KR20010086005A - Tricyclic pyrazole derivatives - Google Patents

Abstract

The present invention relates to certain 3-aryl or 3-heteroarylpyrazoles (some of which are novel compounds) with 4,5 (3,4) -bicyclic ring fusions which are inhibitors of protein kinase activity, And to a process for preparing the pyrazole.

Description

TRICYCLIC PYRAZOLE DERIVATIVES < RTI ID = 0.0 >

At least 400 enzymes have been identified as protein kinases. These enzymes catalyze the phosphorylation of the target protein substrate. Phosphorylation is typically the transfer of a phosphato group from ATP to a protein substrate. The specific structure of the target substrate to which the phosphite is delivered is a tyrosine, serine, or threonine residue. Because the amino acid residues are the target structure for phosphate transfer, the protein kinase enzymes are generally referred to as tyrosine kinases or serine / threonine kinases.

Phosphorylation reactions at tyrosine, serine, and threonine residues and counteracting phosphatase responses are mediated by responses to various intracellular signals (typically mediated through cell receptors), regulation of cellular function, and activation and inactivation of cellular action It is associated with a number of underlying cellular effects. The chain reaction of protein kinases often participates in intercellular signaling, which is necessary for the realization of the cellular action. Owing to their omnipresence in this action, protein kinases can be found as essential parts of the plasma membrane or as cytoplasmic enzymes or can often be located in the nucleus as a component of the enzyme complex. In many instances, the protein kinase is an essential component of enzymes and structural protein complexes that determine when and where cellular action occurs within a protein complex that determines when and where cellular action occurs within the cell.

Protein tyrosine kinase . Protein tyrosine kinases (PTKs) are enzymes that catalyze the phosphorylation of specific tyrosine residues in cellular proteins. The post-translational modification of the substrate protein, often the enzyme itself, serves as a molecular switch to control cell proliferation, activation or differentiation (Schlessinger and Ulrich, 1992, Neuron 9: 383-391). Abnormal or excessive PTK activity has been observed in many disease states, including benign and malignant proliferative disorders as well as diseases that result in inappropriate activation of the immune system (e.g., autoimmune disorders), allograft rejection, and graft versus host disease . In addition, epithelial cell-specific receptor PTKs, such as KDR and Tie-2, mediate angiogenesis and are therefore useful in the treatment of cancer and other inappropriate vascularization (e.g., diabetic retinopathy, choroidal neovascularization due to age- Psoriasis, arthritis, retinopathy of prematurity, infantile hemangioma).

The tyrosine kinase may be a receptor-type (with extracellular, transmembrane and intracellular domains) or a non-receptor type (present within cells as a whole).

Receptor tyrosine kinase (RTK) . RTKs include a large family of transmembrane receptors with diverse biological activities. Currently, at least 19 different RTK subfamilies have been identified. The receptor tyrosine kinase (RTK) family includes receptors important for growth and differentiation of various cell types (Yarden and Ullrich, Ann. Rev. Biochem. 57: 433-478, 1988; Ullrich and Schlessinger, Cell 61: 243-254, 1990). The intrinsic function of the RTK is activated upon ligand binding, which causes phosphorylation of the receptor and multiple cell substrates followed by a variety of cellular responses (Ullrich & Schlessinger, 1990, Cell 61: 203-212). Thus, receptor tyrosine kinase mediated signal transduction is typically initiated by extracellular interactions with specific growth factors (ligands), following receptor dimerization, stimulation of native protein tyrosine kinase activity, and phosphorylation. Thereby forming a complex with a variety of cytoplasmic signaling molecules that promote binding sites for intercellular signaling molecules and promote appropriate cell responses (eg, cell division, differentiation, metabolic effects, changes in the extracellular microenvironment) (Schlessinger and Ullrich, 1992, Neuron 9: 1-20).

Proteins with SH2 (src homology-2) or phosphotyrosine binding (PTB) domains bind to highly-activated activated tyrosine kinases and their substrates that propagate signals into cells. Both domains recognize phosphotyrosine (Fantl et al ., 1992, Cell 69: 413-423; Songyang et al ., 1994, Mol. Cell. Biol . 14: 2777-2785; Songyang et al ., 1993, Cell 72: 767-778; and Koch et al ., 1991, Science 252: 668-678; Shoelson, Curr. Opin. Chem. Biol . (1997), 1 (2), 227-234; Cowburn, Curr. Opin. Struct. Bio . (1997), 7 (6), 835-838). Several intracellular substrate proteins that bind receptor tyrosine kinase (RTK) have been identified. These can be divided into two major groups: (1) substrates with a catalytic domain; And (2) a substrate lacking the domain but acting as an adapter and binding to a catalytically active molecule (Songyang et al ., 1993, Cell 72: 767-778). The specificity of the interaction between the receptor or protein and the SH2 or PTB domains of their substrate 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 surrounding phosphotyrosine residues on a particular receptor are correlated with differences observed in their substrate phosphorylation profile (Songyang et al ., 1993, Cell 72: 767-778). Observations suggest that the function of each receptor tyrosine kinase was determined not only by its expression pattern and ligand availability, but also by the arrangement of the downstream signaling pathway, which is activated by the timing and duration of the particular receptors as well as by the stimuli. Thus, phosphorylation provides an important regulatory step in determining the selectivity of the signaling pathway supplemented by the specific growth factor receptor as well as the differentiation factor receptor.

Several receptor tyrosine kinases and their associated growth factors have been suggested to play a role in angiogenesis, although some may indirectly promote angiogenesis (see 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 RTK. Another notation for human FLK-1 is the " kinase insert domain-containing receptor " (KDR) (Terman et al ., Oncogene 6: 1677-83, 1991). Another alternative notation for FLK-1 / KDR is " Vascular Endothelial Growth Factor Receptor 2 " (VEGFR-2) because it binds with high affinity VEGF. The murine version of FLK-1 / VEGFR-2 is also referred to as NYK (Oelrichs et al , Oncogene 8 (1): 11-15, 1993). DNA encoding the mouse, rat and human FLK-1 has been isolated and this nucleotide and encoded amino acid sequence has been reported (Matthews et al ., Proc. Natl. Acad. Sci . USA, 88: 9026-30, 1991; Terman et al, 1991, supra; Terman et al, B iochem Biophys Res Comm 187:...... 1579-86, 1992; Sarzani et al, supra; and Millauer et al, Cell 72:.. 835 -846, 1993). A number of studies, such as those reported in Millauer et al., Have shown that VEGF and FLK-1 / KDR / VEGFR-2 are important for the proliferation of vascular endothelial cells and the formation and production of blood vessels, respectively called angiogenesis and angiogenesis, Lt; / RTI > is a ligand-acceptor pair that acts as a ligand.

Another type III subclass RTK, designated "fms-like tyrosine kinase-1" (Flt-1), is associated with FLK-1 / KDR (DeVries et al. Science 255; 989-991, 1992; Shibuya et al., Oncogene 5: 519-524, 1990). Another notation for Flt-1 is " Vascular Endothelial Growth Factor Receptor 1 " (VEGFR-1). To date, members of the FLK-1 / KDR / VEGFR-2 and Flt-1 / VEGER-1 subfamilies have been found to be mainly expressed on endothelial cells. These subclass members are characteristically stimulated by members of the vascular endothelial growth factor (VEGF) family of ligands (Klagsburn and D'Amore, Cytokine & Growth Factor Reviews 7: 259-270, 1996). Vascular endothelial growth factor (VEGF) binds to Flt-1 with a higher affinity for FLK-1 / KDR and is fragmented into vascular endothelial cells (Terman et al., 1992, supra ; Mustonen et al. supra ; DeVries et al., supra ). Flt-1 is thought to be essential for endothelial cell organization during angiogenesis. Flt-1 expression is associated with angiogenesis during early angiogenesis and wound healing in mouse embryos (Mustonen and Alitalo, supra ). Expression of Flt-1 in adult tissues, such as the renal glomeruli, suggests an additional function on the receptor that is not associated with cell growth (Mustonen and Alitalo, supra ).

As described above, recent evidence suggests that VEGF plays a role in stimulating both normal angiogenesis 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 associated with the control and enhancement 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].

Other forms of VEGF due to another splicing of mRNA have been reported, including four species described by Ferrara et al . ( J. Cell, Biochem . 47: 211-218, 1991). Both secreted and predominantly cell-associated species of VEGF have been identified by Ferrara et al. (Supra), and the protein has been found to be present in the form of a disulfide linked dimer.

Several related isomorphs of VEGF have recently been identified. However, their role in normal physiological and pathological function has not yet been elucidated. In addition, members of the VEGF family are often co-expressed with VEGF in a number of tissues, and can generally form heterodimers with VEGF. These properties seem to alter receptor specificity and the biological effects of heterodimers and make it difficult to explain their specific function as further illustrated below (see Korpelainen and Alitalo, Curr. Opin. Cell Biol , 159-164, 1998, and references cited within the document).

Placental growth factor (PlGF) has an amino acid sequence that exhibits significant homology with the VEGF sequence (Park et al., J. Biol. Chem . 269: 25646-54, 1994; Maglione et al. -31, 1993). Like VEGF, another species of PlGF results from another splicing of mRNA, and the protein is present in dimeric form (Park et al., Supra ). PlGF-1 and PlGF-2 bind to Flt-1 with high affinity and also PlGF-2 binds well to neurofilin-1 (Migdal et al., J. Biol. Chem . 273 (35): 22272 -22278), but not FLK-1 / KDR (Park et al., Supra ). PlGF has been reported to affect both vascular permeability and mitogenic effects on endothelial cells when VEGF is present at low concentrations (intentionally due to heterodimer formation) (Park et al., Supra ).

VEGF-B is produced as two homologues (167 and 185 residues), such as binding to Flt-1 / VEGFR-1. This can serve to regulate extracellular matrix degradation, cell adhesion and migration through regulation of the expression and activity of the urokinase-type plasminogen activator 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 predominantly expressed by lymphatic endothelial cells. In its fully processed form, VEGF-C may bind to KDR / VEGFR-2 and stimulate endothelial cell proliferation and migration in vitro and angiogenesis 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 results in proliferation and expansion of the lymphatic vessel only, without affecting the blood vessels. Unlike VEGF, expression of VEGF-C is not induced by hypoxia (Ristimaki et al, J. Biol. Chem . (1998), 273 (14), 8413-8418).

The most recently discovered VEGF-D is structurally very similar to VEGF-C. VEGF-D has been reported to bind and activate at least two VEGFRs, VEGFR-3 / Flt-4 and KDR / VEGFR-2. It is originally cloned as c-fos capable of inducing mitotic material for fibroblasts and is predominantly expressed in mesoderm cells of lung and skin (Achen et al, Proc. Natl. Acad. Sci. U.S.A. (1998), 95 (2), 548-553 and references in the document).

It has been postulated that VEGF-C and VEGF-D, when injected into dermal tissues, induce an increase in vascular permeability in vivo in Miles assay (see PCT / US97 / 14696; WO98 / 07832, Witzenbichler et al ., supra ). The physiological role and importance of the ligand in controlling the blood vessel, permeability and endothelial cell response in the tissues in which the ligand is expressed are unclear.

VEGF and VEGFR Based on the novel discovery of the animal and the precedent for ligand and receptor heterodimerization, the action of the VEGF-phase animal is to determine the hemodynamics of the VEGF ligand heterodimer and / or the heterodimerization of the receptor, 0.0 > VEGFR < / RTI > (Witzenbichler et al., Supra). Recent reports also suggest that receptors other than neurotrophilin-1 (see Migdal et al, supra ) or VEGFR-3 / Flt-4 (Witzenbichler et al., Supra) or KDR / VEGFR- Suggest that it may be related to the induction of atherosclerosis (Stacker, SA, Vitali, A., Domagala, T., Nice, E., and Wilks, AF, "Angiogenesis and Cancer" Assoc. Cancer Res., Jan. 1998, Orlando, FL; Williams, Diabetelogia 40: S118-120 (1997)]. To date, no direct evidence has been found for the essential role of KDR in VEGF-mediated blood vessels and permeability.

Nonreceptor tyrosine kinase . Non-receptor tyrosine kinases represent a collection of extracellular and membrane-bound cellular enzymes. Currently, more than 24 individual non-receptor tyrosine kinases have been identified, including 11 subfamilies (Src, Frk, Btk, Csk, Abl, Zap70, Fes / Fps, Fak, Jak, Ack and LIMK). Currently, the Src subfamily of non-receptor tyrosine kinases is composed of the largest number of PTKs and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr and Yrk. The Src subfamily of enzymes is involved in tumorigenesis. A more detailed description of nonreceptor tyrosine kinases is provided in Bolen, 1993, Oncogene 8: 2025-2031, which is incorporated herein by reference.

A variety of tyrosine kinases, which are RTK or non-receptor tyrosine kinases, psoriasis; ≪ / RTI > and other hyperproliferative diseases or hyperimmune responses.

Development of compounds that modulate PTKs . In view of the presumed importance of PTKs to the control and regulation of cell proliferation, diseases and disorders associated with abnormal cell proliferation, mutant ligands (US Patent No. 4,966,849), soluble receptors and antibodies (WO94 / 10202; 1993, Nature 362: 841-844), RNA ligands (Jellinek, et al., Biochemistry 33: 10450-56; 1992, J. Cellular Phys., 152: 272-402, 1992. Exp. Cell Res. 199: 56-62; Wright et al., 1993, Mol. Bio. Cell 4: 358A; Kinsella, et al. 448-57) and tyrosine kinase inhibitors (WO 94/03427, WO 91/15495, WO 94/14808, US Patent No. 5,330,922; Mariani, et al., 1994, Proc. Am. Assoc. Cancer Res. 35: 2268) have been attempted to identify receptor and non-receptor tyrosine kinases.

More recently, attempts have been made to identify small molecules that act as tyrosine kinase inhibitors. For example, bis-monocyclic, bicyclic or heterocyclic aryl compounds (PCT WO 92/20642) and vinylene-azaindole derivatives (PCT WO 94/14808) are generally described as tyrosine kinase inhibitors. (US Patent Application No. 5,302,606), some quinazoline derivatives (EP Patent Application No. 0 566 266 A1; Expert Opin. Ther. Paat. (1998), 8 (4): 475-478) (PCT WO 94/03427), tricyclic polyhydroxy compounds (PCT WO 92/21660) and benzylphosphonic acid compounds (PCT WO 91/15495) as tyrosine kinase inhibitors for use in the treatment of cancer Is described as a compound to be used. Anilinocinoline (PCT WO 97/34876) and quinazoline derivative compounds (PCT WO 97/22596; PCT WO 97/42187) are described as inhibitors of angiogenesis and vascular permeability.

Attempts have also been made to identify small molecules that act as serine / threonine kinase inhibitors. For example, bis (indolylmaleimide) compounds have been described as inhibiting certain PKC serine / threonine kinase isoforms that are associated with vascular permeability that has been dysfunctional in VEGF-related diseases.

In order to regulate and regulate abnormal or inappropriate cell proliferation, differentiation, or metabolism, it is desirable to identify effective small compounds that specifically inhibit signal transduction by modulating the activity of receptor and non-receptor tyrosine and serine / threonine kinases. In particular, angiogenesis methods; It is beneficial to identify methods and compounds that specifically inhibit the function of tyrosine kinases that are essential for the formation of edema, ascites, exudates, exudates, and extracellular efflux and matrix deposition as well as associated disorders of blood vessels and permeability.

SUMMARY OF THE INVENTION

The present invention provides a pharmaceutical composition comprising a compound represented by formula I and a pharmaceutically acceptable salt thereof, wherein the tyrosine kinase and the serine / threonine kinase inhibitor, including administration to a tyrosine kinase and serine / threonine kinase at a concentration sufficient to inhibit its enzymatic activity, A method of inhibiting the kinase activity of a kinase is provided:

In this formula,

X represents a) substituted methylene, b) carbonyl, c) oxygen, d) a group of the formula -C = NOR ₇ (wherein, R ₇ represents H or C _1-4 alkyl group), e) of the formula NR ₈ F) a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3, or a group of the formula (CH ₂ ) _n , wherein R ₈ represents H, an optionally substituted C _1-4 alkyl group or an optionally substituted phenyl; Or g) a group of the formula S (O) _p , wherein p is 0, 1 or 2;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j D) a C _1-6 alkoxy group optionally substituted by one or more of the following: hydroxy, halo, or an amino group of the formula NR _h R _j (wherein R _h and R _j are as defined below) Wherein R _h and R _j are as defined below, provided that these groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxy, g) _a group of formula COR _a wherein R _a represents hydroxy, 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 are independently hydrogen, C _{1 -6} represents an alkyl group or a phenyl group, an alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or chemical NR _h R _j group of (wherein, R _h and R _j are independently represents hydrogen or C _1-6 alkyl group, or, R _h and R _j is selected from O, S, or N together with the nitrogen atom to which they are attached an additional 6 or 7 membered saturated heterocyclic ring optionally containing a heteroatom and optionally substituted by 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 hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl or phenyl or a group of the formula COR _f wherein R _f is hydrogen, C _1-12 alkyl, C _3-12 shows a cycloalkyl group, a phenyl C _1-6 alkyl or phenyl) (in each case, an alkyl group, cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or the formula NR amino group of R _{h j} (wherein, R _h and R _j is a Defined as the same)), i) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, 4 or 5, R _g is hydroxy or a group (wherein, R of formula NR _d R _{e d} and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group,

Provided that 1) when X represents carbonyl or substituted methylene, R ₁ represents hydrogen and R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, R ₂ represents pyridyl, phenyl or C _{1- 2} alkyl, halogen atom, lower alkoxy group, a hydroxy is not a phenyl substituted by a hydroxyl group or an amino group;

2) when X is a group of the 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 are independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl and the remaining two are hydrogen, R ₂ is unsubstituted thienyl, unsubstituted furyl, Unsubstituted pyrrolyl, unsubstituted pyridyl, or phenyl having less than two substituents wherein the substituent is halogen having an atomic weight of about 19 to 36, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl, no.

R ₃ , R ₄ , R ₅ and R ₆ are independently a) H, b) halo, c) C _1-6 alkyl optionally substituted by one or more of the following: hydroxy, halo, NR _h R _j , wherein R _h and R _j are as defined below, d) a C _1-6 alkoxy group optionally substituted by one or more of the following: hydroxy, C _1-6 alkoxy, Halo or an 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 bonded to a carbon bonded to the oxygen of the alkoxy group, f) , g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are independently hydrogen, C _1-6 denotes a alkyl group or a phenyl group, an alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or screen An amino group of formula NR _h R _j (wherein, R _h and R _j are independently hydrogen or C _1-6 alkyl, (C ₃ -C ₆₎ heterocycloalkyl - (C ₀ -C ₆₎ alkyl (heterocycloalkyl = R _h and R _j together with the nitrogen atom to which they are attached optionally contain an additional heteroatom selected from O, S or N and C ₁ < RTI ID = 0.0 > _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently selected from the group consisting of hydrogen (optionally substituted with one or more substituents independently selected from the group consisting of hydrogen , C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _1- It represents a ₆ alkyl or phenyl) (in each case, an alkyl group, cycloalkyl group and phenyl are one or more of the following: Optionally substituted by: halo, hydroxy, nitro or an amino group of 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 _g Wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e , wherein R _d and R _e are as defined above; R _g represents _a group of the 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 by _-6 alkyl, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, phenyl optionally substituted by one or more C _1-6 alkoxy groups or halo Each represent an optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group.

Certain compounds of formula I are known in the literature. Compounds of formula I wherein X represents methylene, ethylene, trimethylene, vinylene, substituted methylene are described in US 3,932,430, US 3,843,665 and US 3,848,666. Compounds in which X represents carbonyl are described in JP 60-13521. Wherein X represents O and R ₁ , R ₃ , R ₄ , R ₅ and R ₆ represent hydrogen and R ₂ represents phenyl, 2,4-dimethylphenyl, 2-thienyl, 3-thienyl and 2- Compounds that show 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. Compounds 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 can be prepared as described in Monatsh Chem. 1974, 105 , 869). Compounds in which X represents SO ₂ and R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen and R ₂ represents phenyl can be prepared as described in Liebigs Ann. Chem. 1974, 1248).

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

Certain fused pyrazoles of Formula I are commercially available, but no pharmacological activity has been identified for this compound. Commercially available compounds are as follows:

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

In yet another aspect, the invention provides a first group of novel compounds of formula I and pharmaceutically acceptable salts thereof:

In the formula (I)

X represents a group of the formula S (O) _p , wherein p represents 0, 1 or 2;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

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

only,

1) when R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen and X represents SO ₂ , R ₂ does not represent phenyl,

2) When X represents S and R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, then R ₂ does not represent 2,4-dichlorophenyl.

In yet another aspect, the invention provides a second group of novel compounds of formula I and pharmaceutically acceptable salts thereof:

In the formula (I)

X represents oxygen;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

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

only,

When R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, R ₂ does not represent phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl.

In yet another aspect, the invention provides a third group of novel compounds and pharmaceutically acceptable salts thereof:

here,

X represents a group of the formula NR ₈ ;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

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

In yet another aspect, the invention provides a fourth group of novel compounds of formula I and pharmaceutically acceptable salts thereof:

In the formula (I)

X represents a group of the formula -C = NOR ₇ , wherein R ₇ represents H or a C _1-4 alkyl group;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

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

Provided that when R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen and X represents C═NOH, then R ₂ does not represent 4-methylphenyl or 3,4-dimethoxyphenyl.

In yet another aspect, the invention provides a fifth group of novel compounds of formula I and pharmaceutically acceptable salts thereof:

In the formula (I)

X represents a methylene or carbonyl group;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

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

only,

1) when X represents 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 pyridyl, 2-thienyl, 3-thione Phenyl, or is not phenyl substituted by C _1-2 alkyl, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group;

2) X represents methylene, R ₁ represents hydrogen, and two of R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, halogen having an atomic weight of about 19 to 36, C _1-4 alkyl, C _{1 -4} alkoxy or trifluoromethyl and the remaining two represent hydrogen, R ₂ is selected from the group consisting of unsubstituted thiethyl, unsubstituted furyl, unsubstituted pyrrolyl, unsubstituted pyridyl, Not phenyl having up to two substituents which are halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl with an atomic weight of 36;

3) when X represents a carbonyl group and R ₂ represents phenyl, 4-chlorophenyl or 4-methoxyphenyl, then R ₃ , R ₄ , R ₅ and R ₆ are not trifluoromethyl;

4) when X represents a carbonyl group, R ₂ represents phenyl, R ₃ represents bromo, R ₄ represents hydroxy and R ₅ represents methoxy, R ₆ is not hydrogen,

5) when X represents carbonyl and R ₃ , R ₄ , R ₅ and R ₆ represent hydrogen, then R ₆ is not aryl.

