherein R ^b and R ^c , independently of one another, represent hydrogen, C 1-6 -alkyl or phenyl, wherein alkyl and phenyl are optionally substituted with one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 -alkyl, (C 3) -C6) -heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent five-, six- or seven-membered a saturated heterocyclic ring which optionally contains a further heteroatom selected from O, S or N and is optionally substituted with a C 1-4 alkyl group; h) a group of the formula NR ^d R ® in which R ^d and R ^e are independently selected from each other from hydrogen, C 12 -alkyl, C ₃ . ₁₂ cycloalkyl group or phenyl or a group of formula COR ^f wherein R ^f is hydrogen, Zvi ₂ -alkyl, C ₃ -i2-cycloalkyl, phenyl-C ^ alkyl group or phenyl wherein in each case the alkyl group, a cycloalkyl and phenyl is optionally substituted with one or more of the following substituents, such as: halogen, hydroxyl, nitro or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above i) a group of the formula -206 ······················································· ·· ·· · O (CH ₂ ) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ^e , wherein R ^d and R ^e are as defined above; or R ⁹ represents a group of formula COR ^a , wherein R ^a is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 alkyl, I) optionally substituted phenyl-C 1-6 alkyl alkoxy m) cyano or o) C ₂ -4 alkenyl group or a _C2 _4-alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents are: Cis-alkyl , C 1-4 -alkoxy or halogen, provided that: 2- (diethylamino) -1-methylethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate N- [2- (diethylamino) ethyl] -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea -177 ·· ··· ······ · 9 · 9 · 9 N - ^ - OAdihydroindenoll.Z-cJpyrazol-S-N ' ylJfenylJ-referred-morfolinoetyQmočovina N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -1-piperidinecarboxamide N- [4- ( _1,4 -dihydro-indeno [1,2-c] pyrazol-3-yl) -phenyl] -N '- [2- (dimethylamino) -1-methyl-ethyl] -urea N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N'-Tetrahydro-2-furanylmetylmočovina N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2-furylmethyl) urea N- (1,3-benzodioxol-5-ylmethyl) -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea N-cyclobutyl-N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- (2-piperidinoethyl) urea N-benzyl-N' - [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea N- [4- (diethylamino) butyl] -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea N- [4- (1,4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) phenyl] -N '- [2- (2-thienyl) ethyl] urea N-IS-ídietylaminoJpropyll-fuel-N ' ^ dihydroindenon -cjpyrazol-S-yOfenyl] -urea N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [(1-ethyltetrahydro-1H-2-pyrrolyl) methyl] urea N- (2,5-difluorobenzyl) -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N ^, - [2- (2-hydroxyethoxy) ethyl] urea N - ^ - ^ im-dihydroindenon -cJpyrazol yOfenylJ-S-N '- ^ - l-hydroxy (hydroxymethyl) -etyljmočovina N- [4- (1,4-dihydro-indeno [1 ₁ 2-c] pyrazol-3-yl) phenyl] -N '- (2,3-dihydroxypropyl) urea N1- [4- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) phenyl] -4- (2-pyridyl) -1-piperazinecarboxamide -17899 • 9 9 9 9 • 9 9 9 9 99 · 9 9 9 999 9 9 9 9 9 9 999 99 99 99 N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N- [3- (dimethylamino) propyl] -Nmetylmočovina N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -1-azetánkarboxamid N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4- (4-fluorophenyl) -1-piperazinecarboxamide N-benzyl-N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N-methyl urea ^N - [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N-ethyl-N- (2-hydroxyethyl) urea N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4- (2-methoxyphenyl) carboxamide -1piperazín N '- [4- (1,4-dihydro-indeno [1,2-cJpyrazol-3-yl) phenyl] -N- [2- (dimethylamino) ethyl] -N-methyl-urea N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4-methyl-1piperazínkarboxamid N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4- (4-hydroxyphenyl) -1piperazín-carboxamide N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4 - [(E) -3-phenyl-2-propenyl] -1piperazínkarboxamid N1- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -4-phenyl-1piperazínkarboxamid N '- [4- (1 _L 4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N, N-di (2-methoxy-ethyl) -urea N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] -N- (2,3-dihydroxypropyl) -N-methyl-urea N, N-di [2- (diethylamino) ethyl] -N '- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] urea N- [4- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) phenyl] -N ^, - (2-pyridylmethyl) urea N- [4- (1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) phenyl] -N '- (3-pyridylmethyl) urea N- [4- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) phenyl] -N ^- (4-pyridylmethyl) urea -179 • ··· · ··· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·· · ··· ·· ·· ·· ·· · N - ^ - IM-dÍhydroindenon.ľ-cIpyrazol yOfenylJ-S-N '- ^ - hydroxyetyOmočovina N - ^ - CM-dihydroindenotl.ž-cJpyrazol-S-ylJfenylJ-N '- ^ - ídimetylaminoJheptyl] -urea. 68. A compound selected from i R ¹ = H R ^z X R ³ , R ⁴ , R ', R ° 4- (Ph) phenyl ch ₂ H 4- (OPh) phenyl ch ₂ H 4- (SO ₂ Me) phenyl (CH ₂ ) ₂ R ⁴ = MeO 3- (CO ₂ H), 4- (OH) phenyl ch ₂ H 3- (NO ₂ ), 4- (OH) phenyl ch ₂ H 3- (OCH ₂ CONH ₂ ) phenyl ch ₂ H 4- (OCH ₂ Ph) phenyl ch ₂ R ⁴ . R = ³ (MeO) ₂ 4- (OCH ₂ Ph) phenyl ch ₂ R '= MeO 4 (OH) -phenyl ch ₂ R ^4, R = ³ (MeO) ₂ 3- (CONH (CH ₂ ) ₂ MOR), 4 (OH) phenyl ch ₂ H 3- (CONH (CH ₂ ) ₂ NEt ₂ ), 4 (OH) phenyl ch ₂ H 4- (Br) PHENYL ch ₂ H 4 (OH) -phenyl ch ₂ R ⁴ = MeO 4- (CONH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ H 4- (CONH (CH _{2) 2} OMe) phenyl ch ₂ H 4- (CONH (4-NO ₂ Ph)) phenyl ch ₂ H 4 (OH) -phenyl ch ₂ R ³ = MeO 4- (CONH (CH ₂ ) ₂ NEt ₂ ) phenyl ch ₂ R ⁴ = NH ₂ 4- (Br) phenyl with H 4 (OH) -phenyl ch ₂ R ³ = 0 _{(CH2) 2} OMe 4- (SO ₂ NH (CH ₂ ) ₂ MOR) phenyl ch ₂ H 4- (SO ₂ NH (CH ₂ ) ₂ OMe) phenyl ch ₂ H 3- _{{CH2 NMe2)} 4 (OH) -phenyl ch ₂ H -180 ··· ······ t · · · ··· · · · ··· · · · ·············· · 2- [2- (dimethylamino) ethoxy] ethyl N- [4- (1,4-dihydroindeno [1,2c] pyrazol-3-yl) phenyl] carbamate N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -phenyl] -carbamic acid 2- (1-methyl-tetrahydro-1H-2-pyrrolyl) -ethyl ester N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -phenyl] -carbamic acid 2 - [[2- (dimethylamino) ethyl] (methyl) amino] ethyl ester 2- [ethyl (2-hydroxyethyl) amino] ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate 2-morpholinoethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate 2- (diethylamino) ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate 2- (N, N-diethylamino) -N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide, N- (3-phenyl-1,4-dihydroindeno) [1,2-c] pyrazol-6-yl) -2- (dimethylamino) acetamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2- ( dipropylamino) acetamide, 2-hydroxy-N- [3- (perhydroazepin-1-yl) propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (perhydroazepin-1-yl) ethyl] -5- ( _1,4 -dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [3- (homopiperazine-1-yl) propyl] -5- (1 _L 4-dihydro-indeno [1 2 _I-c] pyrazol3- yl) benzamide, 2-hydroxy-N- [2- (homopiperazin-1-yl) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -benzamide, 2-hydroxy-N- [3- (thiomorpholin-1-yl) propyl] -5- (1 _L 4-dihydro-indeno [1 _l2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- (2- (thiomorpholin-1-yl) ethyl) -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, * -170 • ···················· ·· ·· · 2-hydroxy-N- [3- (4-methylpiperazin-1-yl) propyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (4-methylpiperazin-1-yl) ethyl] -5- ( _1,4 -dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [3- (piperazin-1-yl) propyl] -5- (1 _l 4-dihydro-indeno [1,2-c] pyrazol-3yObenz-amide, 2-hydroxy-N- [2- (piperazin-1-yl) ethyl] -5- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) benzamide, 2-hydroxy-N- (2-piperidino-propyl) -5- (1,4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- (2-piperidinoethyl) -5- ( _1,4 -dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [3- (N _I, N-diisopropylamino) propyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [3- (N, N-dipropylamino) propyl] -5- ( _1,4 -dihydroindeno [ _1,2 -c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (N, N-diisopropylamino) ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (N, N-dipropylamino) ethyl-5- (1 _L 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -benzamide, 2-hydroxy-N- [3- (N, N-dimethylamino) propyl] -5- (1,4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) -benzamide, 2-hydroxy-N- [2- (N, N-dimethylamino) ethyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -benzamide, 2-hydroxy-N- [3- (pyrrolidin-1-yl) propyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benz amide, -169 • ········································· N- [2- (N, N-diethylamino) ethyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) amide -2hydroxybenz, N- [3- (N, N-diethylamino) propyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -2-hydroxy-benzamide, 2-hydroxy-N- [2- (pyrrolidin-1-yl) ethyl] -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 2-Hydroxy-N- (2-morpholinopropyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- (2-morpholinoethyl) -5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 2-Ethyl-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) butanamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) neopentanamid. 2-methyl-N- (3-phenyl-1,4-dihydro-indeno [1 2 _I-c] pyrazol-6-yl) pentanamide, 2-methyl-N- (3-phenyl-1,4-dihydroindeno [ _1,2 -c] pyrazol-6-yl) butanamide, 2,5-Difluoro-N- (3-phenyl-1,4-dihydroindeno [ _1,2 -c] pyrazol-6-yl) benzylamide _I 2,3- difluoro-N- _{(3-phenyl-1-I,} 4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide _l 2,4- difluoro-N- (3-phenyl-1 _l 4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide, 2-fluoro-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide, -168 ·· BB ·· · · · · · · B B B B B 99 B · B 99 99 · 2- (4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] acetamide, 2-Methoxy-4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol 2-chloro-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenol, 2-methoxy-5- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenol, 2-morpholinoethyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoate, 2- (3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenoxy] ethanol, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3 (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy) , lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially) dimethylamino), a polyhalogen-lower-alkyl group, -159polyhalogen-lower-alkoxy (especially difluoromethoxy), nitro, cyano, lower-alkylthio (especially methylthio), carboxyl, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted groups carbamoyl, Nmethylcarbamoyl, N-phenylcarbamoyl) and pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted with one or more of the following groups, such as trifluoromethyl or nitro. Compounds according to claim 49, wherein R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2 (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) ) phenyl, 4-carbamoylmethoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 2- (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) phenyl, 4-carbamoylmethoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl . 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3 (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4yl) propoxy ), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino ( especially dimethylamino), polyhalogen-lower-alkyl, polyhalogen-lower-alkoxy (especially difluoromethoxy), nitro, cyano, lower-alkylthio (especially methylthio), carboxyl, lower-alkoxycarbonyl (especially methoxycarbonyl), amido acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted with one or more of the following groups such as trifluoromethyl or nitro. -15546. Compounds according to claim 43, wherein R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-yl, 2) when X is methylene, R ¹ is hydrogen and two of R ³ , R ⁴ , R ⁵ and R ⁶ are independently from each other hydrogen, halogen having an atomic mass of from about 19 to 36, C 1-6 -alkyl, C 1-6 -alkyl, alkoxy or trifluoromethyl and the other two are hydrogen, then R ^{2 is} not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl containing two or fewer substituents, wherein the substituents are halogen having an atomic mass of from about 19 to 36; 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylamino -ethoxy, 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), ary, alkoxy (especially benzyloxy), di-lower- alkylamino (especially dimethylamino), polyhalogen-lower-alkyl, polyhalogen-lower-alkoxy (especially difluoromethoxy), nitro, cyano, lower alkylthio (especially methylthio), carboxyl, lower alkoxycarbonyl (especially methoxycarbonyl) m acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted with one or more of the following groups such as a trifluoromethyl or nitro. The compounds of claim 31, wherein R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2 (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) ) phenyl, 4-carbamoyl-methoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3 (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4yl) propoxy ), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially) dimethylamino), polyhalogen-lower-alkyl, polyhalogen-loweralkoxy (especially difluoromethoxy), nitro, cyano, lower-alkylthio (especially methylthio), carboxyl, loweralkoxycarbonyl (especially methoxycarbonyl), and amido cetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted by one or more -146 ·· ··································· The following substituents, such as trifluoromethyl or nitro. The compound of claim 25, wherein R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl ₁ 2-aminomethyl-4-pyridyl, 2 (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) ) phenyl, 4-carbamoylmethoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3 (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy ), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially dimethylamino) ), polyhalogen-lower-alkyl, polyhalogen-lower-alkoxy (especially difluoromethoxy), nitro, cyano, lower-alkylthio (especially methylthio), carboxyl, lower-alkoxycarbonyl (especially methoxycarbonyl), especially amido m acetamido and benzamido) and optionally substituted carbamoyl (particularly carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of the following substituents is trifluoromethyl or nitro. The compound of claim 19, wherein R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2 (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) phenyl, 4-carbamoyl-methoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 3- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3 -carbamoyl-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert -butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-5-144 ·· ·· ·· · · · · · · · · Nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3 -phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-acetamidophenyl - [N- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-phenyloxy) phenyl, 3- (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3 - [3 (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl , 2-furyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl. Compounds according to claim 19, wherein R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. Compounds according to claim 19, in which R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, -143 · ftft ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3 (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4yl) propoxy), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially dimethylamino) ), polyhalogen-lower-alkyl, polyhalogen-loweralkoxy (especially difluoromethoxy), nitro, cyano, lower-alkylthio (especially methylthio), carboxyl, loweralkoxycarbonyl (especially methoxycarbonyl), amido (especially acetyl) amido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and pyridyloxy or pyridylthio, wherein the pyridyl ring is optionally substituted with one or more of the following groups, such as trifluoromethyl or nitro. -141 · · 14 14 14 14 14 14 14 14 14 14 14 Compounds according to claim 13, in which R ² is 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2 (hydroxyamidino) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) ) phenyl, 4-carbamoyl-methoxyphenyl, 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 2) when X represents S and R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not 2,4-dichlorophenyl. Compounds according to claim 13, wherein R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. Compounds according to claim 13, in which R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, 2. The method of claim 1 wherein said protein kinase is a tyrosine kinase. 2) when X is a group of formula (CH 2) _n wherein n is 1, 2 or 3, R ¹ is hydrogen and two of R ³ , R ⁴ , R ⁵ and R ⁶ independently of one another are hydrogen, halogen having an atomic mass of from about 19 to 36, C 1-4 -alkyl, C 1-4 -alkoxy or trifluoromethyl and the other two represent hydrogen when R ² is thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted or phenyl containing two or less substituents, the substituents being halogen having an atomic mass of from about 19 to 36, C 1-4 alkyl, C 1-4 -alkoxy or trifluoromethyl; to said kinase at a sufficient concentration to inhibit the enzyme activity of said kinase. 3) when X is carbonyl, R ² is phenyl, 4-chlorophenyl or 4-methoxyphenyl, then ^{R3, R4, R5} and ^R6 are not trifluoromethyl; and 3- (dibenzylamino) propyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate 3- [2- (2H-1,2,3, _l 4-tetraazol-5-yl) -4-pyridinyl] -4 _l 5-dihydro-2H-benzo [g] indazole 3- (4-lzokyanatofenyl) -1 , 4-dihydro-indeno [1,2-c] pyrazole, 3- [4- (2-morpholinoethoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole 3- {4 - [(2-diethylaminoethyl) aminomethyl] phenyl} -1,4-dihydroindeno [1,2-c] pyrazole trihydrochloride -176 · · 9 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 17 9 99 ·· ·· · N- [4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenyl] benzenesulfonamide N- (2-morpholinoethyl) -4'-dihydroindeno [1,2-c] pyrazol-3-ylaniline dihydrochloride N- (1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -2-morpholinoacetamide N- (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-ylamine trihydrochloride 3 * Γ ŕ R. R. R. R. X L R H C = O ___ NO, - ¹ ¾. and pharmaceutically acceptable salts and tautomers thereof. -175 ························· 9 9 9 9 9 99 99 99 9 59. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 together with a pharmaceutically acceptable diluent or carrier. A compound of formula I, according to claim 1, for use as a medicament. 61. A compound of formula I, according to 1, for use as a medicament for inhibiting protein kinase activity. Use of a compound of formula I, according to 1, in the manufacture of a medicament for use in inhibiting protein kinase activity. 63. The method of claim 1, wherein said compound is in enantiomeric form, is in admixture with one or more other said compounds, or is in both enantiomeric form and in admixture with one or more other said compounds. 64. The method of claim 1, wherein said protein kinase is a serine kinase. 65. The method of claim 1 wherein said protein kinase is a threonine kinase. 66. The method of claim 2, wherein said tyrosine kinase is KDR. 67. A compound selected from the group consisting of dihydroxy 4- (4H-indeno- [1,2-c] pyrazol-3-yl) phenylborane 3- {3- [2- (N, N-diethylamine) ethoxy] phenyl} -1,4-dihydro-indeno [1 _L 2 c] pyrazol _l S-fS-p-In.na dietylaminoJpropoxyjfenylJ-M-cJpyrazol dihydroindenon ^, 3-3- [2- (N _I, N-dimethylamino) ethoxy] phenyl} -1 _l 4-dihydro-indeno [1 _L 2 c] pyrazole 3 _I - {343- (N, N- (Jimethylamino) propoxy) phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (N, N-dipropylamino) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, a S-N-N-N, N-dipropylamino-propoxy-phenyl-l-N-dihydro-indenofi-4-pyrazole, and pharmaceutically acceptable salts and tautomers thereof. 56. A compound selected from X = (CH ₂ ) n Table 1 i ψ r c R R R R N R H 1 2— S—. 5 NO ₂ H I 3-NO2 6,7- (OMe) 2 I 3-OPh H 1 4-SMe H 1 H 1 3-OH, 4-OMe H l 4-OMe-OH.3 whether 1 2-OH 6,7- (OMe) 2 1 4-i-iMcq- 9 9 9 f 9 .9 9 -173 • é ··· 9 · 9 999 99 99 99 99 999 j k r c R. R. R. R. N r * H l "-X) 6.7, S (O \ fe) 3 1 2,3,4- (OMe) ₃ H 1 4-OCHF 2 H I 4-OH, 3,5- (But) 2 H 2 4-NHAc H 2 4-OCH 2 CH = CH 2 H 2 4-NEt 2 H 2 4-NO2 H 2 4-OCH 2 Ph H 2 4-CN H 2 2-Cl, 5-NO2 and pharmaceutically acceptable salts and tautomers thereof. 57. A compound selected from X = (CH ₂ ) n Table 2 R ^J RR ^r R ^ï N 2 R 6-AcNH 1 X? -174 · 9 · 9 9 9 · 9 9 9 «9 9 9 · j + r & R R * R R N Second R H 1 cf ₃ H I / ^3r J j 7-OMe 2 YY H 2 ΛΚ. and pharmaceutically acceptable salts and tautomers thereof. 