In yet another aspect, the invention provides a sixth group of novel compounds of formula I and pharmaceutically acceptable salts thereof:

In the formula (I)

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

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

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

With the proviso that when X is a group of the 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 are independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl and the remaining two are hydrogen, R ₂ is unsubstituted thienyl, unsubstituted furyl, Unsubstituted pyrrolyl, unsubstituted pyridyl, or phenyl having up to two substituents wherein the substituents are halogen with an atomic weight of about 19 to 36, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl, No,

only,

When n is 2 and R ₃ , R ₄ , R ₅ and R ₆ are each hydrogen or methoxy, then R ₂ is 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid-2-yl or Carboxy-phenyl. ≪ / RTI >

In yet another aspect, the invention provides a seventh group of novel compounds of formula I and pharmaceutically acceptable salts thereof:

In the formula (I)

X represents a) substituted methylene, b) carbonyl, c) oxygen, d) a group of the formula -C = NOR ₇ (wherein, R ₇ represents H or C _1-4 alkyl group), e) of the formula NR ₈ F) a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3, or a group of the formula (CH ₂ ) _n , wherein R ₈ represents H, an optionally substituted C _1-4 alkyl group or an optionally substituted phenyl; Or g) a group of the formula S (O) _p , wherein p is 0, 1 or 2;

R ₁ represents H;

R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl;

R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j D) a C _1-6 alkoxy group optionally substituted by one or more of the following: hydroxy, an amino group of the formula NR _h R _j , wherein R _h and R _j are as defined below, R _h and R _j are as defined below, with the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group; Or halo, e) optionally substituted phenoxy, f) hydroxy, g) _a group of the formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a represents _a radical of formula NR _b R _c Wherein R _b and R _c independently represent hydrogen, a C _1-6 alkyl group or phenyl, wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy or an amino group of the formula NR _h R _j Wherein R _h and R _j independently represent hydrogen or a C _1-6 alkyl group or R _h and R _j together with the nitrogen atom to which they are attached optionally contain a further heteroatom selected from O, S or N, 6 or 7 membered saturated heterocyclic ring which is optionally substituted by a C _1-6 alkyl group))), h) a group of the formula NR _d R _e , wherein R _d and R _e Is independently selected from hydrogen, a C _1-6 alkyl group or phenyl, (In each case, an alkyl group, a cycloalkyl group and a phenyl group are optionally substituted by one or more of the following: a group of the formula COR _f wherein R _f represents hydrogen, a C _1-6 alkyl group, a C _3-8 cycloalkyl group, to be substituted with hydroxy or amino group of formula NR _h R _j (here, the same as R _h and R _j are as defined above)), i) a group of the formula _{O (CH 2) m R g} ( wherein, m is 2, 3, 4 or 5, R _g represents hydroxy or a group of the formula NR _d R _e , wherein R _d and R _e are as defined above, or R _g represents _a group of the formula COR _a wherein R _a represents the same meaning as defined above), m is 1, 2, 3, 4 or 5), j) nitro, k) optionally substituted phenyl C _1-6 alkyl, l) optionally substituted phenyl C _{1 -6} alkoxy, or o) C _1-6 alkyl, each optionally substituted by an optionally phenyl substituted by one or more of the C _1-6 alkoxy group or halo C _2-4 alkenyl or C _2-4 alkynyl group represents a group,

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: a) a group of the formula O (CH ₂ ) _m R _g , 4 or 5, R _g is hydroxy or a group of the formula NR _d R _e , wherein R _d and R _e are as defined above, or R _g is _a group of the formula COR _a wherein R _a is B) a C _1-6 alkyl group substituted by one or more of the following: hydroxy or an amino group of the formula NR _h R _j , wherein (a) are as defined above, R _h and R _j is a), c) the following group c _1-6 optionally substituted by one or more alkoxy: hydroxy, halo or an amino group of formula NR _h R _j (wherein, R _h and R _j are as defined above) (where such groups are not bonded to the carbon bonded to the oxygen of the alkoxy group), d) a group of the formula COR _a (wherein, R _a Hydroxy, C _1-6 alkoxy, or represents a group, R _a denotes a (shown here, R _b and R _c are as defined above) a group of formula NR _b R _c), e) a group of formula NR _d R _e ( Wherein R _d and R _e are as defined above.

The term " aryl " as used herein means phenyl or naphthyl. The term " optionally substituted " as used herein means substituted by one or more of the following: a) halo, b) C _1-6 alkyl optionally substituted by one or more of the following: hydroxy Halo, 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: hydroxy, halo or An 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 bound to the carbon bound to the oxygen of the alkoxy group, d) F) _a group of formula COR _a wherein R _a represents hydroxy, 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 represents independently hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl or phenyl Alkyl, cycloalkyl, and phenyl are optionally substituted by one or more of the following: hydroxy, halo, a C _3-12 cycloalkyl group, or an amino group of the formula NR _h R _j wherein R _h and R _j are hydrogen or represent a C _1-6 alkyl group, or, R _h and R _j represents a hydrogen, or a C _1-6 alkyl group, or an independent, R _h and R _j is selected from O, S, or N together with the nitrogen atom to which they are attached an additional 6 or 7 membered saturated heterocyclic ring optionally containing a heteroatom and optionally substituted by a C _1-6 alkyl group))), g) a group of the formula NR _d R _e wherein , R _d and R _e are independently selected from hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl or phenyl or a group of the formula COR _f wherein R _f is hydrogen, C _1-12 alkyl, C _3-12 showing a cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl ) (In each case, an alkyl group, cycloalkyl group and phenyl are optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group (wherein, R _h and R _j in the formula NR _h R _j are as defined above H) a group of the formula O (CH ₂ ) _m R _g , wherein m is 2, 3, 4 or 5, R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e is as defined above; R _g is _a group of the 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 _3-6 alkenyloxy group, n) a pyridine ring optionally substituted by one or more methyl or nitro trifluoromethyl a pyridyloxy or pyrido dilti come, o) hydroxy-amidino, p) aminomethyl, q) formamido methyl, r) C _1-6 alkylthio group, s) phenyl, t) C _1-6 alkyl group, A C _2-4 alkenyl group or a C _2-4 alkynyl group each optionally substituted by phenyl optionally substituted by one or more of C _1-6 alkoxy groups or halo.

In a further aspect, the term " optionally substituted " as used herein means substituted by one or more of the following:

a) halo,

b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo,

d) optionally substituted phenoxy,

e) hydroxy,

f) a group of the formula COR _a or SO ₂ R _a wherein R _a represents hydroxy, (C ₁ -C ₆ ) alkyl or (C ₁ -C ₆ ) alkoxy or R _a represents a radical of formula NR _b R _c Lt; / RTI >

Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl is optionally substituted with one of the following: halogen, alkyl, cycloalkyl, It is optionally substituted by or more: hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- (C ₁ -C ₆₎ alkyl-hydroxy, C _3-12 cycloalkyl group or an amino group of formula NR _h R _j;

Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, A 6-membered or 7-membered heterocyclic ring,

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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, Is selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) Lt; / RTI >group;

g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f )

Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl, in each case, the alkyl group, cycloalkyl group and phenyl are optionally substituted is replaced by: halo, 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 wherein the pyrrolidine is 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 _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group,

n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro,

o) hydroxyamidino,

p) aminomethyl,

q) formamidomethyl,

r) C _1-6 alkylthio group,

s) phenyl,

t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo,

u) CHO,

v) dihydroxyborane,

w) tetrazolyl.

When R < ₂ > represents optionally substituted pyridyl, the pyridine ring may be present in the form of its N-oxides.

NR _d R _e represents a saturated heterocyclic ring, the ring is preferably selected from the group consisting of morpholino, perhydrothiazin-4-yl, piperidino, pyrrolidin-1-yl, Yl or 4-methylpiperazin-4-yl.

The term " substituted methylene " means, for example, methylene substituted by one or more of the following: a hydroxy or C _1-4 alkyl group wherein the alkyl group is a group of the formula NR _r R _s wherein R _r and R _s Lt; / RTI > independently represent H or a _C1-6 alkyl group).

It will be appreciated that any of the groups mentioned herein that contain three or more atoms represent a group, which chain may be straight or branched. For example, the alkyl group is n-butyl may include including a butyl-propyl and n, including propyl and isopropyl-butyl, secondary-butyl, isobutyl and tertiary. The term " C _3-12 cycloalkyl group " includes, for example, adamantyl. As used herein, the term " halo " denotes fluoro, chloro, bromo, and iodo.

The compounds of formula I may exist as salts with pharmaceutically acceptable acids. The present invention includes the above salts. Examples of such salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, maleates, acetates, citrates, fumarates, tartrates such as (+) - tartrates, Mixtures thereof including racemic mixtures], salts with amino acids such as succinate, benzoate and glutamic acid. The salts may be prepared by methods known to those skilled in the art.

Certain compounds of formula (I) having an acidic substituent may be present as a salt with a pharmaceutically acceptable base. The present invention includes such salts. Examples of such salts include sodium salts, potassium salts, lysine salts and arginine salts. The salts may be prepared by methods known to those skilled in the art.

Certain compounds of formula I and their salts may exist in one or more crystalline forms and the present invention includes each crystalline form and mixtures thereof.

Certain compounds of formula I and their salts may also be present in the form of a solvate, e. G. A hydrate, and the invention includes each solvate and mixtures thereof.

Certain compounds of formula I may contain one or more chiral centers and may exist in optically different active forms. When the compound of formula (I) contains one chiral center, the compound is in two enantiomeric forms and the invention encompasses both enantiomers and enantiomers. The enantiomers can be prepared by methods known to those skilled in the art, for example, formation of diastereomeric salts which can be separated by crystallization; For example, formation of diastereomeric derivatives or complexes which can be separated by crystallization, gas-liquid chromatography or liquid chromatography; Selective reactions of an enantiomer-specific reagent with one enantiomer, e. G. Enzymatic esterification; Or may be resolved by gas-liquid chromatography or liquid chromatography in the presence of a chiral environment, such as a chiral support, e. G., A coupled chiral ligand in the presence of silica or a chiral solvent. Where the desired enantiomer is converted to another chemical entity by one of the separation methods described above, additional steps are needed to liberate the desired enantiomeric form. In addition, certain enantiomers can be synthesized by converting one enantiomer to another enantiomer by asymmetric synthesis using an optically active reagent, substrate, catalyst or solvent, or by asymmetric transformation.

Where the compound of formula I contains one or more chiral centers, it may exist in diastereomeric forms. The diastereoisomeric pairs can be separated by methods known to those skilled in the art, e.g., by chromatography or crystallization, and the individual enantiomers in each pair can be separated as described above. The present invention includes each diastereomer of a compound of formula I and mixtures thereof.

Certain compounds of formula (I) may exist in different tautomeric forms or different geometric isomers, and the invention includes each tautomer and / or geometric isomer of a compound of formula (I) and mixtures thereof.

Certain compounds of formula I may exist in different stable morphological forms which may be isolated. Restricted rotation to an asymmetric single bond, such as torsional asymmetry due to steric hindrance or ring tension, allows separation of different amorphous bodies. The present invention includes each morphologic isomer of a compound of formula I and mixtures thereof.

Certain compounds of formula I may exist in amphoteric forms and the invention includes each amphoteric form of a compound of formula I and mixtures thereof.

The compounds of the present invention are useful as inhibitors of serine / threonine and tyrosine kinases. In particular, the compounds of the present invention are useful as inhibitors of tyrosine kinases that are hyperprogesic, particularly important in the progression of angiogenesis. Because the compounds are antiangiogenic, they are important substances for inhibiting the progression of disease states in which angiogenesis is an important component.

A preferred definition of a substituent will now be provided.

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

More preferably, R ₂ is selected from the group consisting of optionally substituted 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2- pyridyl, 3- pyridyl or 4- pyridyl, , Wherein the substituents are selected from optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy, 2-piperidinoethoxy, 2- (piperazin-1-yl) - piperazin-1-yl, 2- (perhydro-thiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- ( (Perhydrothiazin-4-yl) propoxy), lower alkyl ((lower alkyl) piperidinyl) Especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially phenoxy), arylalkoxy (especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy) (Particularly methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl Carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl), and pyridyloxy or pyridylthio groups optionally substituted by at least one of pyridine ring, trifluoromethyl or nitro.

Most preferably, R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4- pyridyl, 2- cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-tri 4- (3-carboxypropoxy) phenyl, 4-carboxymethoxyphenyl, 4 (3-morpholinoethoxy) phenyl, 4- 3- (3-carbamoylpropoxy) phenyl, 4-carbamoylmethoxyphenyl, 3- (3-morpholino-propoxy) 3-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxycyclohexyl) phenyl, 4-carboxymethoxyphenyl, 3- Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hi 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethylaminophenyl, 4-methoxycarbonylphenyl, 4-carbamoylphenyl , 4-cyanophenyl, 4-carboxyphenyl, 4- [N- ((4-fluorophenyl) 3- (2-diethylaminoethyl) carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoylmethoxy) phenyl, 3- [3- ) Phenyl] -2-furyl, 5- [3,5-bis (trifluoromethyl) phenyl] -2 2-furyl, 3-N- (2-morpholinyl) -2-furyl, (2-morpholinoethyl) carbamoyl) -propoxyphenyl], 4- (N- (2-morpholinoethyl) (Morpholinylmethoxy) phenyl, 4-morpholinoacetamido) phenyl and 4- [3- (N- (2-morpholinoethyl) carbamoyl) -propoxy] phenyl.

Preferably R ₃ , R ₄ , R ₅ and R ₆ are independently selected from hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, Carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- (Perhydrothiazin-1-yl) ethoxy, 3-piperidinopropoxy, 3-piperidinoethoxy, 3- (perhydrothiazin-4-yl) propoxy), < / RTI > Propoxy, 2-morpholino) ethoxy), amido (especially acetamido and benzamido), optionally substituted (methoxy) (Especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl), It represents a double vision, nitro and amino.

More preferably R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6-acetamido, 7-methoxy , 6-carbamoyl, 6- (N-methyl-carbamoyl), 6- (N-phenylcarbamoyl), (3-morpholino) propoxy and 2-morpholino) -ethoxy.

The term " lower ", as used herein, means a group having from one to six carbon atoms.

Certain compounds of the present invention include the following compounds and their pharmaceutically acceptable salts and tautomers thereof:

3- (3,4,5-trimethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole,

3- (1, 4-dihydroindeno [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-

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

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

Dimethoxyphenyl) indeno [1,2-c] pyrazole-4 (1H) -one oxime,

(3-methylphenyl) indeno [1,2-c] pyrazole-4 (1H)

(2-thienyl) indeno [1,2-c] pyrazole-4 (1H)

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

Dihydro-3-phenylpyrazolo [4,3-b] indole,

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,

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

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

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

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

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

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

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,

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

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

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl)

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

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

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

6- (2-morpholinoethoxy) -3- (2-thienyl) -1,4-dihydroindeno [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,

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide, N-

Dihydroindeno [l, 2-c] pyrazol-3-yl) phenoxyacetamide, N- (2-morpholinoethyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butyric acid,

Ethyl 4- {3- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) phenoxy}

4- {3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butyramide,

Dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} -butyramide, N- (2-

Dihydroindeno [l, 2-c] pyrazol-3-yl) phenoxy} -butyramide, N- (2-morpholinoethyl) -4- {3-

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,

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

3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxyanilide;

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

3-phenyl-1,4-dihydroindeno [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-lH-benzo [g] indazol-3-yl) pyridine 1-oxide,

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

Benzo [g] indazol-3-yl) -2-pyridinecarbonitrile, 4- (4,5-

Benzo [g] indazol-3-yl) -2-pyridinecarboxamide oxime, 4-

Benzo [g] indazol-3-yl) -2-pyridinecarboxamide, 4- (4,5-dihydro-

Benzo [g] indazol-3-yl) -2-pyridyl] methyl} ammonium chloride,

Benzo [g] -indazol-3-yl) -2-pyridyl] methyl} formamide, N - {[4- (4,5-

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

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

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

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

Dihydroindeno [l, 2-c] pyrazole, l- (4-bromo-2-thienyl)

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

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

Pyridyloxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole,

6,7,8-triethoxy-3- (2,3,4-trimethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole,

Dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxymethyl) phenol,

2-methoxy-5- (1, 4-dihydroindeno [1,2-c] pyrazol-

2-chloro-4- (1, 4-dihydroindeno [1,2-c] pyrazol-

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

4-dihydroindeno [l, 2-c] pyrazol-3-yl) phenol,

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

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

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

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

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

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl)

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

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

Methyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (N-

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (N, N- dimethylamino) ethyl] -4-

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (N,

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (N, N- di-

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N- dimethylamino)

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (N,

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-piperidinoethyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-piperidinopropyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinopropyl)

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (piperazin-

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

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (pyrrolidin-

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (pyrrolidin-

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (4-methylpiperazin-

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (thiomorpholin-

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (thiomorpholin-

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (homopiperazin-

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

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

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

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

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

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

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

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

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

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

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

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-chlorocyclopentyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N-dimethylamino)

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-methylbut-

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (pyrrolidin-

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

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [7- (N, N- dimethylamino)

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-methylbut-

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3,3-dimethylbutyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2,2,3,3,3-pentafluoropropyl) -4-

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

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- (2,2-difluoroethyl)

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-morpholinopropyl)

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (pyrrolidin-

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

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

4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -4-methyl 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) 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-difluorobenzyl anilide,

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

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

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

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

4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,5-difluorobenzyl anilide,

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

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

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

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

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- methylpentanilide,

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

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

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

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) pentafluoropropan-

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

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

4-dihydroindeno [l, 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-1,4-dihydroindeno [1,2- c] pyrazol-6- yl) benzylamide,

2,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide, 2,5-difluoro-

4-dihydroindeno [l, 2-c] pyrazol-6-yl) benzylamide,

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

3,3,3-trifluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-

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

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

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

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

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

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

4-dihydroindeno [1,2-c] pyrazol-6-yl) pentanamide,

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

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

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

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

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, 2-hydroxy-

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

2-hydroxy-N- [2- (pyrrolidin-1-yl) ethyl] -5- (1,4-

Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

Dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxybenzamide, N- [2- (N, N-diethylamino) ethyl]

Dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxybenzamide, N- [3- (N,

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (N, N- dimethylamino) ethyl]

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

2-hydroxy-N- [2- (N, N-dipropylamino) ethyl] -5- (1,4- dihydroindeno [

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzene (hereinafter referred to as " amides,

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

Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzene amides,

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

2-hydroxy-N- (2-piperidinopropyl) -5- (1,4-dihydroindeno [1,2- c] pyrazol-

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

Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzene (hereinafter referred to as " amides,

Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzene amides,

Ethyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

Propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

Ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide,

2-hydroxy-N- [2- (perhydroazepin-1-yl) ethyl] -5- ,

Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide ,

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2-morpholinoethyl) aniline,

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2 -morpholinopropyl) aniline,

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2-piperidinoethyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2-piperidinopropyl) aniline,

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (thiomorphyrin 1-yl) ethyl] aniline,

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (thiomorpholin-1- yl) propyl] aniline,

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin- 1- yl) ethyl] aniline,

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

Dihydroindeno [1,2-c] pyrazol-3-yl) aniline, N- [2- (N, N-

Dihydroindeno [1,2-c] pyrazol-3-yl) aniline, N- [3- (N,

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

N- (3- (N, N-dipropylamino) propyl] aniline,

Dihydroindeno [l, 2-c] pyrazol-3-yl) -N- [2- (N, N- dimethylamino) ethyl] aniline,

N- [3- (N, N-dimethylamino) propyl] aniline,

Methyl 4- (6-acetamido-1,4-dihydroindeno [1,2-c] pyrazol-3- yl) benzoate,

Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-methoxypropyl)

Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (4-nitrophenyl)

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

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

(3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) piperidino acetamide,

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

Dihydroindeno [1,2-c] pyrazol-6-yl) -4-methylpiperazin-1-ylacetamide, N-

Dihydroindeno [1,2-c] pyrazol-6-yl) piperazin-1-ylacetamide, N- (3-phenyl-

Dihydroindeno [1,2-c] pyrazol-6-yl) pyrrolidin-1-ylacetamide, N-

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

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

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

N, N-diethylamino) ethyl] - < RTI ID = 0.0 > benzamide, <

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

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

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

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

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

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

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

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

3- {3- [3- (N, N-diethylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2 c] pyrazole,

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

3- {3- [3- (N, N-dimethylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole,

3- {3- [2- (N, N-dipropylamino) ethoxy] phenyl} -1,4-dihydroindeno [1,2 c] pyrazole, and

3- {3- [3- (N, N-dipropylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole

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

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

Yl) -N- [3- (imidazol-1-yl) propyl] benzylamine trihydrochloride,

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

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

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

Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] benzenesulfonamide, N- [4-

Dihydroindeno [l, 2-c] pyrazol-3-ylaniline dihydrochloride, N- (2-morpholinoethyl)

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

Dihydroindeno [1,2-c] pyrazol-6-ylamine trihydrochloride, N- (2-morpholinoethyl)

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,

4-pyridyl] -4,5-dihydro-2H-benzo [g] indazole,

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

Dihydroindeno [l, 2-c] pyrazol-3-yl) phenyl] carbamate, 2- (diethylamino) ethyl N- [4-

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

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

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

2-c] pyrazol-3-yl) phenyl] carbamate < / RTI > ,

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

Yl) phenyl] carbamate, < RTI ID = 0.0 > 2- (1-methyltetrahydro-lH-

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

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

Yl] phenyl] urea, < / RTI > < RTI ID = 0.0 &

Yl] phenyl] -N'- (2-morpholinoethyl) urea, < / RTI >

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

N '- [2- (dimethylamino) -1-methylethyl] urea, < / RTI >

Yl] phenyl] -N ' -tetrahydro-2-furanylmethyl < / RTI >

Yl] phenyl] -N '- (2-furylmethyl) urea, N- [4-

Phenyl] urea, < / RTI > < RTI ID = 0.0 &

N-cyclohexyl-N '- [4- (1, 4-dihydroindeno [1,2- c] pyrazol-

Yl] phenyl] -N '- (2-piperidinoethyl) urea [0157]

N-benzyl-N '- [4- (1,4-dihydroindeno [1,2- c] pyrazol-

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

N '- [2- (2-thienyl) ethyl] urea, < / RTI >

Phenyl] urea, < / RTI > < RTI ID = 0.0 &

Yl] phenyl] -N '- [(1-ethyltetrahydro-1H-2-pyrrolyl) methyl] ]Element,

Phenyl] urea, < / RTI > < RTI ID = 0.0 &

N '- [2- (2-hydroxyethoxy) ethyl] urea, < / RTI >

- [2-hydroxy-1-hydroxymethyl] ethyl] urea, < / RTI >

Yl] phenyl] -N '- (2,3-dihydroxypropyl) urea, N- [4- (1,4-dihydroindeno [

Yl) phenyl] -4- (2-pyridyl) -1-piperazinecarboxamide, N1- [4- (1,4-dihydroindeno [1,2- c] pyrazol-

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

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

Yl) phenyl] -4- (4-fluorophenyl) -1-piperazinecarboxamide, N1- [4- (1,4- dihydroindeno [1,2- c] pyrazol-

Yl] phenyl] -N-methyl urea, < / RTI >

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

Yl) phenyl] -4- (2-methoxyphenyl) -1-piperazinecarboxamide, N1- [4- (1,4- dihydroindeno [1,2- c] pyrazol-

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

Yl] phenyl] -4-methyl-1-piperazinecarboxamide, N1- [4- (1,4-

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

Phenyl] -4 - [(E) -3-phenyl-2-propenyl] -l- [4- (1,4- dihydroindeno [1,2- c] pyrazol- Piperazine carboxamide,

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

N, N-di (2-methoxyethyl) urea, N '- [4- (1,4- dihydroindeno [

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

N, N-di [2- (diethylamino) ethyl] -N '- [4- (1,4- dihydroindeno [1,2- c] pyrazol-

Yl] phenyl] -N '- (2-pyridylmethyl) urea, N- [4-

Yl] phenyl] -N '- (3-pyridylmethyl) urea, N- [4- (1,4-dihydroindeno [

Yl] phenyl] -N '- (4-pyridylmethyl) urea,

Phenyl] -N '- (2-hydroxyethyl) urea, < / RTI >

N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -N '- [7- (dimethylamino) heptyl]

Additional specific compounds of formula I represented by the following formulas are shown in the following Tables. Also encompassed by the present invention are the pharmaceutically acceptable salts and tautomers of these compounds.

In this formula,

R ₂ is ego,

X is (CH _{2) n,}

Definitions for the remaining groups are given in Table 1:

Table 1

In this formula,

X is (CH _{2) n,}

Definitions for the remaining groups are given in Table 2:

Table 2

In this formula,

The definition of the term is given in Table 3:

Table 3

In this formula,

R < ₁ > is H,

The definitions of the remaining groups are as follows:

In this formula,

The definitions of the groups are as follows:

In this formula,

The definitions of the groups are as follows:

The present invention further includes the use of these compounds in pharmaceutical compositions containing a pharmaceutically effective amount of the compound and a pharmaceutically acceptable carrier or excipient. These pharmaceutical compositions can be administered to an individual to slow or stop the angiogenic process in diseases promoted by angiogenesis or to treat other conditions associated with edema, effusion, exudate, or vaginal hyperplasia have.

The present invention relates to certain 3-aryl or 3-heteroarylpyrazoles with 4,5 (3,4) -bicyclic ring fusions which are inhibitors of protein kinases, in particular tyrosine kinases and serine / threonine kinases, , A pharmaceutical composition containing the pyrazole, and a method for producing the pyrazole.

The compounds of the present invention have anti-angiogenic properties. Such anti-angiogenic properties are due to inhibition of protein tyrosine kinases which are necessary for the partial or complete angiogenic process. For these reasons, these compounds are useful in the treatment of arthritis, atherosclerosis, psoriasis, hemangiomas, myocardial angiogenesis, coronary and cerebral palsy, ischemic limb angiogenesis, wound healing, peptic ulcer Helicobacter related diseases, fractures, cat scratch fever ), Rubeosis, angiogenesis glaucoma, and retinopathy associated with diabetic retinopathy, retinopathy such as retinopathy of prematurity, retinopathy of premature keratosis, and the like. In addition, some of these compounds have been shown to be useful in the treatment of solid tumors, malignant ascites, hematopoietic carcinomas, and thyroid hyperplasia, particularly Grave's disease, cysts (e. G., Polycystic ovary syndrome (Stein-Leventhal syndrome and ovarian hypervascularisation characterized by hyperglycemia and syndrome), since this disease requires the proliferation of vascular cells for proliferation and / or metastasis.

Some of these compounds may also be used in the treatment of inflammation of the brain or lungs due to burns, chronic lung disease, stroke, polyps, anaphylaxis, chronic and allergic inflammation, ovarian hyperstimulation syndrome, brain tumor associated brain edema, elevation, trauma or hypoxemia, And corneal hemorrhage, ascites, vascular and permeability, effusion, exudation, protein efflux, or edema may be used as active agents for other diseases in which the disease is a symptom. Such compounds would also be useful for treating diseases in which protein efflux causes precipitation of fibrin and extracellular matrices to promote matrix proliferation (e.g., fibrosis, sclerosis, carpal tunnel syndrome).

VEGF is unique in that it is the only angiogenic growth factor known to contribute to blood vessel and permeability and edema formation. Indeed, the vasculature, permeability and edema associated with the expression or administration of many other growth factors appear to be mediated by VEGF production. Inflammatory cytokines stimulate VEGF production. Since hypoxia leads to significant upregulation of VEGF in many tissues, conditions involving infarction, obstruction, ischemia, anemia, or circulatory disturbance typically result in a VEGF / VPF mediated response. Changes in blood vessels and permeability, associated edema, changes in vascular endothelial exchange and polymer leakage are often accompanied by diapedesis, which can lead to excessive matrix accumulation, abnormal substrate proliferation, fibrosis, and the like. Therefore, VEGF mediated and permeability can contribute significantly to diseases with these pathologic features.

It is believed that the diseases listed above are mediated to a significant extent by protein tyrosine kinase activity, including KDR / VEGFR-2 and / or Flt-1 / VEGFR-1 tyrosine kinase. By inhibiting the activity of these tyrosine kinases, the progression of the diseases listed above is inhibited because of the severity of angiogenic or vascular and transmissible components of the disease state. The action of the compounds of the present invention minimizes side effects that occur when less selective tyrosine kinases are used, due to their selectivity for specific tyrosine kinases.

The compounds of the present invention have inhibitory activity against protein kinases. That is, these compounds regulate signal transduction by protein kinases. The compounds of the present invention inhibit protein kinases of serine / threonine and tyrosine kinase classes. Specifically, these compounds selectively inhibit the activity of KDR / FLK-1 / VEGFR-2 tyrosine kinase. Certain compounds of the invention also inhibit the activity of additional tyrosine kinases such as Flt-1 / VEGFR-1, Src-subtype kinases such as Lck, Src, fyn, yes, In addition, some compounds of the present invention significantly inhibit serine / threonine kinases such as CDK, which play an important role in cell cycle progression. The potency and specificity of the generic compounds of the invention for a particular protein kinase will often depend upon the nature, number and arrangement of substituents (i.e., R ₁ , R ₂ , R ₃ , R ₄ , R ₅ and R ₆ ) Lt; / RTI > In addition, metabolites of certain compounds may also have significant protein kinase inhibitory activity.

The compounds of the present invention, when administered to an individual in need of such a compound, inhibit blood vessel and permeability and edema formation in these individuals. These compounds are believed to act by inhibiting the activity of KDR tyrosine kinase in relation to blood vessel and permeability and edema formation processes. The KDR tyrosine kinase may also be referred to as FLK-1 tyrosine kinase, NYK tyrosine kinase, or VEGFR-2 tyrosine kinase. KDR tyrosine kinase binds to KDR tyrosine kinase where vascular endothelial growth factor (VEGF) or other activating ligand (e.g., VEGF-C, VEGF-D or HIV Tat protein) is present on the surface of vascular endothelial cells Activated. After activation of this KDR tyrosine kinase, hyperpermeability of the blood vessels occurs and body fluids migrate from the bloodstream to the interstitial space through the blood vessel walls, forming a swelling site. Extravasation often involves these reactions. Similarly, excessive blood vessels and permeability can cause polymer leakage and precipitation by interrupting normal molecular exchange across the endothelium of important tissues and organs (e.g., lungs and kidneys). Following this acute response to KDR stimulation, which is believed to promote subsequent angiogenic responses, subsequent KDR tyrosine kinase stimulation results in vascular endothelial cell proliferation and chemotaxis and formation of new blood vessels. By inhibiting the enzyme activity of KDR tyrosine kinase (inhibiting the phosphorylation function of the enzyme) by inhibiting KDR tyrosine kinase activity, or by blocking the binding of the activating ligand to the KDR tyrosine kinase receptor, by inhibiting receptor dimerization and phosphorylation, Or by other mechanisms that interfere with downstream signaling (D. Mukhopedhay et al. Cancer Res 58: 1278-1284 (1998) and references to the literature), over permeability as well as related efflux, subsequent edema formation and matrix precipitation and angiogenic responses can be suppressed or minimized.

One of the preferred compounds of the present invention has the property of inhibiting KDR tyrosine kinase activity without significantly inhibiting Flt-1 tyrosine kinase activity (Flt-1 tyrosine kinase also referred to as VEGFR-1 tyrosine kinase). Both KDR tyrosine kinase and Flt-1 tyrosine kinase are activated by binding of VEGF to the KDR tyrosine kinase receptor and the Flt-1 tyrosine kinase receptor, respectively. Since Flt-1 tyrosine kinase activity can mediate important events in endothelial maintenance and vascular function, inhibition of such enzymatic activity can lead to toxic effects or side effects. At the very least, this inhibition is useless and worthless to an individual, as it is unnecessary to block angiogenic responses, induce blood vessels and permeability, and block the formation of edema. Certain preferred compounds of the invention inhibit the activity of one VEGF-receptor tyrosine kinase (KDR) that is activated by an activating ligand, but inhibit other receptor tyrosine kinases, such as Flt-1, which may also be activated by certain activating ligands It is unusual because it does not. Thus, preferred compounds of the invention are selective for tyrosine kinase inhibitory activity.

The compounds of the present invention are also useful for the treatment of ulcers, i.e. bacterial, fungal, ulcerative ulcers and ulcerative colitis.

The compounds of the present invention may also be used in the treatment of viral infections such as herpes simplex, herpes zoster, AIDS, Kaposi sarcoma, protozoan infections and endocytosis, endometriosis, ovarian hyperstimulation syndrome, systemic lupus, sarcoidosis, Anemia, Lyme disease, pemphigoid, Paget's disease, oligohydrologic syndrome, Osler-Weber-Ranges disease, chronic inflammation, chronic obstructive pulmonary disease, asthma, rheumatoid arthritis, osteoarthritis, and edema after trauma, It is also useful for the treatment of diseases in which angiogenesis, edema, or substrate precipitation occurs.

The compounds of the present invention can be used in the treatment of ocular and corneal edema, ocular angiogenesis, scleritis, radial keratectomy, uveitis, vitreous hemorrhage, myopia, optic pits, chronic retinal detachment, rheumatic complication, conjunctivitis, Stargardt's disease, as well as eye diseases such as retinopathy and corneal degeneration.

The compounds of the present invention are also useful for the treatment of cardiovascular diseases such as atherosclerosis, restenosis, vascular occlusion, and carotid obesity.

The compounds of the present invention are useful for the treatment and prophylaxis of a variety of diseases including solid tumors, hematopoietic malignancies including sarcoma (especially, wing sarcoma and osteosarcoma), retinoblastoma, rhabdomyosarcoma, neuroblastoma, leukemia and lymphoma, It is useful for the treatment of indications related to carcinoma.

The compounds of the present invention are also useful in the treatment of diabetic diseases such as glaucoma, diabetic retinopathy, and capillary blood vessels.

It is believed that the disorders listed above are mediated to a significant extent by protein tyrosine kinase activity, including VEGF receptors (e. G., KDR and Flt-1). By inhibiting the activity of these tyrosine kinases, the progression of the diseases listed above is inhibited because the angiogenic components of the disease state are severely reduced. The action of the compounds of the present invention minimizes side effects that occur when less selective tyrosine kinases are used, due to their selectivity for specific tyrosine kinases.

In another aspect, the present invention provides a use as a medicament of the compound of formula (I) (including conditions) as defined above, in particular as a protein kinase activity, for example as a tyrosine kinase activity, a serine kinase activity and an inhibitor of threonine kinase activity . In yet another aspect, the invention provides the use of a compound of formula I as defined above (including conditions) for the manufacture of a medicament for use in the inhibition of protein kinase activity.

In the present invention, the following definitions apply:

&Quot; Pharmaceutically acceptable salts " are those salts which possess the biological effectiveness and properties of the free base and which are inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or sulfonic acids, carboxylic acids, organic phosphoric acids, methanesulfonic acids, ethanesulfonic acids, -Toluenesulfonic acid, salicylic acid, lactic acid, tartaric acid, and the like.

&Quot; Alkyl " refers to saturated aliphatic hydrocarbons including straight and branched chain groups having from one to four carbons.

&Quot; Alkoxy " refers to " O-alkyl ", wherein " alkyl " is as defined above.

Pharmaceutical composition

The compounds of the present invention may be administered to a human patient as a pharmaceutical composition, either alone or in admixture with a suitable carrier or excipient, in order to treat or ameliorate vascular and permeability, edema and related diseases. A mixture of such compounds may be administered to a patient in a simple mixture or suitably formulated pharmaceutical composition. A therapeutically effective amount refers to an amount of a compound sufficient to prevent or attenuate the progression of inappropriate angiogenesis, hyperproliferative disease, edema, VEGF-related and permeability and / or VEGF-associated hypotension. Formulation and administration techniques of the compounds of the present application can be found in "Remington's Pharmaceutical Science", Mack Publishing Co., Easton, PA, latest edition.

Route of administration

Suitable routes of administration include, for example, oral, topical, rectal, transmucosal, topical, or intestinal administration; Intramuscular, subcutaneous, intramedullary injection as well as parenteral administration including intravenous, direct intraventricular, intravenous, intraperitoneal, intranasal, or intramuscular injection.

Alternatively, the compound may be administered topically rather than systemically, for example by direct injection of the compound into the depression site, often with a depot or sustained release formulation.

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

Composition / Formulation

The pharmaceutical compositions of the present invention can be prepared by per se known methods such as conventional mixing, dissolving, granulating, dragee manufacturing, levigating, emulsifying, encapsulating, entrapping or lyophilizing methods .

Pharmaceutical compositions for use in accordance with the present invention may be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate processing of the active compounds into preparations that can be used pharmaceutically . The appropriate formulation depends on the chosen route of administration.

For injection, the agents of the invention may be formulated into physiologically compatible buffers, such as aqueous solutions, preferably Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants used to permeate the carrier are used for formulation. Such penetrants are generally known in the art.

For oral administration, the compounds can be formulated readily by combining the active compound with a pharmaceutically acceptable carrier well known in the art. Such carriers may be formulated into tablets, pills, dragees, capsules, solutions, gels, syrups, slurries, suspensions, and the like, for oral ingestion to the subject being treated. Oral pharmaceutical compositions may be prepared by processing the granulation mixture after mixing the active compound with a solid excipient, optionally grinding the resultant compound and adding suitable auxiliaries as needed to obtain a tablet or a dragee core of the sugar . In particular, suitable excipients are sugars, including lactose, sucrose, mannitol, or sorbitol; For example, fillers such as corn starch, wheat starch, rice starch, sweet potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP) to be. If desired, disintegrating agents such as crosslinked polyvinylpyrrolidone, agar, or salts thereof such as alginic acid or sodium alginate may be added.

The core of the sugar has a suitable coating. To this end, a concentrated sugar solution, which may optionally contain gum arabic, talc, polyvinylpyrrolidone, carbo-gel gel, polyethylene glycol, and / or titanium dioxide, a lactic acid solution, and a suitable organic solvent or solvent mixture, Can be used. Dyestuffs or pigments may be added to the tablets or coatings of the saccharides for identification or to characterize different combinations of active compound doses.

Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. The push-fit capsules may contain the active ingredient in admixture with a filler such as lactose, a binder such as starch, and / or a lubricant such as talc, magnesium stearate, and optionally a stabilizer. In soft capsules, the active compound may be dissolved or suspended in suitable liquids such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, a stabilization system can be added. All formulations for oral administration should be in dosages suitable for such administration.

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

In the case of inhalation administration, the compounds used according to the invention may be formulated in the form of an aerosol spray or nebuliser in pressurized pack, in the presence of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoro Ethane, carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve for administering the metered amount. Capsules and cartridges of, for example, gelatin for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e. G. By large dose or continuous infusion. The injectable formulations may be presented in unit dosage form, for example in ampoules or in multi-dose containers, with a preservative added. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain adjuvants such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical compositions for parenteral administration include aqueous solutions of the active compound in water-soluble form. Additionally, suspensions of the active compounds may be prepared as suitable oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters such as ethyl oleate or triglycerides, or liposomes. The aqueous injection suspension may contain a substance that increases the viscosity of the suspension, for example, sodium carboxycellulose, sorbitol, or dextran. Optionally, the suspension may contain a suitable stabilizing agent or a medicament which increases the solubility of the compound to produce a highly concentrated solution.

Alternatively, the active ingredient may be in powder form for reconstitution into a liquid form using a suitable vehicle, e. G., Sterile, non-pyrogen-free water prior to use.

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

In addition to the formulations described above, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (e. G., Subcutaneously or intramuscularly or by intramuscular injection). Thus, for example, the compounds may be formulated or sparingly soluble with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins and may be, for example, ≪ / RTI >

An example of a pharmaceutical carrier for the hydrophobic compounds of the present invention is a cosovent system comprising benzyl alcohol, a nonpolar surfactant, an organic polymer that is miscible with water, and a water phase. The co-solvent system may be a VPD co-solvent system. VPD is a solution of 3 w / v% benzyl alcohol, 8 w / v% nonpolar surfactant polysorbate 80, and 65 w / v% polyethylene glycol 300, prepared in volume in absolute ethanol. The VPD co-solvent system (VPD: 5W) consists of VPD diluted 1: 1 in 5% glucose in aqueous solution. These cosolvent systems dissolve hydrophobic compounds well, and themselves exhibit low toxicity when administered systemically. In essence, the proportion of the co-solvent system can vary considerably without eliminating solubility and toxicity characteristics. In addition, the nature of the cosolvent component may vary, for example, other non-toxic nonpolar surfactants may be used in place of polysorbate 80; The fraction size of the polyethylene glycol may vary; Other biocompatible polymers may be substituted for polyethylene glycols, such as polyvinylpyrrolidone; Other sugars or polysaccharides may replace glucose.

Alternatively, other delivery systems for hydrophobic drug compounds may be used. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. In addition, certain organic solvents, such as dimethylsulfoxide, can be used in spite of greater toxicity. Additionally, the compound may be administered using a sustained release system, such as a semi-permeable matrix of a solid hydrophobic polymer containing the therapeutic agent. Various sustained-release materials have been established and are well known to those skilled in the art. Sustained-release capsules can release compounds over a period of several days to 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic agent, additional strategies for protein stabilization may be used.

The pharmaceutical composition may also comprise a suitable solid or gel carrier or excipient. Examples of such carriers or excipients include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starch, cellulose derivatives, gelatin, and polymers such as polyethylene glycol.

Many organic molecules of the present invention can be provided as 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. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.

Effective dose

Pharmaceutical compositions suitable for use in the present invention include compositions wherein the active ingredient is contained in an amount effective to achieve its intended purpose. More specifically, the therapeutically effective amount refers to an amount effective to prevent or alleviate the development of existing symptoms of the subject being treated. Determination of an effective amount can be made sufficiently by the ability of those skilled in the art.

For compounds used in the methods of the invention, a therapeutically effective amount can be estimated initially from cellular assays. For example, the dosage can be formulated in cell and animal models to achieve a circulating concentration range that includes the IC ₅₀ (the concentration of the test compound that achieves half the maximum inhibition rate of a given protein kinase activity) as measured in cellular assays have. In some cases it is appropriate to measure the IC ₅₀ in the presence of 3 to 5% serum albumin as this approach approaches the binding effect of the plasma protein on the compound. Moreover, the most preferred compounds for systemic administration effectively inhibit intact intracellular protein kinase signaling at levels that can be safely achieved in plasma.

A therapeutically effective amount refers to that amount of a compound that improves patient symptoms. The toxicity and therapeutic efficacy of these compounds can be determined, for example, by standard pharmaceutical procedures in cell cultures or experimental animals to determine the maximum tolerated dose (MTD) and the ED ₅₀ (effective dose for 50% of the maximal response) Lt; / RTI > The dose ratio between toxic and therapeutic effects is the therapeutic index, which can be expressed as the ratio between MTD and ED ₅₀ . Compounds that exhibit a high therapeutic index are preferred. Data obtained from such cell culture assays and animal studies can be used to formulate dosage ranges for use in humans. The dosage of such compounds is preferably within the range of circulating concentrations that include the ED ₅₀ with little or no toxicity. The dosage may vary within this range depending on the dosage form employed and the route of administration employed. The exact formulation, route of administration and dosage can be chosen by the individual physician in light of the patient's condition (see, e.g., Fingl et al., 1975, " The Pharmacological Basis of Therapeutics ", Ch. 1 pl]. In the treatment of seizures, administration of an acute bolus or injection that approaches MTD may be required to obtain a rapid response.

The dosage and administration interval can be adjusted individually to provide a plasma level or minimal effect concentration (MEC) of the active moiety sufficient to maintain the kinase modulating effect. The MEC will vary for each compound, but can be estimated from the in vitro data, e.g., the concentrations needed to achieve 50-90% inhibition of the protein kinase using assays described herein. The dosage required to achieve the MEC will depend on the nature of the individual and the route of administration. However, HPLC assays or in vivo assays can be used to measure plasma concentrations.

Dosage intervals can also be determined using MEC values. The compound should be administered using a treatment that maintains plasma levels higher than the MEC for 10 to 90%, preferably 30 to 90%, and very preferably 50 to 90% of the time until a desired improvement of symptoms is achieved . In the case of local administration or selective absorption, effective local concentrations of such agents may not be related to plasma concentrations.

The amount of composition administered will, of course, be dependent upon the subject being treated, the weight of the subject, the severity of the disease, the manner of administration and the judgment of the prescribing physician.

Packaging

The composition may optionally be provided in a pack or dispensing device which may contain one or more unit dosage forms containing the active ingredient. Such a pack may comprise a metal or plastic foil, such as a blister pack. Such packs or dispensing devices may be accompanied by instructions for administration. Compositions comprising a compound of the invention formulated with a suitable pharmaceutical carrier can also be prepared in a suitable container, embedded and labeled for treatment of the indicated conditions.

In some formulations, it may be advantageous to use the compounds of the present invention in the form of very small sized particles, for example as obtained by fluid energy milling.

In the compositions of the present invention, the active compound may optionally be combined with other suitable pharmacologically active ingredients. For example, the compounds of the present invention inhibit or prevent the production of VEGF, weaken the intracellular response to VEGF, block intracellular signaling, inhibit vascular permeability hyperactivity, reduce inflammation, Or one or more additional pharmacological agents that inhibit or prevent the formation of angiogenesis. The compounds of the present invention may be administered concurrently with, after, or prior to an additional pharmaceutical agent, whatever the route of administration is appropriate. Additional pharmacologic agents include, but are not limited to, antidepressant steroids, NSAIDS, ras inhibitors, anti-TNF agents, anti-IL1 agents, antihistamines, PAF-antagonists, COX-1 inhibitors, COX- But are not limited to, PKC inhibitors and PI3 kinase inhibitors. The compounds of the present invention and further pharmaceutical agents act additionally or synergistically. Thus, the administration of such a combination of substances that inhibit angiogenesis, vascular permeability hyperactivity, and / or inhibit the formation of edema results in a more severe adverse effect of angiogenic diseases such as angiogenesis, vascular permeability hypertrophy or edema Can be reduced. In the treatment of malignant diseases, antiproliferative or cytotoxic chemotherapy or combination with radiotherapy is expected.

The invention also encompasses the use of a compound of formula (I) as a medicament.

Both Src and Syk of kinases play an important role in the regulation of immune function. The Src classes now include Fyn, Lck, Fgr, Fes, Lyn, Src, Yes, Hck and Blk. Syk is currently understood to include only Zap and Syk. These two classes of kinases are involved in the alteration of proinflammatory cytokine signals and growth factors through multiple receptors. Although BTK and ITK, members of the kinase Tec family, play roles that are less important in immunology, their modulation by inhibitors can prove to be therapeutically beneficial. Kinases RIP, IRAK-1, IRAK-2, NIK, IKK-1 and IKK-2 are involved in the signal transduction pathway for important pro-inflammatory cytokines TNF and IL-1. In view of the ability to inhibit one or more of these kinases, the compounds of formula (I) may function as immunomodulators useful in the maintenance of allografts and the treatment of autoimmune diseases. Through their ability to activate inflammatory processes or T cell activation, these compounds can be used to treat such autoimmune diseases. Graft versus host for host or graft versus transplant tissue due to rejection is limited by the toxicity of currently available immunosuppressive agents and may benefit from efficacious agents with improved therapeutic indices. Gene targeting experiments have demonstrated the essential role of Src in the biology of osteoclasts, the cells responsible for aggregate absorption. Through their ability to modulate Src, compounds of formula (I) may also be useful in the treatment of osteoporosis, marble osteoporosis, Paget's disease, tumor-induced hypercalcemia and bone metastasis.

Many protein kinases have been demonstrated to be protooncogenes. A truncation or mutation in the case of the Abl gene having a BCR (such as a chromosomal breakage (at the breakpoint of the ltk kinase on chromosome 5), such as translocation (Philadelphia chromosome), c-Kit or EGFR as in ) Result in the generation of poorly regulated proteins in which these kinases convert the original tumor gene into a tumor gene product. In another tumor, oncogenes are caused by autocrine or paracrine ligand / growth factor receptor interactions. Members of src kinases generally engage downstream signaling to activate oncogenes, which can be oncogenic or mutated into oncogenes. By inhibiting the protein kinase activity of these proteins, the disease process can be interrupted. The vascular recurrent stricture layer may include a process of FGF and / or PDGF-stimulated smooth muscle and endothelial cell proliferation. Inhibition of FGRr or PDFGr kinase activity may be an efficacious way to inhibit this phenomenon. Thus, the kinase activity of the normal or modified c-kit, c-met, c-fms, src-family members, EGFr, erbB2, erbB4, BCR- Ab1, PDGFr, FGFr and other receptors or cytosol tyrosine kinases Compounds of formula (I) which inhibit may be of value in the treatment of benign and tumor proliferative diseases.