58. A compound selected from r ' Table 3 3- {3- [3- (4-methylhomopiperazin-1-yl) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (4-methylhomopiperazin-1-yl) -ethoxy] -phenyl} -1,4-dihydro-indeno [1,2-c] pyrazole, 3- {3- [3- (homopiperazin-1-yl) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (4-methylpiperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [3- (4-methylpiperazin-1-yl)] Propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (homopiperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, -172 ·········· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 3- {3- [3- (piperazin-1-yl) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (piperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- [3- (3-piperidino-propoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole, 3- [3- (2-piperidino-ethoxy) -phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole, 3- [3- (3-morpholinopropoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole, 3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydro-indeno [1,2-c] pyrazole, 3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydroindeno [1,2c] pyrazole, 3-nitro-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide, 3-fluoro-N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzylamide, 3- (4-hydroxy-phenyl) -1H- [1] benzothieno [3,2-c] pyrazole, N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) benzamide, N- (2-morpholinoethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, -164 · β · β β β 16 16 16 16 16 16 16 16 16 16 3- (4-methoxyphenyl) -1 H -benzo [3,2-c] pyrazole, 3- (4-aminophenyl) -1H- [1] benzothieno [3,2-c] pyrazole, 3-Chloro-4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol 3- [4- (5-Trifluoromethyl-2-pyridyloxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole, 6 _{L of} 7,8-trimethoxy-3- (2 _I 3 _I 4-trimethoxyphenyl) -1,4-dihydro-indeno [1,2-c] pyrazole, 3- (4-benzyloxyphenyl) -4,5-dihydro-2H-benz [g] indazole, 6,7-dimethoxy-3- (3-phenoxyphenyl) -1,4-dihydro-indeno [1,2-c] pyrazole, 3- (4-bromo-2-thienyl) -4,5-dihydroindeno ( _1,2 -c) pyrazole, 3- (4-acetamidophenyl) -4,5-dihydro-2H-benz [g] indazole, 3- (4-difluoromethoxy-phenyl) -1,4-dihydro-indeno [1,2-cJpyrazol, 3- (2-naphthyl) -1,4-dihydro-indeno [1,2-c] pyrazole, 3- (4-tiometoxyfenyl) -1,4-dihydro-indeno [1,2-c] pyrazole, 3- (3-nitrophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 3- (2-chloro-4-pyridyl) -4,5-dihydro-1 H -benzo [g] indazole, 3- (4-nitrophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-ylamine 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide N- (2-diethylaminoethyl) -3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide, N- (2-morpholinoethyl) -3- (1,4-dihydroindeno [1, 2-c] pyrazol-3-yl) phenoxyacetamide, 4- (3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butanoic acid, ethyl 4- (3- (1) , 4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenoxy} butanoic acid, 3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole, 3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazol-6-ol . 6- (2-morpholinoethoxy) -3- (2-thienyl) -1,4-dihydro-indeno [1,2-cjpyrazol, -1623- [3- (2-hydroxyethoxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole, 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) ) phenoxyacetic acid, 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetic acid ethyl ester, 3-Morpholino-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) propionamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzanilide. 3-phenyl-1 H -benzofuro [3,2-c] pyrazole, 3- (2-thienyl) indeno [1,2-c] pyrazol-4 (1H) -one, 3- (4-methylphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime, 3- (3,4-dimethoxyphenyl) indeno [1,2-c] pyrazol-4 (1H) -one oxime, 3-phenylindeno [1,2-c] pyrazol-4 (1H) -one oxime, 3- (2-thienyl) -1H- [1] benzothieno [3,2-c] pyrazole, -161 ·· 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole 4,4-dioxide, 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole 4-oxide, 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole, 3- (2-thienyl) -1H- [1] benzothieno [3,2-c] pyrazole, 3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenol, 3- (3,4,5-trimethoxyphenyl) -1,4-dihydro-indeno [1,2-c] pyrazole, 3- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3-carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy- 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2, 4-dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-phenyloxy) phenyl 3- (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3 (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- ( 2-diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 2-furyl, 3- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3-carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy- 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4- dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-carbamamoyl cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-phenyloxy) phenyl, 3 - (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3 (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- (2 -diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 2-furyl, 5- [3,5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3- N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3- [3- (N- (2-morpholinoethyl) carbamoyl) propoxyphenyl], 4- (N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 4- (morpholinacetamido) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. The compound of claim 43, wherein R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy , 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-156-yl) ethoxy, 2-dimethylaminoethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) -propoxy, 3- (pyrrolidin-1-yl) propoxy, 3dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) -propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, ( 3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido), optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl and Nphenylcarbamoyl), carboxyl, nitro and amino. The compound of claim 43, wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the following group, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- (N- methylcarbamoyl) 6- (N-phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy. 49. Compounds of formula I and pharmaceutically acceptable salts thereof, in which X is a) substituted methylene b) carbonyl, c) oxygen, d) -C = NOR ⁷ in which R ⁷ is H or C 1-4 -alkyl, e) NR ⁸ in which R ⁸ is H, an optionally substituted C 1-4 -alkyl group or an optionally substituted phenyl, f) a group of formula (CH 2) n in which n is 1, 2 or 3, or g) a group of formula S (O) _P in which p is 0, 1 or 2; R ¹ represents hydrogen; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) a C 1-6 alkyl group which is optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ¹ , wherein R ^h and R ^j are as defined below; an alkoxy group which is optionally substituted by one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , where R ^h and R ^j are as defined below, provided that these groups are not carbon-bound, which is attached to the alkoxy oxygen -157skupiny; or halo e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a in which R ^a represents a hydroxyl group, a C 1-6 -alkoxy group or R ^a represents a group of the formula NR ^b R ^c in which R ^b and R ^c , independently of one another, are hydrogen, C 1-6 -alkyl or phenyl, the alkyl and phenyl being optionally substituted by one or more of the following substituents, such as: hydroxyl or amino of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 -alkyl or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered saturated heterocyclic ring optionally containing a further heteroatom selected from h) a group of the formula NR ^d R ^e , wherein R ^d and R ^e are independently selected from the group consisting of O, S or N; hydrogen, Cv 6-alkyl or phenyl or groups of formula COR ^f , wherein R ^f represents hydrogen, C 1-4 -alkyl, C 3-8 -cycloalkyl or phenyl, in each case alkyl, cycloalkyl and phenyl being optionally substituted by one or more of the following substituents such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, i) a group of the formula O (CH 2) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ^e , wherein R ^d and R ® are as defined above; or R ⁹ is a group of formula COR ^a wherein R ^a is as defined above and m is 1,2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-Ci_6-alkyl, l) optionally substituted _phenyl-6 Cv -alkoxy or o) C ₂ . 3) when X is carbonyl, R ² is phenyl, 4-chlorophenyl or 4-methoxyphenyl, then ^{R3, R4, R5} and ^R6 are not trifluoromethyl; -151 · · 3- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3-carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, -1493-hydroxy-4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl , 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl , 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N- (2-diethylaminoethyl) carbamoylethyl] carbamoylphenyl 4- (prop-1-phenyloxy) phenyl, 3- (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3 (N- (2-diethylaminoethyl) carbamoyl) Propoxy] phenyl, 4- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 2-furyl, 5- [3 5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3-N- (2 -morfolinoetyl) -carbonyl oylmethoxy) phenyl, 3- [3- (N- (2-morpholinoethyl) carbamoyl) propoxyphenyl], 4- (N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 4- (morpholinoacetamido) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. Compounds according to claim 31, wherein R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido), optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl and Nphenylcarbamoyl), carboxyl, nitro and amino. The compound of claim 31, wherein -150R ²³ , R ⁴ , R ⁵ and R ⁶ represent the following groups, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- ( N-methylcarbamoyl); 6- (N-phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy. 37. Compounds of formula I and pharmaceutically acceptable salts thereof, in which X represents a substituted methylene group or a carbonyl group; R ¹ represents H; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and R ^3, R ^4, R ⁵ and R ⁶ are as defined above; provided that: 3- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3-carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy- 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4- dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-carbamamoyl cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-phenyloxy) phenyl, 3 - (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3 (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- (2 (diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 2-furyl, S -PS-bis-trifluoromethyl-phenyl-2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3-N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3- [3- (N- (2-morpholinoethyl) carbamoyl) propoxyphenyl], 4- (N- (2-morpholinoethyl) carbamoyl-methoxy) phenyl, 4- (morpholinoacetamido) phenyl and 4- [3- (N - (2-morpholinoethyl) carbamoyl) propoxy] phenyl. The compound of claim 25, wherein R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group -147 ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · (Especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2 - (pyrrolidin-1-yl) ethoxy, 2-dimethylamino-ethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) -propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido), optionally substituted carbamoyl group (especially carbamoyl, N-methylcarbamoyl and N-phenylcarbamoyl), carboxyl, nitro and amino. The compound of claim 25, wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the following groups, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- (N- methylcarbamoyl) 6- (N-phenylcarbamoyl), 3-morpholinopropoxy and 2-morphophinoethoxy. Compounds of formula I and their pharmaceutically acceptable salts, in which X is -C = NOR ⁷ wherein R ⁷ is hydrogen or C 1-4 -alkyl; R ¹ is hydrogen; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and R ^3, R ^4, R ⁵ and R ⁶ are as defined above; with the proviso that when R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen and X represents C = NOH, then R ^{2 is} not 4-methylphenyl or 3,4-dimethoxyphenyl. Compounds according to claim 31, wherein R 2 represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. The compound of claim 31, wherein -148 R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from an optionally substituted alkoxy group (especially methoxy, 3-morpholinopropoxy, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4-biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 3- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3-carbamoylmethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, The method of claim 2, wherein said tyrosine kinase is either a receptor tyrosine kinase or a non-receptor tyrosine kinase. 4) when X is carbonyl, ^R2 is phenyl, ^R3 represents bromo, ^R4 represents hydroxy and ^R5 represents methoxy, then ^R6 is not hydrogen -207 · 4 · · 4 · · · · · · · · · · · · · · · · · · 4-alkenyl or _C2 ^ -aIkinylovú group, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents, such as: C ^ -alkyl, C ^ alkoxy group or a halogen, provided that 4 (OH) -phenyl ch ₂ R ^J = O (CH _{2) 2} MOR 4 (with _Z NH (CH _{2) 2} NEt ₂₎ phenyl CK ₂ H 4- (OCH ₂ CONH ₂₎ phenyl ch ₂ R ^J = O (CH ₂ ) ₂ OMe 4 (OH) -phenyl ch ₂ R 5 = (OH), R ⁵ = O (CH ₂ ) ₂ OMe 4 (OH) -phenyl ch ₂ R 1 = O (CH ₂ ) ₂ OMe 4- (CONH (CH _{2) 2} NHEt) phenyl ch ₂ H 4- (CONHCH ₂ -2-pyr) phenyl ch ₂ H 4- (OCH ₂ CONH ₂₎ phenyl ch ₂ ^RJ = OH 4- (OCH ₂ CO ₂ H) phenyl ch ₂ H 69. A compound selected from X NRR ' CH2 NHN-Ci2H25 CH2 __. .OMe CH2 CH2 CH2 -about - 181 · 181 · 181 181 181 181 181 181 181 181 181 181 I · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · CH2 CH2 jQ HN-'x / x / CH2 Ϊ> ~ N CH2 hk-A ' ⁼ N . CH2 IN  ABOUT CH2 HN ^ y CH2 0 HN— - 0 Z ~ \ N Nf.íe \_IN 0 O ™ 0 ^hn O 0 HN - ^ 2 ^ —NMe _z 0 ^H V <^ NH (HCl) 0 ^h V'm M ^C 'N 0 ^{HnX > S} ^ ~ / ^H WITH KN ^ x ^ / Λ \ _y WITH HN ^ WZej with £ hh) with £ KM) with HM -182 ··················································· ·· ·· · with CH2 NHIS-Pr CH2 NHcyc-PR CH2 NHN-Hex CH2 CK2 ABOUT CK2 N NMs CH2 / \ N 0 ' \ 7 CH2 HN - ^^ - OMe CH2 ^hn ~ EN ^ ~ ^oh CH2 Ν-Λ CH2 z ~ N ^HN Ch.2 CH2 ΗΝχ ^ Ν Y'nh iW CH2 ^H Vs ϊ> 0 ABOUT 0 HN- -183 ··· ·· 0 ' ^{HN —} NMe, 0 (2ΗΛ) 70. A compound selected from x NRR ' CH2 KM. \ N 0 (2HCI) v_v CH2 about CH2 / - \ N KMa V_7 CH2 «« - (J CH2 HM-H0 CH2 71. The compounds of formula I and their pharmaceutically acceptable salts, in which X is S (O) _P wherein p is 0, 1 or 2; R ¹ represents hydrogen; R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, -184 ·· ·· ·· ·· ················································ · · b) a C 1-6 alkyl group optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ^j , wherein R ^h and R 'are as defined below, c) a C 1-6 -alkoxy group optionally substituted with one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ⁱ , where R ^h and R ^j are as defined below; with the proviso that these groups are not bound to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, f) a group formula COR ^a or SO 2 R ^a wherein R ^a is hydroxy, (C, -C6) alkyl, (CrCeJalkoxy or R ^a is a group of formula NR ^b R ^c; wherein R ^b and R ^c are, independently of one another, hydrogen, C 1-12 alkyl, C 3-12 cycloalkyl, phenyl (C ₀ -C 6) alkyl or heterocyclyl- (C ₀ -C 6) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl) , 1,3-benzodioxole, pyridinyl and thiophenyl), wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C 0 -C 6) alkyl group are optionally substituted with one or more of the following substituents such as: hydroxyl, (C 1 -C 8) - hydroxyl, halogen, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy, -O- (C 1 -C ₆ ) alkylhydroxyl, C ₃ . ₁₂ -cycloalkyl or amino of the formula NR ^h R ^j ; wherein R ^h and R ^j are independently from each other hydrogen, (C 1 -C ₁₂ ) alkyl, (C 3 -C ₆ ) cycloalkyl, (C 3 -C 6) heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpholine and piperazine), (C ₁ -C ₆ ) alkenyl, (C 1 -C ₆ ) -alkynyl, (C 3 -C ₆ ) cycloalkenyl (C ₀ -C ₆ ) alkyl, hydroxy (C ₁ -C ₆ ) -alkyl , amino (C _r C6) alkyl, (C6) alkoxy (C, -C6) alkyl, mono- or di- (C, -C6) alkylamino _(Ci-C6) alkyl, morpholinyl (C ₆₎ alkyl, pyrolidinyKCrCejalkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of: -185 halogen, hydroxy, nitro, amino, mono- or di - (C 1 -C ₆ ) alkylamino, (C 1 -C 6 alkyl and (C 1 -C 6) alkoxy; or R ^h and R ^j together with the nitrogen atom to which they are attached represent a four-, five-, six- or seven-membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from O, S and N and is optionally substituted with C 1-4 alkyl or heterocycle, or R ^b and R ^c together with the nitrogen atom to which they are attached form optionally substituted 4-, 5-, 6- or a 7-membered ring, said ring optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring optionally substituted with a substituent such as (C 1 -C 6) alkyl, pyridinyl, phenyl (C ₀ - C ₆ ) alkyl, phenyl (C ₂ -C ₆ alkenyl, wherein the phenyl moiety is optionally substituted with one or more i substituents selected from the group consisting of Br, Cl, F, J, hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C 6) alkyl and (C 1 -C 6) alkoxy; g) a group of formula NR ^d R®, where R ^d and R ^e are, independently, selected from hydrogen, CI.I ₂ -alkyl, C _{3. 12} cycloalkyl, S (O) _2- phenyl, phenyl, heterocycloalkyl- (C 1 -C ₆ ) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O, S and N, or R ^d and R ® each, independently of one another, represent a group of the formula COR ^f where R ^f represents hydrogen, NR ^b R ^c , (C 1 -C 6) alkoxy, amino- (C 1 -C 6) alkoxy- ( C, -C6) alkoxy, mono- (C, -C6) alkyl-amino- (C, -C6) alkoxy- (-C ₆₎ alkoxy, N, N-di (C _-C 6) alkyl-amino- (C, -C6) alkoxy- (C, -C6) alkoxy, and C ₂ -alkyl, C3.12cykloalkylovú group, a phenyl-Ci_6-alkyl or phenyl, wherein in each case the alkoxy, alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents such as: halogen, hydroxy, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, di- (C 1 -C ₆ ) alkylamino- (C 1 -C 6) alkoxy, pyrrolidine which is optionally substituted with (C 1 -C ₆ ) alkyl or amino of the formula NR ^h R ', wherein R ^h and R ^j are as defined above, -186 ·························· h) a group of the formula O (CH ₂ ) m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ represents a group of the formula COR ®, wherein R ® is as defined above and m is 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-4 -alkyl, k) optionally substituted phenyl-C 1-4 -alkoxy, (l) cyano; m) C ₃ -6alkenyloxylová group, n) a pyridyloxy or pyridylthio group, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, q) formamidomethyl group, (r) C1-6 alkyl; s) phenyl group, t) ₂ C ^ -alkenyl or a _C2 -4 alkynyl group, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents, such as: C ^ -alkyl, Ci_6-alkoxy or halogen, u) CHO, v) dihydroxyborane w) tetrazolyl; and -187 ··· ······································ · · R ³ , R ⁴ , R ⁵ and R ⁶ , independently of each other, are a) H, b) halogen, c) and C 1-6 alkyl optionally substituted by one or more of the following substituents such as: hydroxyl , halo or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below; d) C 1-6 -alkoxy optionally substituted by one or more of the following substituents such as: hydroxyl, C 1-6 -alkoxy, halogen or an amino group of formula NR ^h R 1 wherein R ^h and R ^j are as defined below, provided that these groups are not attached to a carbon that is attached to the oxygen of the alkoxy group, e) an optionally substituted phenoxy group, f) a hydroxyl group, g) a group of formula COR ^a in which R ^a represents a hydroxyl group, a C 1-6 -alkoxy group or R ^a represents a group of the formula NR ^b R ^c in which R ^b and R ^c independently of one another represent hydrogen, C 1-6 -alkyl or phenyl, while alkyl and phenyl are optionally substituted with one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 -alkyl, (C 3) -C6) heterocycloalkyl- (C0-C6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent five-, six- or seven-membered saturated a heterocyclic ring which optionally contains another heteroatom selected from O, S or N and is optionally substituted with a C 1-4 alkyl group; h) a group of the formula NR ^d R ^e in which R ^d and R ^e are independently selected from the group hydrogen, CM2 alkyl, C3.i ₂ cycloalkyl group or phenyl or a group of formula COR ^f wherein R ^f is hydrogen, C-i2-alkyl, C3. 