In many pathologies (eg, solid primary tumors and metastasis, Kaposi sarcoma, rheumatoid arthritis, blindness due to improper neovascularization, psoriasis and atherosclerosis), progression of the disease can occur during persistent angiogenesis have. Often, polypeptide growth factors produced by disease tissues or associated inflammatory cells and their corresponding endothelial cell specific receptor tyrosine kinases (e.g., KDR / VEGFR-2, Flt-1 / VEGFR-1, Tie- Tek and Tie) are essential for the stimulation, regulation, organization, differentiation of the endothelial cell growth and establishment of the new functioning vasculature required. As a result of VEGF " vascular permeability enhancing factor " activity in mediating vascular permeability hyperactivity, VEGF stimulation of VEGFR kinase is associated with tumor ascites, cerebral and pulmonary edema, pleural and pericardial effusion, delayed type hypersensitivity reaction, , And guided edema leading to glaucoma or blindness due to trauma, burns, ischemia, diabetic complications, endometriosis, adult respiratory distress syndrome (ARDS), hypertension associated with post-cardiopulmonary bypass and hypertension and inappropriate neovascularization . In addition to VEGF, recently identified VEGF-C and VEGF-D, and HIV-Tat proteins can also induce vascular permeability hyperactivity through VEGFR kinase stimulation. Tie-2 is also expressed as a special population of hematopoietic stem cells that can play a role in the proliferation, adhesion, regulation and differentiation ( Blood 89, 4317-4326 (1997) A specific agent according to formula (I) that is capable of blocking the kinase activity of endothelial cell-specific kinases would be able to inhibit disease progression related to this situation.

Pharmaceutical compositions containing a compound of formula (I) or a salt thereof or a therapeutically effective amount can be used to treat disorders of benign and tumorigenic diseases and immune systems. Such diseases include autoimmune diseases such as rheumatoid arthritis, thyroiditis, type 1 diabetes, multiple sclerosis, sarcoidosis, bowel disease, myasthenia gravis and systemic lupus erythematosus; Cancer of humans such as psoriasis, organ transplant rejection (e.g., kidney rejection, graft versus host disease), benign and tumor proliferative diseases, lung, breast, stomach, bladder, colon, pancreas, ovary, prostate, Hematopoietic malignancies (leukemia and lymphoma), and diseases related to inappropriate angiogenesis, such as diabetic retinopathy, premature retinopathy, choroidal angiogenesis due to age-related macular degeneration, and infantile hemangiomas in human immunity. In addition, such inhibitors may be useful for the treatment of VEFG-mediated edema, ascites, diseases associated with diffusions, and exudates, including spot edema, cerebral edema, and ARDS.

The compounds of the present invention may also be useful in the prevention of such diseases.

Another aspect of the present invention relates to the use of a compound of formula (I) or a salt thereof, for the manufacture of a medicament for the treatment of disorders of vascular permeability, angiogenesis dependent disease, proliferative disease and / or immune system in a mammal, To use.

The present invention also encompasses methods of treating disorders of vascular permeability, inappropriate angiogenesis, proliferative disease and / or immune system, including the administration of a compound of formula (I) to a mammal, particularly a human, in need thereof do.

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

The efficacy of the compounds can be determined by the amount of inhibition of phosphorylation of the exogenous substrate by the test compound (for example, synthetic peptides (Z. Songyang et al., Nature 373: 536-539) against the control.

Preparation of KDR tyrosine kinase using baculovirus system

The coding sequence for the human KDR intracellular domain (aa789-1354) was generated by PCR using cDNA isolated from HUVEC cells. The poly-His ₆ sequence was also introduced at the N-terminus of this protein. This fragment was cloned into the transfection vector pVL1393 at the Xba I and Not I sites. Recombinant baculovirus (BV) was generated via co-transfection using BaculoGold Transfection reagent (PharMingen). Recombinant BV was plaque purified and assayed by Western blot. For protein production, SF-9 cells were grown in SF-900-II medium at 2x10 < 6 > / ml and infected with 0.5 plaque forming units (MOI) per cell. Cells were harvested 48 hours after infection.

Purification of KDR

SF-9 cell expression (His) ₆ KDR (aa789-1354) was dissolved in 50 ml of Triton X-100 lysis buffer (20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X- PMSF, 10 [mu] g / ml aprotinin, 1 [mu] g / ml leupeptin) was added to cell pellets from 1 L cell culture. The lysates were centrifuged at 19,000 rpm in a Sorval SS-34 rotor for 30 min at 4 < 0 > C. The cell lysate was added to the NiCl ₂ chelating sepharose column in 5ml, it was equilibrated with 50mM HEPES, pH 7.5, 0.3M NaCl . KDR was eluted using the same buffer containing 0.25 M imidazole. Column fractions were analyzed using SDS-PAGE and ELISA assays to determine kinase activity (below). The purified KDR was replaced with 25 mM HEPES, pH 7.5, 25 mM NaCl, 5 mM DTT buffer and stored at -80 [deg.] C.

Human Tie-2 Kinase Generation and Purification

The coding sequence for the human-2 intracellular domain (aa775-1124) was generated via PCR isolated from human placenta as a template. The poly-His ₆ sequence was introduced at the N-terminus and this construct was cloned into the transfection vector pVL1939 at the Xba I and Not I sites. Recombinant BV was produced by co-transfection using Baculo Gold transfection reagent (PharMingen). Recombinant BV was plaque purified and assayed by Western blot. For protein production, SF-9 insect cells were grown in SF-900-II medium at 2x10 < 6 > / ml and infected at 0.5 MOI. Purification of the His-tagged kinase used in the screening was similar to that described for KDR.

Human Flt-2 tyrosine kinase generation and purification

The baculovirus expression vector pVL 1393 (Phar Mingen, Los Angeles, CA) was used. The nucleotide sequence encoding poly-His6 was located 5 'to the nucleotide region (amino acids 786-1338) encoding the entire intracellular kinase domain of human Flt-1. Nucleotide sequences encoding the kinase domain were generated by PCR using a cDNA library isolated from HUVEC cells. Histidine residues enabled the affinity purification of proteins in a manner similar to that for KDR and ZAP70. SF-9 insect cells were infected at 0.5 multiplicity and collected at 48 hours post-infection.

EGFR tyrosine kinase source

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

Expression of ZAP70

The baculovirus expression vector used was pVL1393 (Pharmingen, Los Angeles, Ca.). The nucleotide sequence encoding the amino acid M (H) 6 LVPR ₆ S was located 5 'to the region encoding all of ZAP70 (amino acids 1-619). Tucleotide sequences encoding the ZAP70 coding region were generated by PCR using a cDNA library isolated from the jurquat immortalized T-cells. Histidine residues made it possible to purify the affinity of the protein (see below). The LVPR ₆ S bridge constitutes a recognition sequence for proteolytic degradation by thrombin, enabling the removal of affinity tags from the enzyme. SF-9 insect cells were infected at 0.5 MOI and collected at 48 hours post-infection.

Extraction and purification of ZAP70

SF-9 cells were cultured in RPMI 1640 medium supplemented with 20 mM Tris, pH 8.0, 137 mM NaCl, 10% glycerol, 1% Triton X-100, 1 mM PMSF, 1 μg / ml leupeptin, 10 μg / ml aprotinin and 1 mM sodium orthovanadate ≪ / RTI > buffer. The soluble lysate was added to a chelating Sepharose HiTrap column (Pharmacia) equilibrated with 50 mM HEPES, pH 7.5, 0.3 M NaCl. The fusion protein was eluted with 250 mM imidazole. The enzyme was stored in a buffer containing 50 mM HEPES, pH 7.5, 50 mM NaCl and 5 mM DTT.

Lck source

Lck or Lck truncated forms are commercially available (for example, Upstate Biotechnology Inc. (Saranac Lake, NY) and Santa Cruz Biotechnology Inc. (Santa Cruz, Calif.)) Can be purified from natural or recombinant sources.

Enzyme Linked Immunosorbent Assay for PTK (ELISA)

An enzyme-linked immunosorbent assay (ELISA) was used to detect and measure the presence of tyrosine kinase activity. ELISA is described, for example, in Voller, et al, 1980, "Enzyme-Linked Immunosorbent Assay": Manual of Clinical Immunology, 2d, ed ., Edited by Rose and Friedman, pp 359-371 Am. Soc. Of Microbiology, Washington, DC).

The original assay described above was applied to determine activity against a specific PTK. For example, a preferred original for performing an ELISA test is provided below. Those skilled in the art are well aware of the application of such an assay to measure the activity of a compound against non-receptor tyrosine kinases as well as other members of the receptor PTK family. To determine inhibitor selectivity, a universal PTK substrate (for example, a random copolymer of poly (Glu ₄ Tyr), 20,000-50,000 MW) was added at a concentration approximately twice the apparent Km of the assay to ATP ).

The following method is used to analyze the inhibitory effect of the compounds of the present invention on KDR, Flt-1, Tie-2, EGFR and ZAP70 tyrosine kinase activities.

Buffer and solution:

PGT: poly (Glu, Tyr) 4: 1

The powder is stored at -20 < 0 > C. The powder is dissolved in phosphate buffered saline (PBS) to give a 50 mg / ml solution. Store 1 ml aliquots at 120 < 0 > C. When preparing the plate, dilute to 250 μg / ml in Gibco PBS.

Reaction buffer: 100mM HEPES _{(Hepes), 20mM MgCl 2,} 4mM MnCl 2, 5mM DTT, 0.02% BSA, 200μM NaVO 4, pH7.10.

ATP: 100 mM aliquots are stored at -20 < 0 > C. Dilute to 20 μM in water.

Wash Buffer: 0.1% Tween 20 in PBS

Antibody Dilution Buffer: 0.1% bovine serum albumin in PBS

TMB substrate: Mix TMB substrate with peroxide solution at a ratio of 9: 1 immediately before use, or use K-Blue substrate from Neogen.

Final solution: 1 M phosphorphosphoric acid

Way

1. Plate manufacturing:

Dilute PGT stock solution (50 mg / ml, frozen) in PBS to 250 μg / ml. 125 [mu] l per well of a modified flat bottomed high affinity ELISA plate from Corning (Corning # 25805-96) is added. 125 [mu] l of PBS is added to the blank wells. Cover with sealing tape and incubate overnight at 37 ° C. Washed 1x with 250 [mu] l of wash buffer and dried in a 37 [deg.] C dry incubator for 2 hours. The coated plate is stored in a sealed bag until used at 4 ° C.

2. Tyrosine Kinase Reaction:

- Inhibitor solution is prepared by concentrating 4x in 20% DMSO in water.

- Reaction buffer is prepared.

- The enzyme solution is made up to the desired unit in 50 μl. For example, in the case of KDR, 1 ng / μl is prepared, and a total of 50 ng is obtained per well at the time of the reaction.

- Prepare 20μM 4x ATP solution from 100mM stock in water. Store on the ice sheet.

50 μl of the enzyme solution per well is added (generally 5-50 ng enzyme / well depending on the activity of the kinase).

-4x inhibitor is added.

Add 25 μl of 4x ATP for inhibitor analysis.

Incubate at room temperature for 10 minutes.

The reaction is terminated by adding 50 0.05 of 0.05N HCL per well.

- Wash the plate.

** Final concentration of reaction: 5 [mu] M ATP, 5% DMSO

3. Antibody binding

Dilute (100x, then 200x) with 1 mg / ml aliquots of PY20-HRP (Pierce) antibody (phosphotyrosine antibody) to 50 ng / ml in 0.1% BSA in PBS.

Add 100 μl Ab per well. Incubate at room temperature for 1 hour. Incubate at 4 ° C for 1 hour.

Wash the -4x plate.

4. Color reaction

-TMB substrate is prepared and 100 [mu] l / well is added.

Monitor at -650 nm until the OD value reaches 0.6.

-1 M phosphorphosphoric acid. Shake on plate reader.

Read the O.D. value at -450 nm.

The optimal incubation time and enzyme reaction conditions vary somewhat depending on the enzyme preparation and are determined experimentally according to the respective amounts.

The reaction buffer for Lck uses 100 mM MOPSO, pH 6.5, 4 mM MnCl ₂ , 20 mM MgCl ₂ , 5 mM DTT, 0.2% BSA, 200 mM NaVO ₄ under similar assay conditions.

The compounds of formula I may have therapeutic utility in the treatment of diseases which include identified protein tyrosine kinases inhibited by compounds of formula I, including those not mentioned herein, and protein tyrosine kinases not yet identified . All compounds exemplified herein significantly inhibit KDR kinase at 50 [mu] M or less. Certain compounds of the invention also significantly inhibit other PTKs, e.g., lck, at 50 [mu] M or less.

Cdc2 source

Human recombinase and assay buffers can be either commercially available (New England Biolabs, Beverly, Mass., USA) or purified from known natural or recombinant sources using conventional methods.

Cdc2 analysis

The reagents purchased were used only in slight modifications to the protocol provided. Briefly, the reactions were performed in a final concentration of 50 mM Tris pH 7.5, 100 mM NaCl, 1 mM EGTA, 2 mM DTT, 0.01% Brij, 5% DMSO and fresh 300 μM ATP (31 μCi / ml) and 30 μg / Lt; _RTI ID = 0.0 > MgCl2 < / _{RTI >} (a commercial buffer). A reaction volume of 80 占 퐇 containing the enzyme unit was run at 25 占 폚 for 20 minutes in the presence or absence of inhibitor. The reaction was terminated by adding 120 쨉 l of 10% acetic acid. The substrate was removed from the unbound label by spotting the mixture on phosphocellulose paper and subsequently washed three times for 5 minutes each with 75 mM phosphoric acid. And counted using a beta counter in the presence of liquid phase synthon.

Certain compounds of the present invention significantly inhibited cdc2 at concentrations of less than 50 [mu] M.

PKC kinase source

The catalytic subunit of PKC can be purchased from Calbiochem.

PKC kinase assay assay

The radioactive kinase assay was performed according to the published method (Reference: 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 kinase buffer consisting of 50 mM Tris pH 7.5, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 100 μM ATP, 8 μM peptide, 5% DMSO and ³³ P ATP (8 μCi / ml). The compound and the enzyme were mixed in a reaction vessel, and the reaction was started by adding the substrate mixture with ATP. After the reaction was terminated by adding 10 μl of final buffer (5 mM ATP in 75 mM phosphoric acid), a portion of the mixture was spotted onto a phospho-cellulose filter. The spotted sample was washed 3 times with 75 mM phosphoric acid at room temperature for 5 to 15 minutes. Binding to the radioactive label was quantitated using liquid Sinhtenant's coefficient.

Erk2 enzyme source

Recombinant rat enzyme and assay buffer are purchased or purified from a known natural or recombinant source using conventional methods (New England Biolabs, Beverly, Mass., USA).

Erk2 enzyme assay

Briefly, the reaction was incubated under conditions recommended by the supplier, in the presence of fresh 50 mM Tris pH 7.5, 1 mM EGTA, 2 mM DTT, 0.01% Brij (Brij), freshly supplemented with 100 μM ATP (31 μCi / ml) and 30 μM myelin basic protein ), it was carried out in a buffer consisting of 5% DMSO and 10mM MgCl ₂ (commercial buffer). Analysis of the reaction volume and bound radioactivity is as described in the PKC assay (see above).

In vitro model for T cell activity

In the case of activation by mitogen or antigen, T cells are induced to secrete IL-2, a growth factor that supports their subsequent proliferative step. Thus, as a surrogate for T cell activation, IL-2 from primary T cells or appropriate T cell lines can be measured or cell proliferation measured. Both of these assays are well described in the literature and their parameters are documented (cf. Current Protocols in Immunology, Vol 2, 7.10.1-7.11.2).

In summary, T cells can be activated by incubation with allograft cells, and the process is termed a one-way mixed lymphocyte reaction. Reagents and stimulants Peripheral blood mononuclear cells are purified by Ficoll-Hypaque gradient (Pharmacia) according to the manufacturer's instructions. Stimulator cells are mitotically inactivated by mitomycin C (Sigma) or gamma irradiation. Reactants and stimulator cells are co-cultured in the presence of test compound at a ratio of 2: 1. Generally, 10 ⁵ reactants are mixed with 5 x 10 ⁴ stimulants and plated in 200 μl volumes in U-shaped bottom microtiter plates (Costar Scientific). Cells are cultured in heat-inactivated fetal bovine serum (Hyclone Laboratories) or in RPMI 1640, 5x10 ^-5 M mercaptoethanol and 0.5% DMSO supplemented with pooled human AB serum from a male donor. The cultures are pulsed with 0.5 μCi of ³ H thymidine (Amersham) one day prior to harvesting (generally 3 days). The cultures are harvested (beta-plate harvester, Wallac) and isotope adsorption assay is performed with liquid scintillation (Beta plate, Wallac).

The same culture system can be used to measure T cell activation for measurement of IL-2 production. After incubation for 18-24 hours, the supernatant is removed and the IL-2 concentration is measured by ELISA (R and D Syatems) according to the manufacturer's instructions.

In vivo model 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 T cells found to be the working cells for this. T cells can be activated in vivo by binding a certain amount of T cell receptor with monoclonal anti-CD3 antibody (Ab). In this model, BALB / c mice receive 10 mg of anti-CD3 Ab intraperitoneally 2 hours prior to salvage. Animals receiving the test drug are pretreated with a single dose of compound one hour prior to administration of anti-CD3 Ab. Serum levels of the inflammatory cytokines interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), which are T cell activation indicators, are measured by ELISA. A similar model performs in vivo T cell priming using specific antigens, such as keyhole limpet hemocyanin (KLH), and subsequent secondary inoculation of the lymph node cells with the same antigen. As described above, measurement of cytokine production is used to analyze the activated state of the cultured cells. In summary, C57BL / 6 mice are immunized subcutaneously with 100 μg KLH emulsified in complete Freud's adjuvant (CFA) on day 0. Animals are pretreated with compound 1 day before and after immunization on days 1, 2 and 3 after immunization. Drained lymph nodes are harvested at day 4 and their cells are cultured in tissue culture medium (RPMI 1640 supplemented with 5 × 10 ^-5 M 2-mercaptoethanol and 0.5% DMSO, heat-inactivated fetal bovine serum (Hycloe Laboratory) X 10 < ⁶ > / ml for 24 hours and 48 hours. Culture supernatants are assayed for self-secreted T cell growth factor interleukin-2 (IL-2) and / or IFN-y levels by ELISA.

Leading compounds can be tested from animal models of human disease. These are exemplified by experimental autoimmune encephalomyelitis (EAE) and collagen-induced arthritis (CIA). EAE models with similar aspects to human multiple sclerosis have been described in both mice and mice (FASEB J. 5: 2500-2566, 1991; Rat Model: Lab. Invest. 4 (3): 278, 1981 ; Rodent models: J. Immonol 146 (4): 1163-8,1991). In summary, mice or rats are immunized with a herbal basic protein or a neurogenic peptide derivative thereof, and an emulsion of CFA. An acute disease can be induced by the addition of a bacterial toxin, such as bordetella pertussis . Relapsing / remitting disease may be induced by adoptive transfer of T cells from an MBP / peptide immunized animal.

CIA can be immunized with type II collagen in DBA / 1 mice (reference: J. Immunol: 142 (7): 2237-2243). Mice show signs of arthritis early about 10 days after antigen challenge and can be recorded for as long as 90 days after immunization. In both the EAE and CIA models, the compound may be administered prophylactically or at the onset of the disease. Effective drugs should reduce the severity and / or onset.

One or more angiogenic receptor PTKs, and / or protein kinases, such as lcks involved in modulating inflammatory responses, may reduce the severity and onset in these models.

The compounds may also be used in a mouse allograft model, skin (reference: Ann. Rev. Immunol., 10: 333-58, 1992; Transplantation: 57 (12): 1701-17D6, 1994) J. Anat .: 113: 273, 1963). In summary, a sufficient thickness of the epidermal graft can be transplanted from C57BL / 6 mice to BALB / c mice. These grafts are examined daily for evidence of rejection starting on day 6. In a rat newborn heart transplant model, a newborn heart is ectopically transplanted from C57BL / 6 mice into the auricle of mature CBA / J mice. The heart begins to pulsate 4 to 7 days after transplantation, and rejection can be visualized using a dissecting microscope to observe the discontinuation of beating.

Cell receptor PTK analysis

The following cell assays were used to determine the level and effect of the activity of other compounds of the invention on KDR / VEGFR2. Analogous receptor PKT assays using specific ligand stimulation could be designed following the same method for other tyrosine kinases using techniques known in the art.

Western blot measurements on human umbilical vein endothelial cells (HUVEC)

1. HUVEC cells (from pooled donors) were purchased from Clontics (Clonetics, Sandiego, Calif.) And cultured according to the manufacturer's instructions. Only the initial step (3-8) was used for this analysis. Cells were cultured in 100 mm dishes (Falcon for tissue culture; Becton Dickinson; Plymouth, England) using full EBM medium (Clonetics).

2. In order to evaluate the inhibitory activity of the compounds, the cells were Xin trip, a 6-well cluster plates; were seeded 0.5-1.0 × 10 ⁵ cells / well in each well of (Costar Cambridge, MA).

3. 3-4 days after seeding, the plates became 90-100% fluffy. The medium was removed from the wells, and the cells were washed with 5-10 ml of PBS and incubated for 18-24 hours with 5 ml of EBM-based medium without additional feed (i. E., Serum starvation).

4. A series of dilutions of inhibitor were added to 1 ml of EBM medium (25 μM, 5 μM, or 1 μM final concentration for cells) and incubated at 37 ° C for 1 hour. Human recombinant VEGF ₁₆₅ (R & D System) was then added to all wells in 2 ml of EBM medium to a final concentration of 50 ng / ml and incubated at 37 [deg.] C for 10 min. Background phosphorylation and phosphorylation by VEGF were analyzed using VEGF alone or untreated control cells.

Next, all wells are washed with 5-10 ml of cold PBS containing 1 mM sodium orthovanadate (Sigma), the cells are lysed and incubated with protease inhibitor (PMSF 1 mM, aprotinin 1 ug / ml, pepstatin 1 ug / ml (50 mM Tris-HCl pH7, 150 mM NaCl, 1% NP-40, 0.25% sodium deoxycholate, 1 mM EDTA (pH 7.0) containing 1 μg / ml of rubetin, 1 mM Na vanadate, 1 mM Na fluoride) ), And 1 [mu] g / ml Dase (chemicals from Sigma Chemical Company, St Louis, MO). The lysate was centrifuged at 14,000 rpm for 30 minutes to remove nuclei.

Next, the same amount of protein was precipitated by adding cold (-20 ° C) ethanol (2 volumes) for at least 1 hour or up to overnight. The pellet was resuspended in a Laemli sample buffer containing 5% beta mercaptoethanol (BioRad; Hercules, Calif.) And boiled for 5 minutes. Proteins were separated by polyamide gel electrophoresis (6%, 1.5 mm Novex, Sandiego, Calif.) And transferred to the nitrocellulose membrane using the Novex system. Protein was blocked with anti-KDR polyclonal antibody (C20, Santa Cruz, CA) or anti-phosphotyrosine monoclonal antibody (4G10, Upstate Biotechnology, Lake Placid, NY) after blocking with bovine serum albumin (3% ≪ / RTI > overnight at 4 < 0 > C. (ECL) system (Amersham Life Sciences, Arlington Height, Ill.) After incubation for 1 hour with the HRP-condensed F (ab) _{2 of the} wash and goat anti-rabbit or goat- Lt; / RTI > A specific example of the present invention significantly inhibited cellular VEGF-induced KDR tyrosine kinase phosphorylation at a concentration of less than 50 μM.