12-cycloalkyl, phenyl-C 1-6 -alkyl or phenyl, in each case alkyl, cycloalkyl and phenyl being optionally substituted by one or more of the following substituents such as: halogen, hydroxyl, nitro or amino of the formula NR ^ ^1, wherein R ^h and R ^j are as defined above i) a group of formula O (CH 2) m R ^9, wherein m is 2, 3, 4 or 5, and R ⁹ is hydroxy or a group of formula NR ^d R ^e, wherein R ^d and R ^e are as defined above; or R ⁹ represents a group of formula COR ^a , wherein R ^a is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 -alkyl, I) optionally substituted phenyl-C 1-6 N-alkoxy, m) cyano or o) C ₂ . -188 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 4 '- (1-Acetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide oxime 4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) -N- [3- (imidazol-1-yl) propyl] benzylamine trihydrochloride 4- (4-oxo-1, methyl ester) 4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzoic acid 4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) -benzaldehyde 4- (6-amino-1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (N, Ndietylamino) ethyl] benz-amide, 4- (1,4-dihydro-indeno [1 _l2-c] pyrazol-3-yl) -N- (4-nitrophenyl) benzamide _I, N-IS-phenyl-N-dihydroindenoII ^ -clpyrazol-yOmorfolinoacetamid much. N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) morpholinoacetamide, N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) piperidinoacetamide. N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) thiomorpholinoacetamide. N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -4-methylpiperazin-1-ylacetamide; - (c) pyrazol-6-yl) piperazin-1-ylacetamide; N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) pyrrolidin-1-ylacetamide; 4- (1 _l 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [3- (N, N-dimethylamino) propyl] aniline, -171 9 9 9 9 9 9 9 9 9 ·· · · · · · · · · · 9 9 9 9 9 · 9 9 9 9 9 9 9 99 9 9 99 9 4- (6-Acetamido-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid methyl ester, N- (3-methoxypropyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 4- (1 _l 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (N, N-dimethylamino) ethyl] aniline, 4- (1,4-dihydro-indeno [1,2-clpyrazol-3-yl) -N- [3- (N, N-dipropylamino) propyl] aniline, 4- (1 _L 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (N, N-dipropylamino) ethyl] aniline _l 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin-1-yl) propyl] aniline, N- [2- (N, N-diethylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) aniline, N- [3- (N, N-diethylamino) propyl] -4- (1 _l 4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) aniline _I 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin-1-yl) ethyl] aniline, 4- (1 _l 4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) -N- [2- (piperazin-1-yl) propyl] aniline, 4- (1 _l 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (piperazin-1-yl) ethyl] aniline _I 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (thiomorphilin-1-yl) propyl] aniline, 4- (1 _L 4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- [2- (1-tiomorfilin-yl) ethyl] aniline, 4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (2-piperidino-propyl) aniline, 4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) -N- (2-piperidinoethyl) aniline, 4- (1,4-dihydroindeno [ _1,2 -c] pyrazol-3-yl) -N- (2-morphilinopropyl) aniline, 4- (1 _l 4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) -N- (2-morfilinoetyl) aniline, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide 4,4-Dimethyl-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) pentanamide ₁ N-1S-phenyl-1H-dihydroindenol-4-yl-pyrazol-3-yl-cyclohexanecarboxamide, trifluoro-N-15-phenyl-N-dihydro-indeno-4'-pyrazol-2-yl acetamide, pentafluoro-N- (3-phenyl-1,4- dihydro-indeno [1,2-c] pyrazol-6-yl) propanamide; 4-nitro-N- (3-phenyl-1,4-dihydro-indeno [1 2 _I-c] pyrazol-6-yl) benzylamide _l 4-fluoro-N- (3-phenyl-1,4-dihydro-indeno [1 2 _I-c] pyrazol-6-yl) benzylamide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) pentafluoropropananilide, fluoro- N -S-phenyl-1H-dihydroindenol-4-yl-pyrazol-G-ylacetamide, S, S-difluoro-N-IS-phenyl-N-dihydroindenoP ^ -clpyrazol-yObenzylamid much. 4´- (1,4-dihydroindeno [1'-cypyrazol-5-yOtrifluoroacetanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) cyclohexananilide 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4,4-dimethylpentananilide, 4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) neopentylanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-ethylbutananilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-methylpentananilide 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-methylbutananilide 4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) isopentananilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) isobutananilide 4 '- (1,4-dihydroindeno [1 H -pyrazol-5-yO-S.S.-trifluoropropananilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3-nitrobenzylanilide 4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-nitrobenzylanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,3-difluorobenzylanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,5-difluorobenzylanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,4-difluorobenzylanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3-fluorobenzylanilide 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-fluorobenzylanilide 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-fluorobenzylanilide 4 '- (1,4-dihydro-indeno [1 2 _I-c] pyrazol-3-yl) -3,5-difluórbenzylanilid, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) fluoroacetanilide, 4'- (1,4-dihydroindeno [1 H -pyrazol-S-yl] dimethylaminoacetanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) dipropylaminoacetanilide, -167 • ··················· I ····························· · ·· ·· ·· ·· 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) homopiperazin-1-ylacetanilide, 4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) piperazin-1-ylacetanilide, 4´- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-methylhomopiperazin-1-ylacetanilide 4'- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-methylpiperazin-1-ylacetanilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) piperidinoacetanilide, 4-methyl-3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-4-ol, N- [2- (N, N-diethylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-P-In.na-dimetylaminoJetylH-ÍIAdihydroindenon -cjpyrazol ^ S-yObenzamid, N- [2- (N, N-dipropylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-pyridin-3yl) benzamide, N- [2- (N, N-diisopropylamino) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N-diethylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-tS-In.na-dimetylaminoJpropylpl-IIa-dihydroindenon ^ -cJpyrazol-Syl) benzamide, N- [3- (N, N-dipropylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N-diisopropylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benz amide, N- (2-Piperidinoethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-piperidino-propyl) -4- (1 _L 4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl) -4- (1,4 ₎ dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholino-propyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide _I, N- [2- (piperazin-1-yl) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (piperazin-1-yl) propyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (pyrrolidin-1-yl) ethyl] -4- (1,4-dihydiOÍndeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (pyrrolidin-1-yl) propyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (4-methylpiperazin-1-yl) ethyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, -165 • ·· 99 ·· ·· 99 9 9 · 9 · 9 999 ··· 9 9 9 9 99 9 9 9 9 9 999 9 9 9 999 99 99 99 99 N- [3- (4-methylpiperazin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benz amide, N- [2- (thiomorpholin-1-yl) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (thiomorpholin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (homopiperazine-1-yl) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (homopiperazine-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (perhydroazepin-1-yl) ethyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (perhydroazepin-1-yl) propyl] -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N-isopropyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-but-2-yl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N-methyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-ethyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-pentyl-4- (1,4-dihydroindeno [1H-pyrazol-5-yl] benzamide, N- (2-bromoethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N - [(5S, 5-trifluoroprop-1-yl) -N-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (cyclopropylmethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-cyclopentyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (cyclohexylmethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N-referred-chlórcyklopentylH-im-dihydroindenoD.Z-cJpyrazol-S-yQbenzamid, N- [3- (N, N-dimethylamino) -2,2-dimethylpropyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (2-methylpiperidin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, -166 •• β 9 9 9 9 9 9 • · ··· · ····· · · · · N- (3-methyl-but-2-yl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (pyrrolidin-1-yl) ethyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N-dimethylamino) prop-2-yl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-hexyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N-tert-butyl 4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [7- (N, N-Dimethylamino) heptyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-methyl-but-2-yl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-pentyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N-sec-butyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (3,3-dimethylbutyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2,2,3,3, S-pentafluórpropylH-IIa-dihydroindenoll ^ -clpyrazol-Syl) benzamide, N- (2,5-dichlórpentyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2,2-difluoroethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-chloroethyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (N, N-dimethylamino) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-morpholino-propyl) -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (pyrrolidin-1-yl) propyl] -4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzonitrile, 7-methoxy-3- (4-methylsulfonylphenyl) -4,5-dihydro-2H-benz [g] indazole, 4- (1H- [1] -benzo [3 _L 2-c] pyrazol-3-yl) benzamide, 4 '- (1 _L 4-dihydroindeno (1 _L 2 -pyrazol-3-yl) diethylaminoacetanilide, 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxymethyl) phenol, 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridinecarboxamide, {[4- (4,5-dihydro-1H-benzo [g] indazol-3-yl)] - 2-pyridyl] methyl} ammonium chloride, -163 • ··························· · 9 ·· ·· · N - {[4- (4,5-dihydro-1 H -benzo [g] indazol-3-yl) -2-pyridyllmethyl} formamide ₁ 4- (4 _L 5-dihydro-1 H-benzo [g] indazole-3-yl) -2-pyridinecarboxamide oxime, 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) -2-pyridinecarbonitrile, 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) pyridine 1-oxide, 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) aniline, 4- (3- (1,4-dihydroindeno [1H-pyrazol-S-yl] phenoxy) butyramide, N- (2-diethylaminoethyl) -4- {3- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) phenoxy} butyramide, N- (2-morpholinoethyl) -4- {3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butyramide _I 3- (2-thienyl) -1,4-dihydroindeno [ 1,2-c] pyrazole-6-carboxamide, N-methyl-3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide, N- (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1, 2-c] pyrazole-6-carboxamide; 3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxanilide; N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -acetamide, 4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzanilide. N- (2-diethylaminoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl) -4- (1,4-dihydroindeno [1,2- c] pyrazol-3-yl) benzamide; 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol; 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N-methyl-4- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) benzamide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide, N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) -acetamide, 4 '- (1,4-dihydro-indeno [1,2-c] pyrazol-3-yl) morfolinoacetanilid. 4,4-dimethyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazole, 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid, 4- (1-methyl-methyl) ester 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid, 4' - (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide, 4 '- (1,4) -dihydroindeno [1,2-c] pyrazol-3-yl) -3-morfolinopropionanilid, 4-alkenyl or C 2-4 -alkynyl, each of which is optionally substituted with phenyl, which is optionally substituted with one or more of the following substituents, such as: C 1-4 alkyl, C 1-4 alkoxy or halogen, provided that: wherein at least one of R ³ , R ⁴ , R ⁵ and R ⁶ or a substituent on R ² represents one of the following substituents such as: a) a group of the formula O (CH 2) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ is a hydroxy group or a group of the formula NR ^d R ® in which R ^d and R ® have -158 ·· • · meaning as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above ^and m is 1, 2, 3, 4 or 5; b) a C 1-6 -alkyl group substituted with one or more of the following substituents such as: a hydroxyl group; an amino group of the formula NR ^h R ', wherein R ^h and R ^j are as defined above; c) C 1-6 -alkoxy optionally substituted with one or more of the following substituents such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, provided that these groups are not attached to the carbon that is attached to the oxygen of the alkoxy group; or halo d) a group formula COR ^a in which R ^a represents hydroxy, Ci.6-alkoxy, or R ^a is a group of formula NR ^b R ^c wherein R ^b and R ^c are as defined above, e) a group of formula NR ^d R ®, wherein R ^d and R ® are as defined above. Compounds according to claim 49, wherein R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. * Compounds according to claim 49, in which R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, 4) · · · · • • · · · · · · · · where X is carbonyl, ^R2 is phenyl, ^R3 represents bromo, ^R4 represents hydroxy and ^R5 represents methoxy, then ^R6 is not hydrogen, and 4-alkyl, C1-alkoxy or trifluoromethyl; and 4- [N- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-phenyloxy) phenyl, 3- (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy ] phenyl, 2-furyl, 5- [3,5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) - 2-furyl, 3-N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3- [3 (N- (2-morpholinoethyl) carbamoyl) propoxyphenyl], 4- (N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 4 - (morpholinacetamido) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. Compounds according to claim 13, in which R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy , 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidine-1-142) · · ················· Ethoxy, 2-dimethylamino-ethoxy, 2- (2-dimethylamino-ethoxy) 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy) , carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), an amido group (especially acetamido and benzamido), an optionally substituted carbamoyl group (especially carbamoyl, N-methylcarbamoyl and Nphenylcarbamoyl), carboxyl group, it trio and amino. The compounds of claim 13, wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the following groups, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- (N- methylcarbamoyl) 6- (N-phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy. Compounds of formula I and their pharmaceutically acceptable salts, in which X represents oxygen; R ¹ represents hydrogen; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and R ^3, R ^4, R ⁵ and R ⁶ are as defined above; with the proviso that if R ¹ , R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen, then R ^{2 is} not phenyl, 4-N-phenylcarbamoylphenyl, 4-acetamidophenyl, 4-benzamidophenyl, 4-carboxyphenyl, The method of claim 3, wherein said tyrosine kinase is selected from the group consisting of KDR, flt-1, TIE-2, Lck, Src, fyn, and yes. 5) when X is a carbonyl group and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, then R ^{6 is} not aryl. 76. The compounds of formula I and their pharmaceutically acceptable salts in which: X is a group of formula (CH 2) _n wherein n is 1, 2 or 3; R ¹ represents hydrogen; R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, b) C 1-6 -alkyl optionally substituted by one or more of the following substituents such as: hydroxyl, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below, c) C 1-6 -alkoxy optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR ^h R ^j , wherein R ^h and R ^j are as defined below provided that these groups are not bonded to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, f) a group formula COR ^a or SO 2 R ^a wherein R ^a is hydroxy, (C, -C) alkyl, (C, -C6) alkoxy or R ^a is a group of formula NR ^b R ^c; wherein R ^b and R ^c are each, independently of one another, hydrogen, C i ₂ alkyl, _C3-I2 cycloalkyl group, phenyl (C ₀ -C 6) alkyl or heterocyclyl- (C ₀ -C 6) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3-benzodioxole, pyridinyl and thiophenyl), wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C 0 -C 6) alkyl group are optionally -208 substituted with one or more of the following substituents, such as: hydroxyl, (C 1 -C ₆ ) -hydroxyl, halogen, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy, -O- (C 1 -C ₆ ) alkylhydroxyl, C 3-12 cycloalkyl or an amino group of the formula NR ^h R '; • ·· ·· ·· ·· ··· · · · t φφφ ··· ··· I • φ · · · · · * ^{ΦΦ Ι} * · · · · · · · · · · φ · φφ wherein R ^h and R ^j , independently of one another, are hydrogen, (C 1 -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpholine and piperazine), (C 1 -C ₆ ) alkenyl, (C 1 -C ₆ -alkynyl, (C 3 -C ₆ ) cycloalkenyl (C ₀ -C ₆ ) alkyl, hydroxy (C 1 -C ₆ ) - alkyl, amino _(Ci-C6) alkyl, (-C ₆₎ alkoxy (C6) -alkyl, mono- or di-ICR -C 6) alkylamino _(C-C6) alkyl, morpholinyl (C 6) alkyl, pyrrolidinyl (C C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C 6) ₆ ) alkyl and (C 1 -C ₆ ) alkoxy; or R ^h and R ^j together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered heterocyclic ring which optionally contains one or more additional heteroatoms selected from O, S and N and is optionally substituted with a C 1-6 alkyl group or a heterocycle, or R ^b and R ^c together form with the nitrogen atom to which are bound, optionally substituted 4-, 5-, 6- or 7-membered ring, said ring optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, and said ring being optionally substituted with a substituent such as ( C 1 -C ₆ alkyl, pyridinyl, phenyl (C ₀ -C 6) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of Br, Cl, F, J, hydroxy, nitro, amino, mono- or di- (C 1 -C 6) alkylamino, (C 1 -C ₆ ) alkyl and (C ₁ -C ₆ ) alkoxy; g) a group of the formula NR ^d R ^e in which R ^d and R ® are, independently of each other, selected from the group consisting of hydrogen, C 1-12 -alkyl, C ₃ . ₁₂ cycloalkyl, S (O) _2- phenyl, phenyl, heterocycloalkyl- (C ₁ -C ₆ ) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic group -209I · ····· · · · · · · · · · · · · · · · · · · · · · · · · · · · f · one or more heteroatoms selected from the group consisting of O, S and N, or R ^d and R 8 each, independently of one another, denote a group of the formula COR ^f wherein R ^f represents hydrogen, NR ^b R ^c , (C 1 -C ₆ ) alkoxy , amino- (C 1 -C ₆ ) alkoxy- (C ₁ -C 6) alkoxy, mono-C ₁ -C 6 alkyl-amino-C 1 -C ₆ alkoxy-C ₁ -C 6 alkoxy, N, N-di- (C 1 -C 6) alkylamino- (C 1 -C 6) alkoxy- (C 1 -C 6) C6) alkoxy, CI.I ₂ -alkyl, C ₃ .i ₂ is cycloalkyl, phenyl-C ^ alkyl group or phenyl wherein in each case the alkoxy, alkyl, cycloalkyl and phenyl are optionally substituted with one or a plurality of the following substituents such as: halogen, hydroxy, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, di- (C 1 -C 6) alkylamino- (C 1 -C ₆ ) alkoxy, pyrrolidine which is optionally substituted with (C 1 -C ₆ ) alkyl, or amino groups the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, h) a group of the formula O (CH ₂ ) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above ^and m is 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-4 -alkyl, k) optionally substituted phenyl-C 1-6 -alkoxy, (l) cyano; m) C ₃ ^ alkenyloxy, n) a pyridyloxy or pyridylthio group, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, -210 ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · q) formamidomethyl group, (r) Cm alkyl; s) phenyl group, t) ₂ C ^ -alkenyl or a C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: C ^ -alkyl, CM-alkoxy or halogen, u) CHO, v) dihydroxyborane w) tetrazolyl; and R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) and C 1-4 alkyl optionally substituted by one or more of the following substituents such as: hydroxyl, halogen or an amino group of the formula NR ^h R ⁱ , wherein R ^h and R ^j are as defined below, d) a C 1-4 alkoxy group optionally substituted by one or more of the following substituents, such as: hydroxyl, C 1-4 alkoxy, halogen or amino group of the formula NR ^h R ^J , wherein R ^h and R ^j are as defined below, provided that these groups are not attached to a carbon that is attached to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxyl, g) a group of formula COR ^a , v wherein R ^a represents a hydroxyl group, a C 1-4 alkoxy group or R ³ represents a group of the formula NR ^b R ^c , in which R ^b and