In vivo model of uterine edema

This assay measures the ability of a compound to inhibit the rapid increase in uterine weight in mice that occurs within the first few hours after stimulation of estrogen. This early onset of uterine weight gain is known to be caused by edema caused by increased permeability of the uterine vasculature. Cullinan-Bove and Koss (Reference: Endocrinology (1993), 133: 829-837) demonstrated a close temporal relationship between increased expression of estrogen-stimulated uterine edema and intrauterine VEGF mRNA . These results have been confirmed by the use of neutralization of monoclonal antibodies against VEGF, which significantly reduces the rapid increase in uterine weight following estrogen stimulation (WO 97/42187). Thus, such a system contributes as a model for the inhibition of in vivo VEGF signaling and the associated hyperpermeability and edema.

Materials: All hormones were purchased as lyophilized powders from Sigma (St. Louis, Mo.) or Cal Biochem (La Jolla, Calif.) And prepared according to the supplier's instructions.

The vehicle compound (DMSO, Cremaphor EL) was purchased from Sigma.

Mice (Balb / c, 8-12 weeks old) were purchased from Taconic (Germantown, NY) and housed in non-toxic animals according to the Commission's Animal Care and Use Committe Guidelines .

Way:

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

Day 3: Human chorionic gonadotropin (hCG) is administered to mice via i.p. Injected.

Day 4: Mice were randomly divided into two groups of 5-10 mice. The test compounds were tested for i.p., i.v., or p.o. 1 mg / kg, depending on solubility and vehicle. The vehicle control group was administered vehicle only and the two groups were not treated.

After 30 minutes of experiment, one of the vehicle group and the untreated group was ip injected with 17 [beta] -estradiol (500 [mu] g / kg). After 2-3 days, the animals were killed by inhalation of CO ₂ . After the incision of the center line, each uterus was separated and removed by cutting the connection between the uterus and fallopian tubes just below the cervix. Before weighing, lipids and connective tissue were carefully removed, taking care not to damage the entire uterus. As a result of the researcher 's test, the saliency was measured. A non-stimulated control was used to monitor the estradiol response.

The results demonstrate that certain compounds of the invention inhibit the formation of edema when administered systemically via various routes.

Certain compounds of the invention, which are inhibitors of angiogenic receptor tyrosine kinases, have also been shown to be active in the angiogenic Matrigel transplantation model. The matrigel angiogenesis model involved the formation of new blood vessels within an apparent " marble " of subcutaneous implanted extracellular matrix induced by the presence of angiogenic proangiogenic factors producing tumor cells (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 performed over 3 to 4 days and the endpoint is visual / visual scoring of the angiogenesis, microscopic microvascular density measurement, and hemoglobin quantitation (Drabkin method) followed by an inhibitor-free And removal of graft versus control from the animals.

Certain compounds of the invention that inhibit one or more tumorigenic, primitive tumorigenic, or proliferative dependent protein kinases, or angiostatic receptors PKT, also inhibit the proliferation of primary mouse, mouse or human xenograft tumors in mice, Which inhibited the metastasis of mouse models.

Ⅰ. synthesis

There are two general approaches to the synthesis of the ring structure of compounds of formula I, which are disclosed in U.S. Pat. No. 3,843,665 and U.S. Pat. No. 3,843,666.

According to U.S. Patent No. 3,843,665, the cyclization of the pyrazole ring is effected by heating the compound of formula (II) with an aromatic sulfonyl hydrazide of formula (III) with an inert solvent and an acid catalytic amount. The reaction is carried out at preferably 75 ℃ to 100 ℃ for 5 to 30 hours, the compound of formula Ⅰ of R ₁ is hydrogen are obtained.

In this formula,

p is 0, 1, 2; W is lower alkyl; R ₂ , R ₃ , R ₄ , R ₅ , R ₆ and X are as defined above. Compounds of formula (II) are prepared by treating a suitably functionalized compound of formula (IV) with an aldehyde of formula (V) under acid or base catalysis (Braun, RA; Mosher, WA J. Amer. Chem. Soc. 80,2749).

A second method for preparing a cyclic compound of formula (I) wherein R < _{1 >} is hydrogen is disclosed in U.S. Patent No. 3,843,666. Here, the compound of formula (VI) is heated in an inert solvent such as an aromatic hydrocarbon with a catalytic amount of an organic carboxylic acid or an organic sulfonic acid at 75 ° C to 175 ° C for 6 to 24 hours.

In this formula,

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

Compounds of formula (VI) are prepared by treating compounds of formula (VII) with hydrazine in an inert solvent.

The compound of formula (I) may also be prepared by reacting a compound of formula (VII) with hydrazine without isolating the compound of formula (VI), for example by reacting the compound of formula (VII) with acetic acid in an inert solvent such as methanol Can be prepared directly by heating with hydrazine at the temperature of the boiling point of the inert solvent used from 60 占 폚 under the same acid catalyst.

Compounds of formula (I) may be prepared by reacting a compound of formula (XVI) with hydrazine in an inert solvent such as methanol at a temperature from 15 [deg.] C to the boiling point of the inert solvent used:

In this formula,

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 melting point of the inert solvent applied.

Compounds of formula (VII) are prepared by treating compounds of formula (VIII) with an aldehyde of formula (V) under basic conditions. The reaction was carried out in an inert solvent at a temperature of 5 to 10 DEG C for 3 to 6 hours:

Wherein Y is any conventional leaving group such as chlorine, bromine, iodine, tosylate or mesylate, and R ₃ , R ₄ , R ₅ , R ₆ and X are as defined above.

Compounds of formula (VII) can be prepared from compounds of formula (II) in an inert solvent such as methanol, dichloromethane, water or mixtures thereof, optionally in the presence of a base such as sodium hydroxide, at temperatures between 0 and 100 & Or by reacting with a base.

The cyclization of (VI) can also be carried out by treatment with mines such as hydrochloric acid, sulfuric acid or phosphoric acid. The reaction is carried out in a lower alkanol at a temperature of 15 to 20 DEG C for 12 to 48 hours. The following reaction product (IX) can then be aromatized by heating to a temperature of from 50 to 150 DEG C using an organic carboxylic acid or organic sulfuric acid in a straight chain ether or ring ether for 8 to 30 hours:

(IX) is treated with an acid anhydride of the formula (R _x CO) ₂ O (X) wherein R _x is a C _1-4 alkyl group in an inert solvent such as an aromatic hydrocarbon at a temperature of 35-200 ° C for 5-8 hours Can be diacetylated.

(XII) can then be aromatized with compound (XII) by heating to a temperature of 35 to 200 DEG C using a mineral acid or organic acid for 4 to 8 hours in an inert solvent. As a result, compound (XII) (I) in the presence of a metal or alkali metal hydrate in an inert solvent such as water or a lower alcohol for 8 to 30 hours at a temperature of 50 to 150 < 0 > C:

The compound of formula (II) may be cyclized to a compound of formula (XIII) by reaction with hydrazine in an inert solvent such as methanol at a temperature of 35-150 ° C:

Compounds of formula (I) may be prepared by reacting a compound of formula (III) with a dehydrogenating agent such as sulfur, oxygen, palladium, magnesium dioxide or lead dioxide in the presence of an inert solvent such as a hydrocarbon, .

Specific examples of previous variations are disclosed in U.S. Patent Nos. 3,843,665 and 3,843,666.

The bridging carbonyl can be transformed into a methylene group by Wolf-Kishner reduction of the corresponding hydrazone (Mosher, WA, Tawfik, E.-Z., Lipp, DWJOrg.Chem. 1971, 36, 3890).

Additional methods and specific examples for the functionalization of bridged carbonyls are disclosed in Japanese Patent Application JP 60 130521 A2 and B. Loev, U.S. Patent No. 3,004,983 (1960).

Compounds of formula (I) may be prepared by the reaction of a compound of formula (XIV) with a strong base such as n-butyllithium at a temperature of -78 to 25 占 폚, reacting a compound of formula (XIV) wherein R ₂ is as defined above and G is a C _1-6 alkoxy group R < _{2 >} COG (XV).

The compounds of formulas (IV), (VIII), (XIV), (XV) and (XVI) are commercially available or can be prepared by methods known to those skilled in the art.

Compounds of formula (I) wherein X is SO or SO ₂ can be prepared by oxidation of a compound of formula (I) wherein X is S by methods known to those skilled in the art, for example using a suitable molar equivalent of 3-chloroperbenzoic acid have.

Compounds of formula (I) wherein X is a formula (C = NOR ₇ ) group can be prepared by reacting a compound of formula (I) wherein X is carbonyl with a compound of formula H ₂ NOR ₇ by methods known to those skilled in the art .

Compounds of formula (I) wherein R < ₂ > = 4-pyridyl may be further functionalized by methods known to those skilled in the art, e.g. at position 2 of the pyridine ring by pyridine-N-oxide mediated transfer.

Some substituents of formula (I) may be interconverted by methods known in the art. For example, an alkoxy substituent can be reacted with a suitable ether cleavage agent, such as bromic acid, boron tribromide, or pyridine hydrochloride, to provide a compound of formula (I) having a hydroxy substituent. The compound of formula (I) having an alkoxy substituent can also be prepared by alkylating a compound of formula (I) having a hydroxy substituent. The carboxylic acid ester substituent may be converted to a carboxy or amide substituent, and the carboxylic acid substituent may be converted to a carboxylic acid ester or amide substituent. The nitro substituent may be reduced to an amine and the amine may be acylated by methods known in the art.

It will be appreciated by those skilled in the art that some substituents may react with some of the reagents described in the previous process. In this case, another process must be used, or the reaction substituent must be protected prior to reaction and deprotected after reaction.

The invention is illustrated by the following examples given by way of example only. EXAMPLES Each final product is characterized by one or more of the following procedures: high performance liquid chromatography; Elemental analysis, nuclear magnetic resonance spectroscopy, ultraviolet spectroscopy and high-resolution mass spectroscopy. The following abbreviations were used:

IMS = commercial denatured ethanol

LCMS = liquid chromatography / mass spectroscopy

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 boiled under reflux under nitrogen for 1 hour. The mixture was cooled to 20 < 0 > C and the mixture was concentrated under reduced pressure to give a solid which was collected by filtration to give indan-1-one hydrazone having a m.p of 84-86 deg.

b) A solution of n-butyllithium (15.0 ml of a 2.5M solution in hexane) was added dropwise to a hydrazone (1.82 g) mixture of a) in tetrahydrofuran (40 ml) at 0 ° C with stirring under nitrogen . The mixture was stirred for 0.5 h at 0 <0> C, then methyl 3,4,5-trimethoxybenzoate (1.41 g) was added dropwise over 10 min, and the mixture was stirred at 0 <0> C for 20 min. Dilute hydrochloric acid (40 mL, 3M) was added and the mixture was boiled under reflux for 1 hour. The mixture was cooled to ambient 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 as mobile phase using ethyl acetate / petroleum ether (1: 4) to give 3- (3,4,5-trimethoxyphenyl) - 1,4-dihydroindeneol (1,2-c] pyrazole.

Example 2

a) In a manner similar to that of Example 1, indan-1-one hydrazone (3.55 g) was dissolved in tetrahydrofuran (80 ml) at 0 ° C with stirring under nitrogen. n-Butyl lithium (28.8 mL of a 2.5M solution in hexane) was added to the solution, and the mixture was stirred at 0 C for 0.5 hour. After the addition of ethyl 3-methoxybenzoate (2.16 g) and addition of 3 M hydrochloric acid (80 ml), the mixture was terminated as described in Example 1 to give 3- (3 -Methoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole.

b) A solution of boron tribromide in dichloromethane (4.58 ml of a 1M solution) was added to a suspension of the product from a) (0.30 g) in dichloromethane (30 ml) with stirring at -40 <0> C under nitrogen with stirring. The mixture was stirred between -40 &lt; 0 &gt; C and -20 &lt; 0 &gt; C for 0.5 hour and then allowed to warm to ambient temperature. The mixture was stirred at ambient temperature for 0.5 hour at ambient temperature and then poured into 100 ml of methanol. Silica was added and the mixture was pre-absorbed onto silica and then ethyl acetate / petroleum ether (1: 2.5 ethyl acetate / methanol (1: 1) was added to increase the fraction of ethyl acetate until 100% &Lt; / RTI &gt; filtered and concentrated in vacuo). The appropriate fractions were collected, combined and recrystallized from ethanol to give 3- (l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) phenol with m.p.

Example 3

2-benzoylbenzo [b] thiophene-3 (2H) -one (1.50 g, supplied by Maybridge Chemical Company, Tintagel, UK) hydrazine hydrate (0.3 ml) and butan- (50 ml) was boiled under reflux under nitrogen for 7.5 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate, washed with water, dried, filtered and evaporated to give, as a mobile phase on silica, purified by flash column chromatography using toluene / ethyl acetate (7.5: 1) To give a solid. The appropriate fractions were collected, combined and evaporated, triturated with ether and filtered to give a solid that gave 3-phenyl-1H- [1] benzenethieno [3,2- c] pyrazole, mp 236-238 ° C. Respectively.

Example 4

A solution of 3-chloroperoxybenzoic acid (450 mg, 60% purity) in dichloromethane (30 ml) was added to a solution of 3-phenyl-lH- [1] benzothieno [3,2- c] Sol (400 mg) solution at 0-5 &lt; 0 &gt; C over 15 min with stirring. The mixture was stirred at 5-15 [deg.] C for 4 hours, then washed with water, dried and evaporated to give a solid which was chromatographically purified on silica using petroleum ether / ethyl acetate (1: 3) as the mobile phase. The appropriate fractions were collected, combined and evaporated, triturated with ether and filtered to give 3-phenyl-1H- [1] benzothieto [3,2-c] pyrazole-4-oxide, mp 222-224 ° C. Lt; / RTI &gt; was obtained.

Example 5

A solution of 3-dichloroperoxybenzoic acid (440 mg, 60% purity) in dichloromethane (30 ml) was added to a solution of 3-phenyl- lH- [1] benzothieno [3, 2-c] pyrazole (190 mg) over 15 min. 3-Chloroperoxybenzoic acid (220 mg) was further added after 2 hours while stirring the mixture at 5 to 15 占 폚 for 4 hours. The reaction mixture was washed with water, dried, filtered and evaporated to give a solid dissolved in ethyl acetate (100 mL), washed with 1 M sodium hydroxide solution (50 mL, then dried, filtered and evaporated to give Titration and filtration gave a solid which gave 3-phenyl-1H- [1] benzothieno [3,2-c] pyrazole 4,4-dioxide in mp 266-268 ° C.

Example 6

(1.28 g, prepared from JP 60-130521), hydroxylamine hydrochloride (0.5 g), sodium acetate (0.8 g), sodium hydride , Water (10 ml) and methanol (100 ml) was boiled under reflux for 66 hours. Additional hydroxyamine hydrochloride (0.5 g), sodium acetate (0.8 g) and water (10 ml) were added and the mixture was boiled under reflux for an additional 16 h. Additional hydroxyamine hydrochloride (0.5 g) and sodium acetate (0.8 g) were added and the mixture was boiled under reflux for an additional 20 h. The mixture was filtered, and the filtrate was concentrated under reduced pressure to initiate recrystallization. The mixture was cooled, filtered, washed with water and dried to give a solid which gave 3-phenylredino [1,2-c] pyrazole-4 (1H) -one oxime (decomposed) .

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. The solid material obtained was boiled in industrially denatured ethanol (200 ml) and filtered hot. The resulting solid residue was washed with industrial grade denaturated ethanol and dried to give methyl 4- (1-oxoindan-2-ylidenemethyl) benzoic acid salt, m.p.

b) The product from a) (1.5 g) is suspended in methanol (10 ml) and dichloromethane (15 ml) and 2M sodium hydroxide (2.7 ml) is added while stirring at 0-5 [deg.] C and then 30% (100vol, 1.1ml) was added. The mixture was stirred at 0 SIMILAR 5 DEG C for 5 minutes and then at ambient temperature for 24 hours. Dichloromethane (100 ml) was added to the mixture and the mixture was then washed with brine (2x50 ml), dried, filtered and evaporated to give methyl 4- (1-oxospiro [indan-2,2'- ] -3'-yl) benzoic acid salt, mp 160 to 163 &lt; 0 &gt; C. The aqueous phase was acidified with 5M hydrochloric acid, extracted with dichloromethane and decomposed to give 4- (1-oxospiro [indan-2,2'-oxiram] -3'yl) benzoic acid, m.p.

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) While stirring, glacial acetic acid (6 drops) was added. The mixture was boiled under reflux for 24 hours, then allowed to stand at ambient temperature for 24 hours, then cooled to 0 C and filtered to give methyl 4- (1,4-dihydroindeno [1,2 -c] pyrazol-3-yl) benzoic acid salt.

Example 8

(780 mg), methanol (50 ml), hydrazine hydrate (0.18 ml) and glacial acetic acid (10 ml) were added to a solution of 4- (1-oxospiro [indan- 6 drops) was boiled under reflux for 24 hours. The mixture was cooled in ice and filtered to give 4- (l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) benzoic acid in m.p.

Example 9

The mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid (1,05 g) and dry tetrahydrofuran (30 ml) Ethylamine (1.1 ml) was added. The mixture was stirred for 0.5 hour at ambient temperature and then cooled to 3 DEG C and methyl chloroformate (1.2 mL) was added dropwise at 3-9 DEG C over 5-10 minutes. The mixture was stirred at 3 to 9 占 폚 for 1 hour and then added to a concentrated aqueous ammonia solution (70 ml, SG 0.880) with rapid stirring. The mixture was stirred at 5 &lt; 0 &gt; C for 2 hours and allowed to warm to ambient 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 hour and then filtered. The resulting solid was stirred with 2 M sodium hydroxide solution (50 mL) for 6 hours and then kept at ambient temperature for 18 hours. The mixture was filtered to give a solid which was washed with water and filtered. This solid was purified by flash column chromatography on silica using mobile phase of dichloromethane / commercial denatured ethanol / triethylamine (25: 2.5: 1.5). The 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- (l, 4-dihydroindeno [l, 2-c] Yl) benzoamide. &Lt; / RTI &gt;

Examples 10 and 11

A mixture of a) 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) (10.8 g) was heated to 90 &lt; 0 &gt; C under nitrogen. Methanol (200 ml) was added and the mixture was cooled and filtered to give N- (2-benzylidene-1-oxo-indan-5-yl) acetamide (13.47 g).

b) A solution of the product from the preceding a) (9.20 g), dichloromethane (30 ml) and methanol (30 ml) was stirred at 20 ° C and then 2M sodium hydroxide solution (15 ml) and hydrogen peroxide (6.6 ml, Lt; RTI ID = 0.0 &gt; 20 C &lt; / RTI &gt; The mixture was stirred for 24 hours at 20 DEG C. 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- Acetamide was obtained.

c) The product of b) (2.0 g) was dissolved in ethanol (30 ml), hydrazine hydrate (0.34 g) was added and glacial acetic acid (30 drops) was added. The mixture was boiled at reflux for 5 hours and then cooled. The solid was collected by filtration and purified by flash column chromatography on silica using mobile phase dichloromethane / methanol (95: 5) to give N- (3-phenyl-l , 4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide.

Some fractions in chromatography were added to Example 10 to contain other compounds. These fractions were combined and evaporated under reduced pressure. The residue obtained was dissolved in ethyl acetate and extracted with 2M hydrochloric acid. The combined acid extracts were basified with 2M sodium hydroxide solution and filtered to give 3-phenyl-1,4-dihydroindenyl [l, 2-c] pyrazole- 6-ylamine was obtained.

Example 12

a) A mixture of indan-1-one (20.0 g), 4-nitrobenzene aldehyde (27.0 g), glacial acetic acid (3.0 g) and piperidine (3.06 g) was heated at 95 ° C under nitrogen for 3.5 hours. The mixture was cooled to 20 &lt; 0 &gt; C, filtered and recrystallized with commercial denaturated ethanol to give a solid that gave 2- (4-nitrobenzylidene) indan-1-one.

b) The product from 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 and hydrogen peroxide ). The mixture was stirred at 20 &lt; 0 &gt; C for 24 hours. Additional hydrogen peroxide (10.0 mL, 100 volumes) was added and the mixture was stirred for an additional 24 h. Additional hydrogen peroxide (10 mL, 100 vol) was added and the mixture was further stirred for 64 h. The reaction mixture was neutralized with glacial acetic acid and the solid formed was collected by filtration and dried to give 3 '- (4-nitrophenyl) -1-oxospiro [indan-2,2'-oxirane].

c) The product of b) (10.0 g) was dissolved in ethanol (180 ml) and hydrazine hydrate (1.78 g) was added to the resulting solution followed by glacial acetic acid (30 drops). The mixture was boiled under reflux for 5 hours, then cooled to 20 &lt; 0 &gt; C and held 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, m.p.

Example 13

The product from Example 12 (3.0 g) was suspended in an industrially methylated alcohol (200 ml) and palladium (5 ml) palladium on charcoal (250 mg) was added followed by ammonium formate (2.05 g). The resulting mixture was heated with stirring at 70 &lt; 0 &gt; C for 3 hours, then cooled to ambient temperature and then 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 (melting point 253-254 deg.

Example 14

(100 mg, a compound available from Aldrich) was dissolved in tetrahydrofuran (5-10 ml) while warming up. , Followed by the addition of 3-chloroperoxybenzoic acid (1.25 molar equivalents of material with 70-75% purity). The resulting mixture was heated at 55-60 &lt; 0 &gt; C for 4 hours. The precipitate was collected by filtration, washed with tetrahydrofuran and then washed with ether to give 4- (4,5-dihydro-1H-benzo [g] indazol-3-yl) pyridine 1-oxide .

Example 15

The N-oxide product from Example 14 (150 mg) was dissolved in phosphorus oxychloride (6 mL). The resulting mixture was boiled under reflux for 4 hours. The excess phosphorus oxychloride was removed under reduced pressure and the residue was washed with saturated sodium carbonate solution and the product was extracted with 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 from Example 14 (25 mg) was dissolved in dimethyl-formamide (200 uL) and to this suspension was added trimethylsilyl cyanide (5 molar equivalents) and triethylamine (3 molar equivalents). The resulting mixture was heated at 110 &lt; 0 &gt; C for 12 h, then diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was separated, dried, filtered, evaporated and flash-chromatographed using 20-40% acetonitrile in dichloromethane as mobile phase to give 4- (4,5-dihydro-lH- Benzo [g] indazol-3-yl) -2-pyridinecarbonitrile.

Example 17

The product from Example 16 (50 mg) was suspended in a mixture of water (0.5 mL) and ethanol (1 mL) containing sodium carbonate (1 molar equivalent) and hydroxylamine hydrochloride (2 molar equivalents). The resulting mixture was boiled under reflux for 4 hours and then cooled. The formed precipitate 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 from Example 16 (50 mg) and DMSO (600 μl) followed by the addition of hydrogen peroxide (30% solution 250 μl). A precipitate was formed within a few minutes after the addition was completed. The mixture was stirred for 1 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 (10% spatula tip material) was added to a solution of the product from Example 16 (50 mg, 0.25 mmol) in a mixture of trifluoroacetic acid in methanol (5 mL v / v trifluoroacetic acid solution in methanol) ) And the resulting mixture was kept under a hydrogen atmosphere for 24 hours with stirring. The mixture was filtered to remove the catalyst and the filtrate was concentrated (up to about 0.5 ml) under reduced pressure. Ethereal hydrogen chloride (20 ml) was added and the precipitate formed was collected by filtration and dried to give {[4- (4,5-dihydro-lH-benzo [g] indazol- ] Methyl} ammonium chloride.

Example 20

The product from Example 19 (100 mg) was suspended in propyl formate (10 mL) and ethanol (1.5 mL). This mixture was boiled under reflux and, after 2 minutes, triethylamine (0.5 ml) was added. The resulting mixture was boiled under reflux for 4 hours, then cooled and diluted with dichloromethane (50 mL). The mixture was washed with water, 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] - indazol-3-yl) -2-pyridyl] methyl} formamide.

Examples 21-24

The products of the following examples are available or can be prepared by methods analogous to those described in Examples 1-6.

Example 21

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

Example 22

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

Example 23

(2-thienyl) indeno [1,2-c] pyrazole-4 (1H) -one (this product is available or can be prepared by a method similar to that described in JP60-130521).

Example 24

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

Example 25

Benzoic acid (0.8 g), methylamine (0.27 ml of a 33% w / w solution) in ethanol, 4- (2-methyl- A mixture of lauridinopyridine (0.47 g), diisopropylcarbodiimide (0.5 ml) and dichloromethane (30 ml) was stirred at ambient temperature for 20 hours. (0.3 ml of a 33% w / w solution), 4-pyrrolidinopyridine (0.5 g) and diisopropylcarbodiimide (1 ml) in ethanol were added and the resulting mixture was stirred at ambient temperature for 3 hours &Lt; / RTI &gt; The solvent was removed at 50 &lt; 0 &gt; C under reduced pressure. The mixture was kept under vacuum for 2 hours, and then dichloromethane (50 mL) was added. The resulting mixture was stirred at ambient 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 mobile phase to give N-methyl-4- (1,4- dihydroindenyl [ , 2-c] pyrazol-3-yl) benzamide (melting point: 182-188 ° C).

Example 26

a) To a solution of 5-methoxyindan-1-one tert-butyl (2-methylpiperidin-1-one) in tetrahydrofuran (150 ml) under nitrogen at -78 [deg.] C while stirring lithium diisopropylamide (27.2 ml of a 2M solution in heptane / THF / ethylbenzene) Was added dropwise to a stirred solution of butyloxycarbonyl hydrazone (5.0 g). After the addition was complete, the resulting mixture was stirred at -78 &lt; 0 &gt; C for 1.5 h before a solution of ethyl thiophene-2-carboxylate (3.39 g) in tetrahydrofuran (25 ml) was added dropwise. The resulting mixture was stirred at -78 &lt; 0 &gt; C for 1.5 h, then allowed to warm to ambient temperature. After 30 minutes, a saturated solution of ammonium chloride was added to the reaction mixture to quench the reaction mixture and separate the layers. The aqueous layer was extracted with ether. The combined organic layers were washed with 2M hydrochloric acid, dried, filtered and evaporated to give a residue, the residue was dissolved in dichloromethane (100 ml) and trifluoroacetic acid (0.35 ml) was added. The resulting mixture was stirred at ambient temperature under a nitrogen atmosphere and then purified by flash column chromatography using ethyl acetate / petroleum ether (boiling point: 60-80 C (4: 1)) as mobile phase to give 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 1 M solution) was added to the product solution from a) in dichloromethane (5 ml) at -78 <0> C under nitrogen atmosphere with stirring. The resulting mixture was stirred at -78 &lt; 0 &gt; C for 2 hours, then the mixture was slowly warmed to ambient temperature and stirred at this temperature for 18 hours. The mixture was quenched 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-dihydroindeno [l, 6-ol (melting point: &gt; 300 [deg.] C).

Example 27

a) Triethylamine (0.48 ml) was added to a solution of 4- (l, 4-dihydroindeno [l, 2- c] pyrazol-3- yl) aniline (400 mg) in dichloromethane (20 ml) Under nitrogen while stirring, and then benzoyl chloride (0.4 ml) was added. The resulting 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 (melting point: 241 ° C).

b) The product from a) (0.35 g) was dissolved in methanol (20 ml) and 2M sodium hydroxide solution (3.85 ml) was added. The resulting mixture was stirred at 20 &lt; 0 &gt; C for 2 h, then the solids were collected by filtration and dried under vacuum at 60 [deg.] C for 2 h to give 4 '- (l, 4-dihydroindeno [l, 2- Yl) -benzanilide hydrate (melting point: 273-274 占 폚).

Example 28

a) Methyl thiosalicylate (2.0 g) was added dropwise to a stirred solution of sodium methoxide (1.28 g) in methanol (50 mL) at ambient temperature. The resulting mixture was stirred at ambient temperature for 15 hours and then a solution of 2- (bromoacetyl) thiophene (2.26 g) in methanol (50 mL) was added dropwise. After the addition was complete, the resulting mixture was boiled 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-te nooylbenzo [b] thiophen-3-ol.

b) A mixture of the product from a) (500 mg), hydrazine hydrate (106 mg) and n-butanol (5 ml) was boiled under reflux under nitrogen for 7 hours. The resulting mixture was concentrated in vacuo to give gum which was recrystallized from ethyl acetate / petroleum ether (boiling point: 60-80 <0> C) to give a solid which was purified by column chromatography using ethyl acetate / petroleum ether Purification by flash column chromatography on silica using a boiling point: 60-80 C) (3: 7). The appropriate fractions were collected and evaporated to give 3- (2-thienyl) -1H-benzothieno [3,2-c] pyrazole (melting point: 236-238 ° C).

Example 29

A mixture of methyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoate (0.3 g) and N, N-diethylethylenediamine (1 ml) For 3.5 hours and then at 180 &lt; 0 &gt; C for 2 hours. The resulting mixture was cooled and dissolved in industrial methylated sulphate, and this solution was pre-absorbed in the silica applied on top of the flash column. The column was eluted with dichloromethane / industrial methylated spirit / triethylamine (25: 2: 1) to give a solid which was stirred with water for 1 hour, filtered and dried under vacuum at 60 C to give N- (2-diethylaminoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide (melting point: 172-174 deg.

Example 30

(1.67 g, Chem. Ber. 1901, 34 , 413), p-toluenesulfonylhydrazine (1.95 g), p-toluenesulfonic acid (0.27 g) And ethanol (15 mL) was boiled under reflux for 72 h. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography using petroleum ether (boiling point: 60-80 占 폚) / ethyl acetate (1: 1) as mobile phase. The appropriate fractions were collected and combined and evaporated to give a residue which was triturated with petroleum ether (melting point: 60-80 C) to give a solid which was recrystallized from ethanol to give 4- (1, 4-dihydro Indeno [1,2-c] pyrazol-3-yl) phenol (melting point: 266-268 ° C).

Example 31

(0.29 g) of 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol, ethylene carbonate (0.11 g) and a small amount of solid sodium hydroxide Spatula tip) and anhydrous dimethylformamide (3 mL) was stirred under nitrogen and heated at 100 &lt; 0 &gt; C for 45 min. The external temperature was raised to 140 &lt; 0 &gt; C and the mixture was heated at this temperature for 3.5 hours. The reaction mixture was cooled, diluted with ethyl acetate, and the mixture was washed with dilute aqueous sodium hydroxide solution and then with water. The organic layer was dried, filtered and evaporated to give a residue which was purified by flash column chromatography on silica using ethyl acetate as mobile phase. The appropriate fractions were collected and combined and evaporated to give a solid which was triturated with diethyl ether and filtered to give 2- [3- (l, 4-dihydroindeno [l, 2- c] pyrazol- Phenoxy] ethanol (melting point: 203-205 占 폚).

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 After stirring at-20 C, dimethylformamide (3 drops) was added. The resulting mixture was stirred at 15-20 &lt; 0 &gt; C for 30 minutes and then warmed at 40 &lt; 0 &gt; C for 1 hour. The solvent was removed under reduced pressure to give a solid which was dissolved in dichloromethane (20 ml) and then aniline (0.13 ml) and triethylamine (0.38 ml) were added. The resulting mixture was stirred at ambient temperature under nitrogen for 2 hours, then washed with water, dried, filtered and evaporated to give a solid which was purified by flash column chromatography on silica to give 4- (1, Dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide (melting point: 186-190 ° C).

Example 33

(2.4 g), anhydrous potassium carbonate (1.2 g) and ethyl 2-bromoacetate (1.2 ml) were added to a solution of 3- (1,4- And anhydrous dimethylformamide (20 mL) was stirred at ambient temperature for 24 hours. The mixture was diluted with dichloromethane (200 mL), washed with water and then with 1N 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 (boiling point: 60-80 C) (1: 2) Lt; / RTI &gt; The appropriate fractions were combined and evaporated to give ethyl 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetate (mp: 134-136 ° C).

Example 34

(0.66 g), 1 M sodium hydroxide solution (4 ml) and ethanol (20 ml) was added dropwise to a solution of ethyl 3- (1,4-dihydroindeno [1,2- c] pyrazol-3-yl) phenoxyacetate The mixture was heated in 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 ambient temperature for 1 hour. The mixture was filtered to give 3- (l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) phenoxyacetic acid (melting point: 246-248 DEG C).

Example 35

A mixture of 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol (0.20 g) was added to a solution of ethyl 4-bromobutyrate g) to obtain 4- [3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] butyrate (melting point: 142-148 ° C).

Example 36

Phenoxy] butyrate (0.36 g) was dissolved in ethanol (10 ml) in the similar manner as in Example 34, except that ethyl 4- [3- (1,4-dihydroindeno [ (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] butyric acid (melting point: 216 -217 &lt; 0 &gt; C).

Example 37

A mixture of 4- [3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy] butyric acid (0.24 g) in anhydrous tetrahydrofuran , And triethylamine (0.20 ml) was added. The resulting mixture was stirred at ambient temperature for 15 minutes, then cooled in an ice bath for 1 hour and then methyl chloroformate (0.2 ml) was added. The mixture was stirred at an ice bath temperature for 1 hour, and then a concentrated ammonia solution (SG 0.880, 5 ml) was added dropwise with a pipette. The resulting mixture was stirred for 5 minutes at 0 &lt; 0 &gt; C 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 mobile phase. The appropriate fractions were combined and evaporated to give 4- [3- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenoxy] butyramide (melting point: .

Example 38

a) A mixture of 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl] aniline (0.6 g), dichloromethane ) And triethylamine (0.27 g). Additional triethylamine (0.37 ml) and chloroacetyl chloride (0.21 ml) were added and the resulting mixture was stirred for an additional hour. Was filtered and washed with water to give 4 '- (l-chloroacetyl-l, 4-dihydroindeno [l, 2- c] pyrazol-3-yl) chloroacetanilide.

b) Preparation of 4 '- (l-chloroacetyl-l, 4-dihydroindeno [l, 2- c] pyrazol- 3- yl) chloroacetanilide (0.7 g), tetrahydrofuran (0.61 g) was boiled under reflux under nitrogen for 5 h. Potassium carbonate (0.97 g) was added and the resulting mixture was boiled under reflux for an additional hour. The mixture was poured into water and extracted with ethyl acetate to give 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) morpholinoacetanilide (melting point: 291-292 ° C) &Lt; / RTI &gt;

Example 39

Benzoyl chloride [(500mg), the product of Example 8 (1.45g) was dissolved in dichloromethane (100ml) and DMF &lt; RTI ID = 0.0 & (50 ml), 2-morpholinoethanol (0.22 ml), and triethylamine (0.5 ml) in anhydrous tetrahydrofuran (8 drops), followed by evaporation of the solvent) Was stirred at ambient temperature for 3.5 hours. The resulting mixture was washed with water then washed with saturated sodium bicarbonate solution, then dried, filtered and evaporated to give an oil which was purified by column chromatography on silica using dichloromethane / IMS (10: 1) Purification by flash column chromatography afforded an oil which was further purified by flash column chromatography on silica using dichloromethane / IMS (25: 1) as mobile phase to give the product, 2-morpholinoethyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -benzoate (melting point: 168-172 ° C) as a solid.

Example 40

A mixture of methyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl] benzoate (2.2 g, example 7) and N, N- diethylethylenediamine The resulting mixture was cooled and allowed to stand at ambient temperature for 16 h. After addition of petroleum ether (boiling point: 60-80 C) (50 mL), the upper layer solution was added This was further treated with petroleum ether as above and dissolved in dichloromethane and flash column chromatography on silica using dichloromethane / IMS / triethylamine (25: 2: 1) as mobile phase gave the title compound (70 mL), and anhydrous hydrogen chloride gas was passed through the solution. The precipitated solids were collected by filtration, washed with ethanol, and dried to give N- ( Diethylaminoethyl) -4- (1, 4-dihydro Indeno [1,2-c] -pyrazol-3-yl) -benzamide dihydrochloride (melting point: 230 ° C).

Examples 41-50

Step 1

A 1: 1 (volume ratio) mixture of dichloromethane: methanol (1 mL) was added via a Gilson 215 liquid handler to the starting enone in the diaphragm-sealed tube (about 50 mg, see Table A) followed by the addition of 2 M aqueous sodium hydroxide solution (1 molar equivalent, see Table A) was added, followed by the addition of 100 volumes of aqueous hydrogen peroxide (1.8 molar equivalents). The resulting solution / suspension was then shaken and agitated for 20 hours at ambient temperature. After LCMS analysis, an additional 100 volumes of aqueous hydrogen peroxide (1.8 molar equivalents) was added to each reaction tube manually via a pipette equipped with a plastic tip. An additional 1: 1 (volume ratio) of dichloromethane: methanol (1 ml) was added to these tubes containing a significant amount of insoluble material. It was then stirred continuously for an additional 24 hours.

All reagents were analyzed by tlc and an additional 100 volumes of aqueous hydrogen peroxide (1.8 molar equivalents) was added back through the plastic tipped pipette to the reaction which was judged to be an incomplete reagent (indicated by x in Table A) See reactants). The reaction mixture was stirred for 3 days at ambient temperature.

The reaction solution / suspension was equilibrated between dichloromethane (about 5 mL) and water (2 mL), and the organic layer was empore ) Filter cartridge and washed with dichloromethane (ca. 2 mL). The dichloromethane layer was evaporated and the residue was further dried in vacuo.

Table A

Starting enone (mg) 2N aqueous NaOH (l) 100 volumes of aqueous H ₂ O ₂ (μl) 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 44 2- (4-difluoromethoxybenzylidene) -1-indanone (51.3 mg) 89.6 36.7 × 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 2- (4-benzyloxybenzylidene) -1-tetralone (50.7 mg) 74.5 30.5 x 2 48 5,6-dimethoxy-2- (3-phenoxybenzylidene) -1-indanone (50.2 mg) 67.4 27.6 x 3 49 2-pyridyloxy) benzylidene] -1-indanone (50.2 mg) was added to a solution of 2- [4- (5-trifluoromethyl- 65.8 26.9 x 2 50 5,6,7-trimethoxy-2- (2,3,4-trimethoxybenzylidene) -1-indanone (50.0 mg) 62.4 25.5 x 3

The product of Step 1 was taken on the basis of the corresponding 2,3-epoxyketone.

Step 2

To the product from step 1 in the diaphragm sealing tube was added n-butanol (2 ml) via a Gilson 215 liquid handling machine and then hydrazine hydrate as a 10% by volume solution in n-butanol (to the initiator used in step 1 2 molar equivalents based on the amount of the catalyst) (see Table B). To each tube was added cold acetic acid (2 drops), finally using a manual syringe. The reaction was monitored with a t.l.c. analyzer and heated at 100 [deg.] C with vibration for the time indicated in Table B. [ The reaction mixture was evaporated to dryness and the residue was purified by chromatography on silica eluting with ethyl acetate and, if necessary, diluted with petroleum ether (b.p. 40-60 ° C). The appropriate fractions were evaporated and dried in vacuo. If necessary, the product was further purified by preparative HPLC to give the final pyrazole. The product was analyzed by LCMS and the states are shown below.

Table B

Reaction Specification

Example 10% NH ₂ NH ₂ .H ₂ O vol. Heating time (hour) at 100 캜 Additional purification of the product by preparative HPLC 41 182.5 6 Yes 42 183.6 6 no 43 184.8 22 no 44 174.5 6 no 45 168.8 38 Yes 46 162.4 22 no 47 145.1 38 no 48 131.3 22 no 40 128.2 6 no 50 121.6 22 no

Yield / LCMS

Example MF MWt M ⁺ discovery HPLC RT (min) Final mass (mg) 41 C ₁₆ H ₁₁ N ₃ O ₂ 277 Yes 4.67 3.5 42 C ₁₇ H ₁₄ N ₂ S 278 Yes 4.94 5.3 43 C ₂₀ H ₁₄ N ₂ 282 Yes 5.29 21.9 44 C ₁₇ H ₁₂ F ₂ N ₂ O 298 Yes 4.82 21.2 45 C ₁₉ H ₁₇ N ₃ O 303 Yes 3.67 5.0 46 C ₁₄ H ₉ BrN ₂ S 317 Yes 5.16 10.2 47 C ₂₄ H ₂₀ N ₂ O 352 Yes 5.93 2.7 48 C ₂₄ H ₂₀ N ₂ O ₃ 384 Yes 5.16 16.3 49 C ₂₂ H ₁₄ F ₃ N ₃ O 393 Yes 5.56 20.1 50 C ₂₂ H ₂₄ N ₂ O ₆ 412 Yes 4.25 11.9

Example 41

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

Example 42

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

Example 43

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

Example 44

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

Example 45

3- (4-acetamidophenyl) -1,4-dihydro-2H-benz [g]

Example 46

3- (4-bromo-2-thienyl) -4,5-dihydroindeno [1,2-c] pyrazole

Example 47

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

Example 48

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

Example 49

Phenyl] -1,4-dihydroindeno [l, 2-c] pyrazole

Example 50

6,7,8-trimethoxy-3- (2,3,4-trimethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole

LC

Column: 5 HYPERSIL BDS C18 (100 x 2.1 mm)

Mobile phase: 0.1% formic acid: MeCN (gradient - see below)

Conditions: 10-100% MeCN for 8 min

(Gradient) 100% MeCN

100% &lt; / RTI &gt; 10% MeCN

(Total analysis time of 11 minutes)

Flow rate: 1 ml / min

Wavelength range: 206-320 nm

Injection volume: 10 μl

MS

Ionized &lt; RTI ID = 0.0 &gt; APcI + ve /

Mass range 150-500 m / z

Cone 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 a 5M aqueous sodium hydroxide solution (1.6 ml) Boiled in reflux. The mixture was cooled to ambient temperature and held at that temperature for 16 hours. The mixture was diluted with water (45 ml) and then 5M hydrochloric acid (1.6 ml) 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-indanone (m.p.

b) A mixture of the product from a) (0.85 g), p-toluenesulfonylhydrazine (0.9 g), p-toluenesulfonic acid (0.12 g) and ethanol (15 ml) was boiled under reflux for 4.5 hours. The solvent was removed under reduced pressure at ambient temperature and the residue was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic layer was separated, washed with water, and dichloromethane removed from the gum by pipetting. The gum was purified by mobile phase chromatography on silica using 10% and 20% dichloromethane. The appropriate fractions were collected and combined and evaporated to yield a crushed solid with diethyl ether and then 4- (l, 4-dihydroindeno [l, 2-c] pyrazol- Hydroxymethyl) phenol (mp > 300 [deg.] C).

Examples 52-55

The following example was carried out in a similar manner to Example 51 by reacting indan-1-one with the appropriate aldehyde.

Example 52

Methoxy-5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol prepared from 3-hydroxy- ).

Example 53

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

Example 54

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

Example 55

3-Chloro-4- (l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) phenol prepared from 2-chloro-4-methoxybenzaldehyde (m.p. 231-233 [deg.] C).

Example 56

(0.28 g, example 30), potassium carbonate (0.16 g) and 2-bromoacetamide (0.16 g) were added to a solution of 4- (1,4-dihydroindeno [ g) was stirred in dry dimethylformamide (5 ml) for 4 days at ambient temperature and then kept at ambient temperature for 9 days. The mixture was diluted with dichloromethane (50 ml), washed with 1 M aqueous sodium hydroxide solution and then with water. Some insoluble matter that remained during extraction was collected by filtration. The solids were purified by flash column chromatography on silica using mobile phase ethyl acetate. The 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 [ ).

Example 57

(1-Chloroacetyl-l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) -thiourea in 40 ml of THF, 0.73 g of diethylamine and 1.38 g of potassium carbonate. ) Chloroacetaniline (1.0 g) was boiled under reflux for 6 hours, then cooled to 20 &lt; 0 &gt; C and held at this temperature for 16 hours. The mixture was poured into water / ethyl acetate (50 ml each) to separate the organic layer, dried and evaporated to give an oily solid which was purified by flash column chromatography on silica using 5% methanol in dichloromethane as mobile phase The chromatography was then repeated using ethylacetate as the mobile phase, followed by chromatography on a mobile phase of 5% methanol in dichloromethane. The appropriate fractions were collected, blended and evaporated to give 4 &apos;-( 1,4-dihydroindeno [1,2-c] pyrazol-3- yl) diethylamino-acetaniline .

Example 58

a) A mixture of 4-cyanophene acyl bromide (3.0 g), methyl thiosalicylate (2.25 g), methoxysodium (1.52 g) and ethanol (100 ml) was boiled under reflux for 3.5 hours. The mixture was cooled and diluted with 2M 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 (2.0) obtained from a) in ethanol (100 ml) containing cold acetic acid (1 drop) on a 4 A molecular sieve. The mixture was boiled under reflux for 24 hours and then filtered. The filtrate was concentrated under reduced pressure and the obtained residue was purified by flash column chromatography on silica using diethyl ether / petroleum ether (bp 60-80 ° C) (1: 1) as mobile phase to give a solid And recrystallized from ethanol / water to give 4- (1H- [l] benzothio [3,2-c] pyrazol-3-yl) benzamide (mp 290-292 ° C with decomposition).

Example 59

In a manner similar to Example 58, from a mixture of methylthiosalicylate (2.76 g), 4-nitrophenacyl bromide (4.0 g), sodium methoxide (1.94 g) and ethanol (200 ml) Benzoyl) -3-hydroxybenzo [b] thiophene and 2.25 g thereof was reacted with hydrazine hydrate (6 ml) in a similar manner to Example 58 to give 3- (4-aminophenyl) -1H- [l ] Benzothieno [3,2-c] pyrazole (mp 113-115 [deg.] C).

Example 60

Methoxyphenylacyl bromide (0.81 g) was reacted with sodium methoxide and methylthiosalicylate (5.0 g) in methanol to give 2- (4-methoxybenzoyl) -3- (4-methoxyphenyl) -1H-benzothieno [3,2-c] pyrazole (mp 185-187 ° C) was obtained by reacting hydrazine hydrate Respectively.

Example 61

Boron tribromide (3.0 ml of a 1.0 M solution in dichloromethane) was added to a solution of the product (210 mg) from Example 60 in dichloromethane (10 ml) with stirring at -78 <0> C under a nitrogen atmosphere. The mixture was allowed to warm slowly to ambient temperature and stirred at this temperature for 2 days, then the mixture was quenched by the 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 as mobile phase increasing the amount of methanol in dichloromethane to 15%. The appropriate fractions were collected, admixed 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 reacted with benzoyl chloride (2.63 g) in dichloromethane and triethylamine to give 5-benzamidoindan-1-one, Reacting with benzaldehyde in a similar manner to give N- (2-benzylidene-1-oxoindan-5-yl) benzamide, which is reacted with hydrogen peroxide in a similar manner to example 7b) 4-dihydroindenyl [l, 2-c] pyrazol-6-yl) hydrazine hydrate in a similar manner to Example 7c) Benzamide (mp 271 [deg.] C).

Example 63

The 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 ambient temperature for 1.5 hours before adding ethanol (20 ml) to obtain a nearly 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- (l, 4-dihydroindeno [l, 2- c] pyrazol-3- yl) phenol sodium salt Respectively.

The compounds shown in Tables 1, 2 and 3 were prepared in a similar manner to Examples 7b and 7c. These compounds were also prepared in a similar manner to Example 30.