R ^c , independently of one another, represent hydrogen, a C 1-4 alkyl group or a phenyl group, and alkyl and phenyl are optionally substituted with one or more of the following substituents, such as: hydroxyl or amino of the formula NR ^h R ¹ , wherein R ^h and R ¹ , independently of one another, represent hydrogen or C 1-4 alkyl, (C ₃ - C 6) -heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered saturated a heterocyclic ring optionally containing a further heteroatom -211 • ······· · a · a · a · a · a · a · a · a Selected from O, S or N and is optionally substituted with a C 1-6 alkyl group, h) a group of the formula NR ^d R ^e , wherein R ^d and R ^e are independently of one another one another from hydrogen, Ci.i2-alkyl, C3.i2 cycloalkyl group or phenyl or a group of formula COR ^f wherein R ^f is hydrogen, Cl-12-alkyl, C3-i2-cycloalkyl, phenyl C 1-6 -alkyl or phenyl, in each case alkyl, cycloalkyl and phenyl are optionally substituted with one or more of the following substituents, such as: halogen, hydroxyl, nitro or amino of the formula NR ^h R ^j , wherein R ^h and R ¹ is as defined above i) a group of the formula O (CH 2) m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group in ZOR NR ^d R ^e , wherein R ^d and R ^e are as defined above; or R ⁹ represents a group of formula COR ^a , wherein R ^a is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1-6 -alkyl, I) optionally substituted phenyl-C 1-6 -alkyl; alkoxy m) cyano or o) C ₂ 4-to alkenyl group or a _C2 -4 alkynyl group each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: Cv β- alkyl, C 1-4 -alkoxy or halogen, provided that when X is a group of formula (CH ₂ ) _n in which n is 1, 2 or 3, R ¹ is hydrogen and two of R ³ , R ⁴ , R R ⁵ and R ⁶ , independently of one another, are hydrogen, halogen having an atomic mass of from about 19 to 36, C 1-4 alkyl, C 1-4 alkoxy or trifluoromethyl and the other two represent hydrogen, then R ^{2 is} not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted or phenyl containing two or fewer substituents, the substituents being halogen having an atomic mass of from about 19 to 36, a C 1-4 -alkyl group, a C 1-4 -alkoxy group or a trifluoromethyl group, and provided that: -212 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · n is 2 and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen or methoxy, then R ^{2 is} not 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid-2-yl or 2-carboxyphenyl. 77. The compounds of formula I and their pharmaceutically acceptable salts in which: X is a) substituted methylene, b) carbonyl, c) oxygen, d) -C = NOR ⁷ wherein R ⁷ is H or C 1-4 alkyl, e) NR ⁸ wherein R ⁸ is H, optionally a substituted C 1-4 alkyl group or an optionally substituted phenyl, f) a group of formula (CH ₂ ) _n in which n is 1, 2 or 3, or g) a group of formula S (O) _P in which p is 0, 1 or 2 ; R ¹ represents H; R ² represents aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted with one or more of the following substituents, such as a) halogen, b) a C 1-6 -alkyl group optionally substituted by one or more of the following substituents, such as: a hydroxyl group, a halogen or an amino group of the formula NR ^h R ', wherein R ^h and R ^j are as defined below, c) C 1-6 -alkoxy optionally substituted by one or more of the following substituents, such as: hydroxyl, COOH, an amino group of the formula NR ^h R ^j , or an amide of the formula CONR b R ', where R ^h and R ^j are as defined below, that these groups are not bonded to the carbon that is attached to the oxygen of the alkoxy group; or halogen d) optionally substituted phenoxy; e) hydroxyl group, f) a group of formula COR ^a or SO ₂ R ^a , wherein R ^a represents a hydroxyl group, (C 1 -C 6) alkyl, (C 1 -C 6) alkoxy or R ^a represents a group of the formula NR ^b R ^c ; -213 and R ^b where R ^b and R ^c mean, independently of one another, hydrogen, C1.12alkylovú group C3.i ₂ cycloalkyl group, phenyl (C ₀ -C ₆₎ alkyl or heterocyclyl- _(Co-C6) alkyl (heterocyclyl = tetrahydrofuranyl, furanyl, 1,3 benzodioxol, pyridinyl and thiophenyl) wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C 0 -C 6) alkyl group are optionally substituted with one or more of the following substituents such as: hydroxyl, (C 1 -C 6) -hydroxyl, halogen, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C ₆ ) alkoxy, -O- (C 1 -C ₆ ) alkylhydroxyl, C 3-12 cycloalkyl or amino of the formula NR ^h R ^j ; wherein R ^h and R 'are each independently hydrogen, (C 1 -C 6) alkyl, (C 3 -C 6) cycloalkyl, (C 3 -C 6) heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = tetrazole, pyridine, piperidine, pyrazine, imidazole, triazole, morpholine and piperazine), (C 1 -C 6) alkenyl, (C 1 -C 6) -alkynyl, (C 3 -C 6) cycloalkenyl (C 0 -C 6) alkyl, hydroxy (C 1 -C 6) -alkyl, amino (C 1 -C 6) alkyl, (C 1 -C 6) C6) alkoxy (C1-C6) alkyl, mono- or di- (C1-C6) alkylamino (C1-C6) alkyl, morpholinyl (C1-C6) alkyl, pyrrolidinyl (C1-C6) alkyl, pyridinyl, phenyl (Co-C6) alkyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, nitro, amino, mono- or di-C 1 -C 6) alkylamino, (C 1 -C 6) alkyl and (C 1 -C 6) alkoxy; ^h and R ^J together with the nitrogen atom to which they are attached represent a four-, five-, six- or seven-membered heterocyclic ring optionally containing one or more additional heteroatoms selected from O, S and N and is optionally substituted with C 1-6 alkyl or heterocycle, or R ^b and R ^c together with the nitrogen atom to which they are attached form an optionally substituted 4-, 5-, 6- or 7-membered ring, said ring optionally having one or more additional rings heteroatoms selected from the group consisting of O, N and S, and said ring is optionally substituted with a substituent such as (C 1 -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C 6) alkenyl, wherein the phenyl moiety is optionally substituted with one or more substituents selected from the group consisting of Br, Cl, F, J, -214 ·· ·· ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Hydroxy, nitro, amino, mono- or di- (C 1 -C ₆ ) alkylamino, (C 1 -C 6) alkyl and (C 1 -C ₆ ) alkoxy; g) a group of the formula NR ^d R ®, wherein R ^d and R ® are, independently of one another, selected from the group consisting of hydrogen, C 1-12 -alkyl, C 3-12cycloalkyl, S (O) 2-phenyl, phenyl , heterocycloalkyl- (C 1 -C 6) alkyl, wherein the heterocycloalkyl is a four-, five-, six- or seven-membered heterocyclic ring containing one or more heteroatoms selected from the group consisting of O, S and N, or R ^d and R ® each, independently of one another, denotes a group of formula COR ^f where R ^f represents hydrogen, NR ^b R ^c , (C 1 -C ₆ ) alkoxy, amino- (C 1 -C ₆ ) alkoxy- (C 1 -C ₆ alkoxy, mono- (C 1 -C 6) alkyl -amino- (C 1 -C 6) alkoxy- (C 1 -C 6) alkoxy, N, N-di- (C 1 -C 6) alkyl-amino- (C 1 -C 6) alkoxy- (C 1 -C 6) alkoxy, C 1-4 -alkyl, C 3-12 cycloalkyl a phenyl, C 1-6 -alkyl or phenyl group, in each case an alkoxy group, an alkyl group, a cycloalkyl group, and a phenyl are optionally substituted with one or more of the following substituents such as: halogen, hydroxy upina, nitro, (C 1 -C ₆ ) alkyl, (C 1 -C 6) alkoxy, di-C 1 -C 6 alkyl-amino-C 1 -C 6 alkoxy, pyrrolidine which is optionally substituted with (C 1 -C 6) alkyl, or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined above, h) a group of the formula O (CH 2) _m R ⁹ in which m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ is a group of formula COR ^a , wherein R ^a is as defined above ^and m is 1, 2, 3, 4 or 5, (i) nitro; j) optionally substituted phenyl-C 1-6 -alkyl, k) optionally substituted phenyl-C 1-6 -alkoxy, (l) cyano; m) C 1-4 alkenyloxy group, -215- · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · «·· ·· n) pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted with one or more of the following substituents such as: trifluoromethyl or nitro; o) hydroxyamidino group, p) aminomethyl group, q) formamidomethyl group, (r) C1-6 alkyl; s) phenyl group, t) C ₂ -4 alkenyl group or a C ₂ ^ -alkynyl, each of which is optionally substituted by phenyl which is optionally substituted by one or more of the following substituents: C ^ -alkyl, CVE-alkoxy or halogen, u) CHO, v) dihydroxyborane w) tetrazolyl; and R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, are a) H, b) halogen, c) and C 1-4 alkyl optionally substituted by one or more of the following substituents such as: hydroxyl, halo or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below; _An alkoxy group, optionally substituted with one or more of the following substituents, such as: hydroxyl, C 1-6 -alkoxy, halogen or amino of the formula NR ^h R ^j , wherein R ^h and R ^j are as defined below, provided that these groups are not e) an optionally substituted phenoxy group, f) a hydroxyl group, g) a group of the formula COR ^a in which R ^a represents a hydroxyl group, a C 1-6 -alkoxy group or R ^a represents a group of the formula NR ^b R ^c , wherein R ^b and R ^c , independently of one another, represent hydrogen, C 1-6 -alkyl or phenyl, the alkyl group and -216phenyl are optionally substituted with one or more of the following substituents, such as: a hydroxyl group or an amino group of the formula NR ^h R ^j , wherein R ^h and R ^j , independently of one another, represent hydrogen or C 1-6 -alkyl, (C 3 -C 6) ) -heterocycloalkyl- (C 0 -C 6) alkyl (heterocycloalkyl = pyridine, morpholine, piperazine and N-methylpiperazine) or wherein R ^h and R ^j together with the nitrogen atom to which they are attached represent a five-, six- or seven-membered saturated heterocyclic a ring which optionally contains another heteroatom selected from O, S or N and is optionally substituted with a C 1-6 alkyl group; h) a group of the formula NR ^d R ^e wherein R ^d and R ® are independently selected from hydrogen; , C 1-6 -alkyl, C 3-12 -cycloalkyl or phenyl or a group of formula COR ^f , wherein R ^f represents hydrogen, C 1-12 -alkyl, C _3-12 -cycloalkyl, phenyl-C 1-6 -alkyl or phenyl, wherein in each case the alkyl, cycloalkyl and phenyl groups are optionally substituted with one or more of the following substituents such as: halogen, hydroxyl, nitro or amino of the formula NR ^h R ', wherein R ^h and R ^j are as defined above i) a group of the formula O (CH ₂ ) _m R ⁹ , _h . wherein m is 2, 3, 4 or 5 and R ⁹ represents a hydroxyl group or a group of the formula NR ^d R ® in which R ^d and R ® are as defined above; or R ⁹ represents a group of formula COR ®, wherein R ® is as defined above and m represents 1, 2, 3, 4 or 5, j) nitro, k) optionally substituted phenyl-C 1. β-alkyl, I) optionally substituted phenyl-C 1-4 -alkoxy, m) cyano or o) C 2-4 -alkenyl or C 2-4 -alkynyl, each of which is optionally substituted with phenyl optionally substituted by one or more of the following substituents such as: Cv 5.5.5-trifluoro-N-15-phenyl-N-dihydroindenol-4-ylpyrazol-e-ylpropanamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) isobutanamide, N- (3-phenyl-1,4-dihydro-indeno [1,2-c] pyrazol-6-yl) izopentanamÍd. 