Example 64

A mixture of methyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoate (100 mg) and N- (2- aminoethyl) morpholine And heated at 150 &lt; 0 &gt; C for 5 hours. The mixture was cooled and washed with petroleum ether (b.p. 40-60 [deg.] C, 20 ml). The mixture was dissolved in a mixture of dichloromethane / IMS / triethylamine (25: 2: 1) and purified by flash column chromatography on silica using the same solvent mixture as the mobile phase. The appropriate fractions were collected, blended and evaporated to give a gum dissolved in dichloromethane, washed with water, then dried, filtered and evaporated to give a solid which was triturated with ether and filtered to give N- (2- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide monohydrate (mp 210-214 ° C).

Example 65

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

Example 66

6-methoxy-2- (4-thiomethoxybenzylidene) -1-tetralone was reacted with hydrogen peroxide and then reacted with hydrazine hydrate according to the procedure generally described in Examples 41-50 to give 7-methoxy (C ₁₉ H ₁₈ N ₂ O ₃ S MWt 354, M ⁺ discovery,% pure by HPLC 66 %)

Example 67

(2.4 g) was suspended in toluene (40 ml) under a nitrogen atmosphere, trimethylaluminum (2.2 ml of a 2M solution in heptane) was added to 20 Lt; 0 &gt; C with stirring. The mixture was heated at 90 &lt; 0 &gt; C for 16 h, then cooled to ambient temperature and poured into crushed ice (about 600 ml) containing concentrated hydrochloric acid (30 ml). The precipitated solids were collected by filtration and recrystallized from ethyl acetate with hot filtration to give 4-methyl-3-phenyl-1,4-dihydroindenyl [l, 2- c] pyrazol- -155 &lt; 0 &gt; C).

Example 68 Dihydroxy 4- (4H-indeno- [l, 2-c] -pyrazol-3-yl)

A solution of 3- (4-bromophenyl) -4H-indeno [1,2-c] pyrazole (2.0 g, 6.43 mmol) in dry THF (50 ml) was treated with potassium hydride Dispersion, 0.365 g, 6.76 mmol) in THF (5 mL). After 10 minutes, the mixture was cooled to about -78 &lt; 0 &gt; C, t-butyllithium (1.5M solution in pentane, 8.78 ml, 13.18 mmol) was added and the mixture was stirred for about 15 minutes. A solution of tri-isopropylborate in THF (1.56 ml, 6.75 mmol) was added to the red solution, and the mixture was warmed to room temperature and stirred overnight. Hydrochloric acid (1M, 150 ml) was added and the solution was stirred for about 30 minutes and extracted with ether (3 x 100 ml). The ether extract obtained was then extracted with sodium hydroxide (3 x 100 ml). The resulting alkaline extract was acidified with hydrochloric acid (2M) and the precipitated solid was filtered off in a pump and dried to obtain dihydroxy 4- (4H-indeno- [l, 2c] pyrazol- (602 mg, 34%) (mp &gt; 300 [deg.] C).

Example 69 4- (lH- [lJbenzothieno [3,2-c] pyrazol-3-yl) benzaldehyde

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 treated with potassium hydride , 1.53 g, 13.4 mmol) in anhydrous tetrahydrofuran (20 mL) was added dropwise while maintaining the temperature at about 0 &lt; 0 &gt; C. After the addition was complete, the reaction mixture was stirred at about 0 &lt; 0 &gt; C for 15 minutes and then cooled to about -78 &lt; 0 &gt; C. T-Butyl lithium (1.5 M solution in pentane, 17 ml, 25.62 mmol) was then added dropwise and the mixture was stirred for about 45 minutes. Dry DMF (61 mmol) was added dropwise maintaining the temperature at -78 &lt; 0 &gt; C. The resulting mixture was stirred at this temperature for about 1 hour, warmed to room temperature and stirred overnight. To the reaction mixture was added carefully hydrochloric acid (1M, 200 ml) and quenched and the two layers were separated. The aqueous layer was extracted with ether (2 x 200 ml). The saturated and the resulting extract and the organic layer aqueous sodium bicarbonate (1 × 200ml), washed with water (3 × 200ml), dried (MgSO _4), filter, and remove the solvent to form a red waxy solid (1.3g) , Which was chromatographed (eluting with 20% ethyl acetate / 80% 60-80 petroleum ether) to give 4- (lH- [l] benzothieno [3,2- c] pyrazol-3- yl) benzaldehyde (200 mg, 6%: mp 261-263 [deg.] C).

Example 70 4- (lH- [lJbenzothieno [3,2-c] pyrazol-3-yl) -N- [3- (imidazol- l-yl) propyl] benzylamine trihydrochloride

(0.1 g, 0.36 mmol), 3- (imidazol-1-yl) benzoic acid ) Propylamine (0.58 g, 0.47 mmol) and cold acetic acid (0.03 ml, 0.47 mmol) was stirred at room temperature for about 1 hour. Solid sodium triacetoxyborohydride (0.084 g, 0.4 mmol) was then added portionwise and the resulting mixture was stirred at room temperature for 16 hours. Additional fractions of sodium triacetoxyborohydride (0.084 g, 0.4 mmol) were added and the mixture was stirred for an additional 24 h. The reaction mixture was poured into a saturated solution of sodium bicarbonate (20 ml) and the layers were separated by stirring for 30 minutes. The aqueous layer was extracted with dichloromethane (2 x 50 ml). The resulting extract and the organic layer were washed with water (1 x 25 ml), dried (MgSO ₄ ), filtered and concentrated in vacuo to give a beeswax-like solid which was taken up in ethanol. 2 drops of hydrochloric acid (concentrated) were added, the solution was cooled, the filtered solid was scraped off and dried in vacuo to give 4- (lH- [l] benzothieno [3,2- c] pyrazol- ) -N- [3- (imidazol-1-yl) propyl] benzylamine trihydrochloride (0.09 g, 50%: mp 206-208 ° C).

Example 71 Methyl 4- (4-oxo-1,4-dihydroindeno [1,2-c] pyrazol-3- yl) benzoate

(6.3 g, Example 7), sodium bismuthate (31 g), cold acetic acid (180 ml), and the mixture was stirred at &lt; RTI ID = And water (60 ml) was boiled under reflux for about 3.5 hours. Sodium bismuthate (33 g) was further added and the mixture was boiled under reflux for about 24 hours and then cooled. The pH of the reaction mixture was adjusted to 8-9 by addition of saturated aqueous sodium bicarbonate solution. The reaction mixture was filtered through a pad of celite and the remaining solid 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 (50 ml), cooled and the solid was isolated by filtration and then dried to give methyl 4- (4-oxo-1,4-dihydroindeno [1,2- c] Yl) benzoate (mp dec. 235 [deg.] C).

Example 72 4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide oxime

(730 mg, Example 65), hydroxylamine hydrochloride (0.4 g), sodium carbonate (0.8 g, 0.10 mmol) and sodium carbonate ) And ethanol (30 mL) was boiled under reflux for about 16 hours. The solvent was removed at ca. 50 &lt; 0 &gt; C under reduced pressure, 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 the eluent to give a solid which was washed with diethyl ether and dried to give 4- (l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide oxime (melting point> 300 ° C).

Example 73 3- {4 - [(2-Diethylaminoethyl) aminomethyl] phenyl} -1,4-dihydroindeno [1,2- c] pyrazole trihydrochloride

Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide (2.75 g, example 29) and anhydrous tetrahydro The mixture of furan (100 mL) was stirred at room temperature under nitrogen, and lithium aluminum hydride (3.4 g) was added in small portions. The reaction mixture was then boiled under reflux for about 2.5 hours and then cooled in an ice / water bath. Ethyl acetate (100 mL) and water (100 mL) were added. The organic phase 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 ethyl acetate / ethanol / triethylamine (7: 2: 1) as eluent to yield a pale yellow gum. The gum was dissolved in warm ethanol (5 mL), hydrochloric acid (concentrated, 0.6 mL) was added and the solvent was removed under reduced pressure. The sticky solid residue was boiled with ethanol (10 mL) and cooled with ice. The precipitated solids were collected by filtration, washed with ethanol and dried to give 3- {4 - [(2-diethylamino) aminomethyl] phenyl} -1,4-dihydroindeno [1,2 -c] pyrazole trihydrochloride (melting point 225 [deg.] C).

Example 74 N- [4- (1,4-Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] benzenesulfonamide

(1 g) was dissolved in dichloromethane (30 ml) and triethylamine (0.62 ml) was added to a solution of 4 '- (1,4- Was added. The reaction mixture was then cooled to about 0 &lt; 0 &gt; C and benzenesulfonyl chloride (0.57 ml) was added dropwise over 5 minutes. The reaction mixture was then allowed to warm to ambient temperature and stirred for about 2 hours. Benzenesulfonyl chloride (0.57 ml) and triethylamine (0.62 ml) were further added, and the mixture was stirred at ambient temperature for about 4 hours. Diethyl ether (80 mL) and water (40 mL) were then added. The precipitated solid was filtered off and washed with an aqueous solution of sodium bicarbonate (40 ml) and diethyl ether (40 ml). The solid was further purified by flash chromatography on silica using dichloromethane as eluent. The initial 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] benzenesulfone The amide was obtained as brown solid (0.35 g) (melting point 251-252 캜), and the latter fractions were obtained as brown solid (0.76 g) (melting point 267-268 캜).

b) A mixture of N- [4- (1-benzenesulfonyl-1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] benzenesulfonamide (0.56 g) ) And a 2N aqueous sodium hydroxide solution (5.3 ml) was added at ambient temperature. A clear solution was obtained. The reaction mixture was stirred at ambient temperature for about 20 minutes and then poured into 2N aqueous hydrochloric acid (75 ml). The precipitated colorless solid was collected by filtration (0.42 g). The solid was partitioned between aqueous sodium bicarbonate (25 mL) and ethyl acetate (25 mL) and stirred at ambient temperature for about 30 minutes. The solids were then collected by filtration and dried under vacuum at about 60 ° C to give N- [4- (1,4-dihydroindeno [1,2-c] pyrazol- Benzenesulfonamide as a colorless solid (0.14 g) (m / e: 286-288 [deg.] C).

Example 75 N- (2-morpholinoethyl) -4 ' -dihydroindeno [1,2-c] pyrazole-3-ylaniline dihydrochloride

4 '- (l, 4-dihydroindeno [l, 2-c] pyrazol-3-yl) morpholinoacetamide (1.5 g, example 38) was dissolved in tetrahydrofuran ML), and lithium aluminum hydride (0.6 g) was added in small portions over 10 minutes. The mixture was stirred at ambient temperature for about 6 hours, then poured into a saturated aqueous sodium sulfate solution (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 on silica using a gradient of 1: 20 to 1: 4 mixture of methanol and dichloromethane as eluent &Lt; / RTI &gt; by flash chromatography on silica gel. The appropriate fractions were combined and evaporated in vacuo to give a yellow oil (0.83 g). The solid was dissolved in ethanol (10 mL) and concentrated hydrochloric acid (0.5 mL) was added. The precipitated colorless solid was collected by filtration to give 0.94 g of N- (2-morpholinoethyl) -4'-dihydroindeno [1,2-c] pyrazole- (Melting point 284-285 [deg.] C).

Example 76 N- (l, 4-Dihydroindeno [1,2- c] pyrazol-6-yl) -2-morpholinoacetamide

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 &lt; 0 &gt; C and chloroacetyl chloride (1.3 ml) was added. The reaction mixture was then stirred at ambient temperature under nitrogen for 10 hours. The precipitated colorless solid was collected by filtration and dried under vacuum at about 60 ° C to give N- (1-chloroacetyl-3-phenyl-1,4-dihydroindeno [ , 2-c] pyrazol-6-yl) -2-chloroacetamide (2.04 g).

b) By reacting N- (1-chloroacetyl-3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol-6-yl) -2- chloroacetamide (1.0 g) in tetrahydrofuran (30 ml), and morpholine (0.87 ml) was added. The mixture was then heated under reflux for about 90 minutes, cooled to ambient temperature and poured into water (100 mL). The precipitated solids were collected by filtration and dried under vacuum at about 60 ° C to give N- (l, 4-dihydroindeno [l, 2-c] pyrazol- The title amide was obtained as brown solid (0.87 g) (melting point 141-148 [deg.] C).

Example 77 N- (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [l, 2-c] pyrazol-6-ylamine trihydrochloride

6-yl) -2-morpholinoacetamide (0.6 g) was added at ambient temperature under nitrogen to a solution of N- (3-phenyl-1,4- dihydroindeno [ (40 ml), and lithium aluminum hydride (0.24 g) was added in small portions over about 10 minutes. The mixture was stirred at ambient temperature for about 24 hours. Lithium aluminum hydride (0.24 g) was further added, and the mixture was stirred for an additional 24 hours at ambient temperature. The mixture was then poured into a saturated aqueous sodium sulfate solution (30 ml) and extracted with diethyl ether (2 x 30 ml). The combined organic extracts were dried (Na ₂ SO _4), evaporated in vacuo, to afford a yellow oil, as this eluent was purified by flash chromatography on silica using a 1:20 mixture of methanol and dichloromethane . The appropriate fractions were combined and evaporated in vacuo to give a yellow oil. 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 N- (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol-6-ylamine trihydro Chloride salt (0.18 g) (mp 180-182 [deg.] C).

Example 78 4 ' - (1-Acetyl-1,4-dihydroindeno [1,2- c] pyrazol-3- yl) acetanilide

(1 g) was dissolved in dichloromethane (40 ml) and triethylamine (1.14 ml) was added to a solution of 4 ' - (1,4-dihydroindeno [ Was added and then acetic anhydride (0.85 ml) was added. The reaction mixture was then stirred under nitrogen at ambient temperature for 2 hours. The precipitated colorless solid was collected by filtration, washed with water and dried under vacuum at about 60 ° C to give 4 '- (l-acetyl-1,4-dihydroindeno [1,2- c] pyrazole- 3-yl) acetanilide as a colorless solid (0.84 g) (mp 245-246 [deg.] C).

b) 4 '- (1-Acetyl-1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide (1.0 g) was suspended in methanol (40 ml) Sodium aqueous solution (15 ml) was added. The mixture was stirred at ambient temperature for about 20 minutes and then poured into 2N aqueous hydrochloric acid (75 mL) and the precipitated solids were collected by filtration and dried under vacuum at about 60 DEG C to give 4 '-( 1,4-di 1,2-c] pyrazol-3-yl) acetanilide dihydrochloride (0.96 g, melting point 295-304 [deg.] C).

Example 79 3- [4- (2-morpholinoethoxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole

(0.76 g, Example 30), 4- (2-hydroxyethyl) morpholine (0.85 g), 4- (1,4-dihydroindeno [ , Triphenylphosphine (1.77 g) and dichloromethane (20 ml) was stirred while cooling on ice / water bath, and diethyl azodicarboxylate (1.16 g) 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), the solid was filtered, washed with diethyl ether and dried at about 65 ° C to give 3- [4- (2-morpholinoethoxy) phenyl] , 4-dihydroindeno [1,2-c] pyrazole (melting point 175-6 캜).

.

Example 112 3- [2- (2H-1,2,3,4-tetraazol-5-yl) -4-pyridyl] -4,5-dihydro-2H- benzo [g]

Benzo [g] indazol-3-yl) -2-pyridinecarbonitrile (50 mg, 0.184 mmol) was dissolved in 5 mL of THF. 900 mg (15 eq) of tributyltin azide was added thereto. The reaction mixture was heated for about 24 hours and the progress of the reaction was analyzed by HPLC. Some starting materials remained still at this point; The reaction was cooled to room temperature. The solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (5 mL), to which was added excess 1N HCl. The formed precipitate was filtered off and dried, yielding 33 mg of a white solid. Product formation was confirmed by HPLC / MS: MH + 316.2, retention time: 1.73 min

Experiments on Examples 113-159

Tri-cyclic pyrazoles, ureas and carbamates.

LC condition (operation for analysis)

Column: PECOSPHERE, C18, 3 mu m, 33 x 4.6 mm

Gradient: 100% pH 4.5 4.5 _{bungan, 50mM NH 4 OAc / H 2} O to 100% CH ₃ CN

Flow rate: 3.5 ml / min

LC / MS Purification Conditions:

Column: Hypersil BDS, C18, 5 DEG, 100x21.2mm

Gradient: 100% pH 4.5, 50 mM NH ₄ OAc / H ₂ O to 100% CH ₃ CN for 8.5 minutes, but depends on the required separation.

Flow rate: 25 ml / min

Melting point:

Melting points were recorded on an Electrothermal 9100 melting point microscope in an open capillary and were not calibrated.

IR:

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

Dihydroindeno [1,2-c] pyrazole, (2): To a solution of 4- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoic acid (a solution of 5.8g, 20.99mmol), diphenylphosphoryl azide (5.22㎖, 23.09mmol) and Et ₃ N (3.35㎖, 23.09mmol) Was added. The reaction mixture was heated to about &lt; RTI ID = 0.0 &gt; 80 C &lt; / RTI &gt; for about 4 hours until N ₂ gas evolution was no longer 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 solids were dried under vacuum to give 2, which was used in the next step without further purification, in quantitative yield. Melting point 338-339 [deg.] C. IR (KBr) 2132, 1723, 1582, 1520

Examples 113-121

General procedure for O- substituted N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate: To a solution of the appropriate alcohol in THF was added NaH (12 eq) was added and the reaction mixture was stirred at about 20 &lt; 0 &gt; C for about 45 minutes. A solid 3- (4-isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole (2) was added. The reaction mixture was stirred at about &lt; RTI ID = 0.0 &gt; 45 C &lt; / RTI &gt; 2M HCl was added until the pH was 7, and the crude was extracted into EtOAc. Purification by flash chromatography (CH ₂ Cl ₂ / MeOH) gave the pure carbamate (3).

Example 113:

Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] carbamate: To a solution of 2- (diethylamino) ethyl N- [4-

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 &lt; 0 &gt; C for about 1 hour and then a solid 3- (4-isocyanatophenyl) -1,4-dihydroindeno [1,2- c] pyrazole (2) Mg, 0.22 mmol). The reaction mixture was heated to about &lt; RTI ID = 0.0 &gt; 45 C &lt; / RTI &gt; The reaction mixture was quenched by addition of 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 min.

Example 114:

The pure product of 56 mg (66%) of the 2-morpholinoethyl N- [4- (1,4-dihydroindeno [1,2- c] pyrazol- Respectively. LC / MS 405 (M + 1); LC retention time 2.69 min.

Example 115:

Yl) phenyl] carbamate: 34 mg (35%) of the pure product of the title compound was obtained as colorless crystals from 3- (dibenzylamino) propyl N- [4- (1,4-dihydroindeno [ Respectively. LC / MS 530 (M + 1); LC retention time 4.18 min.

Example 116:

Dihydroindeno [l, 2-c] pyrazol-3-yl) phenyl] carbamate acetate salt: To a solution of 19 Mg (26%) of pure product was isolated. LC / MS 407 (M + 1); LC retention time 2.65 min.

Example 117:

2-c] pyrazol-3-yl) phenyl] carbamate &lt; / RTI &gt; Acetate salt: 32 mg (42%) of pure product was isolated. LC / MS 420 (M + 1); LC retention time 2.80 min.

Example 118:

Phenyl] carbamate: 42 mg (59%) of pure &lt; RTI ID = 0.0 &gt; The product was isolated. LC / MS 392 (M + 1); LC retention time 3.60 min.

Example 119:

2-pyrrolyl) ethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] carbamate: 4 mg (7%) of pure product was isolated. LC / MS 403 (M + 1); LC retention time 2.81 min.

Example 120:

Yl] phenyl] carbamate acetate salt: To a solution of 2- [2- (dimethylamino) ethoxy] ethyl N- [4- (1,4-dihydroindeno [ (43%) of the pure product. LC / MS 407 (M + 1); LC retention time 2.62 min.

Example 121:

Yl) phenyl] carbamate acetate salt: 7 mg (0.25 mmol) of 2- (diethylamino) -1-methylethyl N- [4- 9%) of the pure product was isolated. LC / MS 405 (M + 1); LC retention time 2.84 min.

Examples 122-159

General procedure for N'-substituted N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea (4) Et ₃ N (5 eq.) And the appropriate amine (5 eq.) Were added to a suspension of 4-isocyanatophenyl) -1,4-dihydroindeno [1,2- c] pyrazole (2). The reaction mixture was stirred at about &lt; RTI ID = 0.0 &gt; 95 C &lt; / RTI &gt; The solid was filtered and washed with EtOAc and Et ₂ O and dried under vacuum to give the desired element (4).

Example 122:

Phenyl] urea: Toluene (3 mL) was added to a solution of 2-amino-2-pyrrolidin-2-yl- (75 mg, 0.274 mmol) and Et ₃ N (0.191 mL, 1.37 mmol) in THF (10 mL) at 0 ° C was added dropwise to a stirred solution of 3- (4-isocyanatophenyl) ) And N, N-diethylethylenediamine (0.112 mL, 1.37 mmol) was heated to about 95 &lt; 0 &gt; C for about 3 hours. The white solid was filtered off, washed with EtOAc and dried in vacuo to give 61 mg (57%) pure product. LC / MS 390 (M + 1); LC retention time 2.76 min.

Example 123:

84 mg (76%) of the pure product was isolated as a colorless oil. LC: LC [M + H] &lt; / MS 404 (M + 1); LC retention time 2.50 min.

Example 124:

Yl] phenyl] -1-piperidinecarboxamide: 32 mg (49%) of the pure product was isolated . LC / MS 359 (M + 1); LC retention time 3.36 min.

Example 125:

Phenyl] -N '- [2- (dimethylamino) -1-methylethyl] urea: To a solution of N- [4- (1,4- 57 mg (55%) of the product was isolated. LC / MS 376 (M + 1); LC retention time 2.72 min.

Example 126:

Furanylmethane &lt; / RTI &gt;: 57 mg (56 &lt; RTI ID = 0.0 &gt; %). LC / MS 375 (M + 1); LC retention time 2.98 min.

Example 127:

66 mg (65%) of pure product was obtained as a colorless oil. &Lt; 1 &gt; H NMR (400 MHz, DMSO-d6) Respectively. LC / MS 371 (M + 1); LC retention time 3.34 min.

Example 128:

Yl) phenyl] urea: &lt; RTI ID = 0.0 &gt; (3-benzodioxol- 75 mg (64%) of the pure product was isolated. LC / MS 425 (M + 1); LC retention time 3.45 min.

Example 129:

Yl] phenyl]: 60 mg (64%) of the pure product was isolated. The title compound was obtained as a white amorphous solid. 1H NMR (400 MHz, CDCl3)? LC / MS 345 (M + 1); LC retention time 3.28 min.

Example 130:

Phenyl] -N '- (2-piperidinoethyl) urea: The pure product was obtained in a yield of 64 mg ( 58%). LC / MS 402 (M + 1); LC retention time 2.84 min.

Example 131:

Phenyl] urea: 47 mg (45%) of pure product was isolated. The title compound was obtained as a white solid. LC / MS 381 (M + 1); LC retention time 3.40 min.

Example 132:

Yl] phenyl] urea: To a solution of 62 mg (0.24 mmol) of the pure product, N- [4- (diethylamino) butyl] -N ' (54%). LC / MS 418 (M + 1); LC retention time 2.76 min.

Example 133:

Yl] phenyl] -N '- [2- (2-thienyl) ethyl] urea: pure product 65 mg (59%) was isolated. LC / MS 401 (M + 1); LC retention time 3.44 min.

Example 134:

Yl] phenyl] urea: To a solution of 50 mg of pure product (45%). LC / MS 404 (M + 1); LC retention time 2.73 min.