5- [3,5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3- N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3-1604- (N- (2-morpholinoethyl) carbamoyl) 4- [3- (N- (2-morpholinoethyl)) [3- (N- (2-morpholinoethyl) carbamoyl) (propoxyphenyl), moyl-methoxy) phenyl, 4- (morpholinacetamido) phenyl carbamoyl) propoxy] phenyl. The compound of claim 49, wherein R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2- morpholinoethoxy), amido (especially acetamido and benzamido), optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl and N-phenylcarbamoyl), carboxyl, nitro and amino. The compound of claim 49, wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the following group, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- (N- methylcarbamoyl) 6- (N-phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy. 55. A compound selected from the group consisting of 5- [3,5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3- N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3 [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] ₁ 4- (N- (2-morpholinoethyl) carbamoyl-methoxy) -phenyl, 4- (morpholineacetamide) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. The compound of claim 37, wherein R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group -153 ·· (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin- 1-yl) ethoxy, 2-dimethylamino-ethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3dimethylaminopropoxy, 3- ( perhydrothiazin-4-yl) propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), an amido group (especially acetamido and benzamido), optionally substituted carbamoyl group (especially carbamoyl, N-methyl- carbamoyl and N-phenylcarbamoyl), carboxy, nitro and amino. The compound of claim 37, wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the following groups, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- (N- methylcarbamoyl) 6- (N-phenylcarbamoyl), 3-morpholinopropoxy and 2-morpholinoethoxy. 43. The compounds of formula I and their pharmaceutically acceptable salts, in which X is a group of formula (CH ₂ ) n wherein n is 1, 2 or 3 R ¹ is hydrogen; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above, provided that when X is a group of formula (CH ₂ ) _n in which n is 1, 2 or 3, R ¹ is hydrogen and two of R ³ R ⁴ , R ⁵ and R ⁶ , independently of one another, are hydrogen, halogen having an atomic mass of from about 19 to 36, C-alkyl, C 1-4 -alkoxy or trifluoromethyl and the other two represent hydrogen, then R ² does not thienyl, furyl, pyrrolyl, pyridyl, each of which is unsubstituted, or phenyl containing two or fewer substituents, wherein the substituents are halogen having an atomic mass of from about 19 to 36, C 1-6 -alkyl, C 1-4 -alkoxy or trifluoromethyl, and • * With the proviso that when n is 2 and R ³ , R ⁴ , R ⁵ and R ⁶ each represent hydrogen or methoxy, then R ^{2 is} not 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid-2-yl or 2- carboxyphenyl. Compounds according to claim 43, wherein R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. The compound of claim 43, wherein R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, 5) when X is a carbonyl group and R ³ , R ⁴ , R ⁵ and R ⁶ are hydrogen, then R ^{6 is} not aryl. Compounds according to claim 37, wherein R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. The compound of claim 37, wherein R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy, 2carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2 (piperazin-1-yl) ethoxy) 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy, 2 (perhydrothiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3 (pyrrolidin-1-yl) propoxy , 3-dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), lower alkyl (especially methyl), halogen (especially fluorine and chlorine), aryl (especially phenyl), hydroxyl, aryloxy (especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially dimethyl) mino), polyhalogen-lower-alkyl, polyhalogen-lower-alkoxy (especially difluoromethoxy), nitro, cyano, lower-alkylthio (especially methylthio), carboxyl, lower-alkoxycarbonyl (especially methoxycarbonyl), amido and amino groups benzamido) and optionally substituted carbamoyl (especially carbamoyl, Nmethylcarbamoyl, N-phenylcarbamoyl) and pyridyloxy or pyridylthio, wherein the pyridine ring is optionally substituted with one or -152 ··· ····································· · Several of the following groups, such as trifluoromethyl or nitro. The compounds of claim 37, wherein R ² represents 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2 (hydroxyamido) -4-pyridyl, 2-carbamoyl-4-pyridyl, 4-pyridyl-N-oxide, 2- chloro-4-pyridyl, 2-cyano-4-pyridyl, 5-methyl-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) fur-2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl , 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4- (3-morpholinopropoxy) phenyl, 4- (2-morpholinoethoxy) phenyl, 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4- (3-carbamoylpropoxy) ) phenyl, 4-carbamoyl · methoxyphenyl ₁ 3- (3-morpholinopropoxy) phenyl, 3- (2-morpholinoethoxy) phenyl, 3- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) phenyl, 3 -carbamoyl-methoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydroxy-3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di-tert-butyl -butyl-4-hydroxyphenyl, 4-methylphenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-5-nitrophenyl, 4-fluoro-2-chlorophenyl, 4-methylthiophenyl, 4 -biphenylyl, 3-phenoxyphenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl, 4-cyanophenyl, 4-N-methylcarbamoylphenyl, 4-N-phenylphenylcarbamoylphenyl, 4-carboxyphenyl, 4- [N- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-phenyloxy) phenyl, 3- (2-hydroxyethoxy) phenyl, 3- (N- (2-diethylaminoethyl) carbamoylmethoxy) ) phenyl, 3- [3- (N- (2-diethylaminoethyl) carbamoyl) propoxy] phenyl, 4- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 4- [3- (N- (2-diethylaminoethyl)) -carbamoyl) propoxy] phenyl, 2-furyl, 5- [3,5-bis (trifluoromethyl) phenyl] -2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) -2-furyl, 3- N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 3- [3- (N- (2-morpholinoethyl) carbamoyl) propoxyphenyl], 4- (N- (2-morpholinoethyl) carbamoylmethoxy) phenyl, 4- (morpholinoacetamido) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. The compound of claim 19, wherein R ³ , R ⁴ , R ⁵ and R ⁶ , independently of one another, represent hydrogen, halogen (especially fluorine), an optionally substituted lower alkoxy group (especially methoxy, 3-morpholinopropoxy, 2-morpholinoethoxy, 3-carboxypropoxy, carboxymethoxy, 2-carboxyethoxy 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylaminoethoxy, 2- (perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3dimethylaminopropoxy, 3- (perhydrothiazin-4-yl) propoxy), carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and ( 2-morpholinoethoxy), amido (especially acetamido and benzamido), optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl and N-phenylcarbamoyl), carboxyl, nitro and amino. The compound of claim 19, wherein R ³ , R ⁴ , R ⁵ and R ⁶ represent the following groups, such as 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy, 6-carbamoyl, 6- (N- methylcarbamoyl) 6- (N-phenylcarbamoyl), 3-mordolinopropoxy and 2-mordolinoethoxy. - 145 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 99 ·· ·· ·· Compounds of formula I and their pharmaceutically acceptable salts, in which X is NR ⁸ ; R ¹ is hydrogen; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and R ^3, R ^4, R ⁵ and R ⁶ are as defined above. Compounds according to claim 25, wherein R ² represents optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl. The compounds of claim 25, wherein R ² represents 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl or 4-pyridyl, each of which is optionally substituted, naphthyl and optionally mono-, dia-tri-substituted phenyl, wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinopropoxy, The method of claim 1, wherein the activity of said tyrosine kinase affects angiogenesis. The method of claim 5, wherein the inhibition of said tyrosine kinase is anti-angiogenic. The method of claim 6, wherein said inhibition of said tyrosine kinase inhibits the progression of a disease state selected from the group consisting of cancer, arthritis, atherosclerosis, psoriasis, hemangioma. myocardial angiogenesis, coronary and cerebral collateral vascularization, ischemic limb angiogenesis, corneal diseases, rubeosis, neovascular -139 9 9 9 9 99 9 999 99 9 9 9 9 9 9 99 99 99 99 glaucoma, macular degeneration, premature retinopathy, wound healing, ulceration, Helicobacter-related diseases, fractures, endometriosis, diabetic retinopathy, cat scratch fever and thyroid hyperplasia. The method of claim 2, wherein the activity of said tyrosine kinase affects vascular hyperpermeability or edema formation. The method of claim 8, wherein the inhibition of said tyrosine kinase is anti-oedematous. The method of claim 9, wherein the inhibition of said tyrosine kinase inhibits the progression of a disease state selected from the group consisting of burns, trauma, chronic lung disease, stroke, polyps, cysts, synovitis, psoriasis, chronic and allergic inflammation, macular degeneration, diabetic retinopathy, retinopathy of prematurity, ovarian hyperstimulation syndrome, pulmonary and cerebral edema, keloid, fibrosis, cirrhosis, carpal canal syndrome, adult respiratory distress syndrome, ascites and tumor-associated effusions and edema. The method of claim 2, wherein inhibiting said tyrosine kinase has an antitumor effect. The method of claim 2, wherein the inhibition of said tyrosine activity is associated with fertility or pregnancy cessation effects. Compounds of formula I and pharmaceutically acceptable salts thereof, wherein: X is a group of formula S (O) _P wherein p is 0, 1 or 2; R ¹ represents hydrogen; R ² is aryl, pyridyl, thienyl, furyl or pyrrolyl, each of which is optionally substituted; and R ^3, R ^4, R ⁵ and R ⁶ are as defined above; provided that: -140 ························· · ··· ·· ·· ·· ·· · 6-alkyl, C 1-6 -alkoxy or halogen.