Example 135:

Yl] phenyl] -N '- [(1-ethyltetrahydro-1H-2-pyrrolyl) methyl] ] Element: 53 mg (48%) of pure product was isolated. LC / MS 402 (M + 1); LC retention time 2.89 min.

Example 136:

Yl) phenyl] urea: To a solution of 15 mg of pure product (0.25 g) in a mixture of tetrahydrofuran and tetrahydrofuran (13%). LC / MS 417 (M + 1); LC retention time 3.50 min.

Example 137:

Yl] phenyl] -N '- [2- (2-hydroxyethoxy) ethyl] urea: To a solution of N- [4- (1,4-dihydroindeno [1,2- c] pyrazol- 34 mg (33%) of the product was isolated. LC / MS 379 (M + 1); LC retention time 2.66 min.

Example 138:

N '- [2-hydroxy-1- (hydroxymethyl) ethyl] urea; N- [4- (1,4-dihydroindeno [1,2- c] pyrazol- : 4 mg (1%) of the pure product was isolated. LC / MS 365 (M + 1); LC retention time 2.48 min.

Example 139:

Yl] phenyl] -N '- (2,3-dihydroxypropyl) urea: 8 mg of the pure product (8%). LC / MS 365 (M + 1); LC retention time 2.54 min.

Example 140:

Yl) phenyl] -4- (2-pyridyl) -1-piperazinecarboxamide: A mixture of pure product 68 mg (71%) was isolated. LC / MS 437 (M + 1); LC retention time 3.13 min.

Example 141:

N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] -N- [3- (dimethylamino) propyl] 54 mg (63%) of the product was isolated. LC / MS 390 (M + 1); LC retention time 2.60 min.

Example 142:

Yl] phenyl] -1-azetanecarboxamide: 48 mg (66%) of pure product was isolated. LC / MS 331 (M + 1); LC retention time 2.86 min.

Example 143:

Yl) phenyl] -4- (4-fluorophenyl) -1-piperazinecarboxamide: To a solution of N1- [4- (1,4- dihydroindeno [ 63 mg (63%) of the product was isolated. LC / MS 454 (M + 1); LC retention time 3.53 min.

Example 144:

Yl] phenyl] -N-methyl urea: 60 mg (69%) of pure product was obtained as a white solid Respectively. LC / MS 395 (M + 1); LC retention time 3.41 min.

Example 145:

N-ethyl-N- (2-hydroxyethyl) urea: To a solution of the pure product 50 mg (63%). LC / MS 363 (M + 1); LC retention time 2.78 min.

Example 146:

Yl) phenyl] -4- (2-methoxyphenyl) -1-piperazinecarboxamide: To a solution of N1- [4- (1,4- dihydroindeno [ 49 mg (48%) of the product was isolated. LC / MS 464 (M-1); LC retention time 3.45 min.

Example 147:

N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] -N- [2- (dimethylamino) ethyl] 55 mg (67%) of the product was isolated. LC / MS 376 (M + 1); LC retention time 2.48 min.

Example 148:

Phenyl] -4-methyl-1-piperazinecarboxamide: To a solution of 16 mg (20%) of N1- [4- (1,4-dihydroindeno [1,2- c] pyrazol- ). LC / MS 374 (M + 1); LC retention time 2.48 min.

Example 149:

Yl) phenyl] -4- (4-hydroxyphenyl) -1-piperazinecarboxamide: To a solution of N1- [4- (1,4- dihydroindeno [ 11 mg (11%) of the product was isolated. LC / MS 452 (M + 1); LC retention time 3.04 min.

Example 150:

Phenyl] -4 - [(E) -3-phenyl-2-propenyl] -l- [4- (1,4- dihydroindeno [1,2- c] pyrazol- Piperazine carboxamide: 47 mg (45%) of the pure product was isolated. LC / MS 476 (M + 1); LC retention time 3.26 min.

Example 151:

Phenyl] -4-phenyl-1-piperazinecarboxamide: 46 mg (48%) of pure product. ). LC / MS 436 (M + 1); LC retention time 3.58 min.

Example 152:

Yl] phenyl] -N, N-di (2-methoxyethyl) urea: Pure product 31 mg (37%). LC / MS 407 (M + 1); LC retention time 3.25 min.

Example 153:

Yl] phenyl] -N- (2,3-dihydroxypropyl) -N-methyl urea: 36 mg (43%) of the pure product was isolated. LC / MS 379 (M + 1); LC retention time 2.62 min.

Example 154:

N, N'-di [2- (diethylamino) ethyl] -N '- [4- (1,4-dihydroindeno [1,2- c] pyrazol- 50 mg (47%) of the product was isolated. LC / MS 489 (M + 1); LC retention time 2.61 min.

Example 155:

Yl) phenyl] -N '- (2-pyridylphenyl) urea: 38 mg (45%) of pure product. ). LC / MS 382 (M + 1); LC retention time 2.85 min.

Example 156:

Yl) phenyl] -N '- (3-pyridylmethyl) urea: 26 mg of the pure product (31% ). LC / MS 382 (M + 1); LC retention time 2.70 min.

Example 157:

N'- (4-pyridylmethyl) urea: 43 mg (51%) of the pure product. ). LC / MS 382 (M + 1); LC retention time 2.69 min.

Example 158:

N'- (2-hydroxyethyl) urea: 7 mg (8%) of the pure product. &Lt; Desc / ). LC / MS 335 (M + 1); LC retention time 2.57 min.

Example 159:

Phenyl] -N '- [7- (dimethylamino) heptyl] urea: Pure product 57 mg ( 48%). LC / MS 432 (M + 1); LC retention time 2.85 min.

Examples 160 to 209

Synthesis of the following compounds

Black: ca. 85%

* Condition A: in EtOH, r.t. (for aliphatic primary amine)

Condition B: p-TSA (cat.) In toluene, reflux (for secondary amine or aromatic amine)

Example A

The use of the compounds of the invention in the preparation of pharmaceutical compositions has been illustrated by the following description. In the present description, the term " active compound " refers to any compound of the present invention, but in particular any compound which is the end product of one of the above embodiments.

a) Capsules

In the preparation of the capsules, 10 parts by weight of the active compound and 240 parts by weight of lactose are disintegrated and mixed. This mixture was filled into hard gelatin capsules so that each capsule contained some of the unit dose or unit dose of active compound.

b) Tablets

Tablets were prepared from the following ingredients.

Weight portion

The active compound 10

Lactose 190

Corn starch 22

Polyvinylpyrrolidone 10

Magnesium stearate 3

Part of the active compound, lactose and starch was disassembled and mixed and the resulting mixture was granulated using a solution of polyvinylpyrrolidone in ethanol. The dried granulate was mixed with magnesium stearate and the remaining starch. The mixture was then extruded in a tablet maker to obtain tablets each containing a unit dose of the active compound or a portion of the unit dose.

c) Enteric coated tablets

The tablets were prepared by the method described in (b) above. The tablets were coated with the enteric coating by conventional means using a solution of 20% cellulose acetate phthalate and 3% diethyl phthalate in ethanol: dichloromethane (1: 1).

d) Suppositories

In the preparation of suppositories, 100 parts by weight of the active compound is incorporated into 1300 parts by weight of the triglyceride supernatant base, and the mixture is formed into suppositories so that each suppository contains a therapeutically effective amount of the active ingredient.

While the invention has been particularly shown and described with reference to preferred embodiments thereof, it will be understood that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Will be understood by those skilled in the art. Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention specifically described herein. The equivalents are intended to be included in the claims.

Claims (77)

A method for inhibiting protein kinase activity, comprising administering to a protein kinase a compound represented by the formula: and a pharmaceutically acceptable salt thereof at a concentration sufficient to inhibit its enzymatic activity: In this formula, X represents a) substituted methylene, b) carbonyl, c) oxygen, d) a group of the formula -C = NOR ₇ (wherein, R ₇ represents H or C _1-4 alkyl group), e) of the formula NR ₈ F) a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3, or g) a group of formula (CH ₂ ) _n wherein R ₈ is H, an optionally substituted C _1-4 alkyl group or an optionally substituted phenyl, a group of the formula S (O) _{p wherein} p is 0, 1 or 2; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R ₃ , R ₄ , R ₅ and R ₆ are independently a) H, b) halo, c) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or R _h and R _j Is an amino group of the formula NR _h R _j as defined below, d) a C _1-6 alkoxy group optionally substituted by one or more of the following: hydroxy, halo or R _h and R _j are as defined below, amino group of NR _h R _j (however, the groups are not bonded to the carbon bonded to the oxygen of the alkoxy group), e) optionally substituted phenoxy, group f) hydroxy, g) the formula COR _a ( Wherein R _a represents a hydroxy or 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 represent hydrogen, a C _1-6 alkyl group or phenyl, and phenyl is optionally substituted by one or more of the following: hydroxy or O of formula NR _h R _j Group (wherein, R _h and R _j are independently represents hydrogen or C _1-6 alkyl group, or R _h and R _j may optionally contain an additional heteroatom selected from O, S, or N together with the nitrogen atom to which they are attached are 6 or 7 membered saturated heterocyclic ring which is optionally substituted by a C _1-6 alkyl group))), h) a group of the formula NR _d R _e , wherein R _d and R _e Is selected from hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl or phenyl, or a group of the formula COR _f wherein R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, a phenyl C _1-6 alkyl group or a phenyl shown) (in each case, an alkyl group, cycloalkyl group and phenyl are optionally substituted by one of the following: halo, hydroxy, nitro or an amino group of formula NR _h R _j (where , R _h and R _j are as defined above) ), i) a group of the formula O (CH ₂ ) _m R _g , wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e Are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group, Provided that when 1) X represents 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 pyridyl, phenyl or C _1-2 Alkyl, a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; 2) X is a group of the 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 are independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl, and the remaining two represent hydrogen, R ₂ is selected from the group consisting of unsubstituted thienyl, unsubstituted furyl, unsubstituted Unsubstituted pyridyl, or phenyl having up to two substituents wherein the substituents are halogen having an atomic weight of about 19 to 36, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl. 2. The method of claim 1, wherein the protein kinase is tyrosine kinase. 3. The method of claim 2 wherein the tyrosine kinase is a receptor tyrosine kinase or a non-receptor tyrosine kinase. 4. The method of claim 3, wherein the tyrosine kinase is selected from the group consisting of KDR, flt-1, TIE-2, Lck, Src, fyn and yes. 2. The method of claim 1, wherein the activity of tyrosine kinase affects angiogenesis. 6. The method of claim 5, wherein the inhibition of tyrosine kinase is antiangiogenic. 7. The method according to claim 6, wherein the inhibition of tyrosine kinase is selected from the group consisting of cancer, arthritis, atherosclerosis, psoriasis, hemangioma, myocardial vascularization, coronary and cerebral vascularization, ischemic limb angiogenesis, castle, retinopathy of prematurity, wound healing, ulcers, Helicobacter pylori (Helicobacter) related diseases, fractures, endometriosis, diabetic retinopathy, mausoleum column (猫搔熱) and inhibit the progression of the disease selected state from the group consisting of thyroid hyperplasia &Lt; / RTI &gt; 3. The method according to claim 2, wherein the activity of tyrosine kinase affects the production of blood vessels and permeability or edema. 9. The method of claim 8, wherein the inhibition of tyrosine kinase is anti-edemic. 10. The use according to claim 9 wherein the inhibition of tyrosine kinase is selected from the group consisting of burns, trauma, chronic lung disease, seizures, polyps, cysts, synovitis, psoriasis, chronic and allergic inflammation, macular degeneration, diabetic retinopathy, Characterized in that it inhibits the progression of a disease state selected from the group consisting of inflammatory bowel syndrome, lung and brain edema, keloid, fibrosis, cirrhosis, carpal tunnel syndrome, adult respiratory distress syndrome, ascites and tumor-associated exudates and edema. 3. The method according to claim 2, wherein the inhibition of tyrosine kinase has an antitumor effect. 3. The method of claim 2, wherein the inhibition of tyrosine activity is associated with a fertility suppression or abortion effect. Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula S (O) _p in which _p represents 0, 1 or 2; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; 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 , R ₂ does not represent phenyl, 2) When X represents S and R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, then R ₂ does not represent 2,4-dichlorophenyl. 14. A compound according to claim 13 characterized in that R &lt; ₂ &gt; is optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl . 14. The compound of claim 13, wherein R &lt; ₂ &gt; is an optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy , Carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2- (piperazin- 2- (perhydro-thiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (pyrrolidin-1-yl) ethoxy, 2- (Piperazin-1-yl) propoxy, 3- (pyrrolidin-1yl) propoxy, 3- dimethylaminopropoxy, 3- (perhydrothiazin- (Especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, cyano (Especially methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group optionally substituted by one or more of pyridine rings, trifluoromethyl or nitro. 14. The compound of claim 13 wherein R &lt; ₂ &gt; is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2- Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoyl) phenyl, 3- Mile-me (Trifluoromethyl) phenyl] - (4-methylphenyl) - phenyl, 4- [3- (N- (2-diethylaminoethyl) 2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) Phenyl), 4- (N- (2-morpholinoethyl) -carbamoylmethoxy) phenyl, 3- [3- Phenyl) -4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. 14. The compound of claim 13, wherein R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 14. The compound of claim 13, wherein R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents oxygen; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R ₃ , R ₄ , R ₅ and R ₆ are as defined above; Provided that when R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, then R ₂ does not represent phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl. 20. Compounds according to claim 19, characterized in that R &lt; ₂ &gt; is optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl compound. 20. The compound of claim 19, wherein R &lt; ₂ &gt; is selected from the group consisting of optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy, Carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2- (pyrazin- Ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylamino-ethoxy, 2- (perhydro- 3- (perhydrothiazin-4-yl) propoxy), lower (tertiary) amines, Alkyl (especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, cyano (Especially methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group optionally substituted by one or more of pyridine rings, trifluoromethyl or nitro. 20. The compound of claim 19, wherein R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoyl) phenyl, 3- Mile-me (Trifluoromethyl) phenyl] - (4-methylphenyl) - phenyl, 4- [3- (N- (2-diethylaminoethyl) 2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) Phenyl), 4- (N- (2-morpholinoethyl) -carbamoylmethoxy) phenyl, 3- [3- Phenyl) -4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. 20. The compound of claim 19, wherein R ₃ , R ₄ , R ₅ and R ₆ are independently hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 20. The compound of claim 19 wherein R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula NR ₈ ; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R ₃ , R ₄ , R ₅ and R ₆ are as defined above. 26. Compounds of formula I according to claim 25, characterized in that R &lt; ₂ &gt; is optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl compound. 26. The compound of claim 25, wherein R &lt; ₂ &gt; is selected from optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxy Carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2- (piperazin- ) Ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylamino-ethoxy, 2- (perhydro- Propoxy, 3- (piperazin-1-yl) propoxy, 3- (pyrrolidin-1-yl) Lower alkyl (especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy Lower alkoxy (especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, (Particularly methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl , N-methylcarbamoyl, N-phenylcarbamoyl) and pyridyloxy or pyridylthio optionally substituted by one or more of pyridine ring, trifluoromethyl or nitro. A compound according to claim 25, wherein R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) (2-aminoethyl) carbamoylmethoxy) phenyl, 3- [3- [N- (2-diethylamino) Mile-me (Trifluoromethyl) phenyl] - (4-methylphenyl) - phenyl, 4- [3- (N- (2-diethylaminoethyl) 2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) Phenyl), 4- (N- (2-morpholinoethyl) -carbamoylmethoxy) phenyl, 3- [3- Phenyl) -4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. Wherein R ₃ , R ₄ , R ₅ and R ₆ are independently selected from the group consisting of hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, 3-morpholinoproxy, 2- Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 26. The compound of claim 25 wherein R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula -C = NOR ₇ , wherein R ₇ represents H or a C _1-4 alkyl group; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R ₃ , R ₄ , R ₅ and R ₆ are as defined above; Provided that when R ₁ , R ₃ , R ₄ R ₅ and R ₆ each represent hydrogen and X represents C═NOH, R ₂ does not represent 4-methylphenyl or 3,4-dimethoxyphenyl. 32. The method of claim 31, characterized in that R ₂ is an optionally substituted phenyl, naphthyl, optionally substituted thienyl, represents an optionally pyridyl, optionally a furyl or optionally substituted pyrrolyl substituted with compound. 32. A compound according to claim 31 wherein R &lt; ₂ &gt; is an optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy, 2-piperidino-ethoxy, 2- (piperazin-1-yl) -methoxy, ethoxy, Ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylamino-ethoxy, 2- (perhydro- 3- (perhydrothiazin-4-yl) propoxy), lower (tertiary) amines, Alkyl (especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, cyano (Especially methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group optionally substituted by one or more of pyridine rings, trifluoromethyl or nitro. 32. The compound of claim 31, wherein R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4- pyridyl, 2-aminomethyl-4- pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoyl) phenyl, 3- Mile-me 2-furyl, 5- [3,5-bis (trifluoromethyl) phenyl] -2 (phenylmethyl) 2-furyl, 3-N- (2-morpholinyl) -2-furyl, Phenyl), 4- (N- (2-morpholinoethyl) - (2-morpholinoethyl) carbamoylmethoxy) Phenyl, 4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. Wherein R ₃ , R ₄ , R ₅ and R ₆ are independently selected from the group consisting of hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, 3-morpholinopropoxy, 2- Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 32. The compound of claim 31 wherein R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . Compounds of formula I and their pharmaceutically acceptable salts: In the above formulas, X represents a substituted methylene or carbonyl group; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R ₃ , R ₄ , R ₅ and R ₆ are as defined above; Provided that when 1) X represents carbonyl or substituted methylene, R ₁ is hydrogen and R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, R ₂ is pyridyl, 2-thienyl, 3 - thienyl, phenyl or C _1-2 alkyl, not phenyl substituted by a halogen atom, a lower alkoxy group, a hydroxy group or an amino group; 2) X represents a methylene, R ₁ is hydrogen and R _3, R _4, R ₅ and R ₆ two are independently hydrogen, halogen having an atomic weight of about 19 to 36, C _1-4 alkyl, C _1- of ₄ alkoxy or trifluoromethyl and the remaining two represent hydrogen, then R ₂ is selected from the group consisting of unsubstituted thienyl, unsubstituted furyl, unsubstituted pyrrolyl, unsubstituted pyridyl, or substituted groups having from about 19 to 36 with a halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl with an atomic weight of not phenyl with a substituent in more than two pieces of methyl; 3) when X represents a carbonyl group and R ₂ represents phenyl, 4-chlorophenyl or 4-methoxyphenyl, then R ₃ , R ₄ , R ₅ and R ₆ are not trifluoromethyl; 4) when X represents a carbonyl group, R ₂ represents phenyl, R ₃ represents bromo, R ₄ represents hydroxy and R ₅ represents methoxy, R ₆ is not hydrogen; 5) when X represents carbonyl and R ₃ , R ₄ , R ₅ and R ₆ represent hydrogen, then R ₆ is not aryl. 38. A compound according to claim 37, characterized in that R &lt; ₂ &gt; is optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl compound. 38. The compound of claim 37, wherein R &lt; ₂ &gt; is selected from optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy , Carboxymethoxy, 2-carboxyethoxy, 2-carbamoylethoxy, carbamoylmethoxy, 3-carbamoylpropoxy, 2-piperidino-ethoxy, 2- (piperazin- 2- (perhydro-thiazin-4-yl) ethoxy, 3-piperidinopropoxy, 3- (pyrrolidin-1-yl) ethoxy, 2- (Piperazin-1-yl) propoxy, 3- (pyrrolidin-1yl) propoxy, 3- dimethylaminopropoxy, 3- (perhydrothiazin- (Especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, cyano (Especially methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group optionally substituted by one or more of pyridine rings, trifluoromethyl or nitro. The compound of claim 37, wherein R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4-pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoyl) phenyl, 3- Mile-me (Trifluoromethyl) phenyl] - (4-methylphenyl) - phenyl, 4- [3- (N- (2-diethylaminoethyl) 2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) Phenyl), 4- (N- (2-morpholinoethyl) -carbamoylmethoxy) phenyl, 3- [3- Phenyl) -4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. The compound of claim 37, wherein R ₃ , R ₄ , R ₅ and R ₆ are independently selected from the group consisting of hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 38. The compound of claim 37, wherein R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6- (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R ₃ , R ₄ , R ₅ and R ₆ are as defined above, With the proviso that when X is a group of the 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 are independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl and the remaining two are hydrogen, R ₂ is unsubstituted thienyl, unsubstituted furyl, Unsubstituted pyrrolyl, unsubstituted pyridyl, or phenyl having up to two substituents wherein the substituents are halogen with an atomic weight of about 19 to 36, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl, No, Provided that when n is 2 and R ₃ , R ₄ , R ₅ and R ₆ are each hydrogen or methoxy, R ₂ is 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid- Carboxyphenyl. &Lt; / RTI &gt; 44. A compound according to claim 43, characterized in that R &lt; ₂ &gt; is optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl compound. 44. The compound of claim 43, wherein R &lt; ₂ &gt; is selected from optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy, 2-piperidino-ethoxy, 2- (piperazin-1-yl) -methoxy, ethoxy, Ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylamino-ethoxy, 2- (perhydro- 3- (perhydrothiazin-4-yl) propoxy), lower (tertiary) amines, Alkyl (especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, cyano (Especially methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group optionally substituted by one or more of pyridine rings, trifluoromethyl or nitro. 44. The compound of claim 43, wherein R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4- pyridyl, 2-aminomethyl-4- pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoyl) phenyl, 3- Mile-me (Trifluoromethyl) phenyl] - (4-methylphenyl) - phenyl, 4- [3- (N- (2-diethylaminoethyl) 2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) Phenyl), 4- (N- (2-morpholinoethyl) -carbamoylmethoxy) phenyl, 3- [3- Phenyl) -4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. 44. The method of claim 43 wherein, R _3, R _4, R ₅ and R ₆ are independently hydrogen, halo (particularly fluoro), optionally substituted lower alkoxy (particularly methoxy, 3-morpholinyl Smirnoff propoxy, 2- Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 44. The method of claim 43 wherein, R _3, R _4, R ₅ and R ₆ are as the following 6,7-dimethoxy, 6,7,8- trimethoxy, 6-fluoro, 6-acetamido, 7- (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a) substituted methylene, b) carbonyl, c) oxygen, d) a group of the formula -C = NOR ₇ (wherein, R ₇ represents H or C _1-4 alkyl group), e) of the formula NR ₈ F) a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3, or g) a group of the formula p (CH ₂ ) _n wherein R ₈ is H, an optionally substituted C _1-4 alkyl group or an optionally substituted phenyl, (O) _{p wherein n} is 0, 1 or 2; R ₁ represents H; R ₂ each represent optionally substituted aryl, pyridyl, thienyl, furyl or pyrrolyl; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j D) an amino group of the formula NR _h R _j , wherein R _h and R _j are as defined below, a C _1-6 alkoxy group optionally substituted by one or more of the following: , R _h and R _j are as defined below, with the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group; Or halo, e) optionally substituted phenoxy, f) hydroxy, g) _a group of the formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a represents _a radical of formula NR _b R _c Wherein R _b and R _c independently represent hydrogen or a C _1-6 alkyl group or phenyl, wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy, or a group of the formula NR _h R _j An amino group, wherein R _h and R _j independently represent hydrogen or a C _1-6 alkyl group, or R _h and R _j , together with the nitrogen atom to which they are attached, optionally further heteroatom selected from O, S or N, and optionally containing, and represents a 5-, 6- or 7-membered saturated hetero cyclic ring is substituted by a C _1-6 alkyl group))), h) group (wherein, of formula NR _d R _e R _d, and R _e is selected from hydrogen, C _1-6 alkyl or phenyl independently) or Group of formula COR _f (wherein, R _f represents hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl or phenyl), (in each case, an alkyl group, cycloalkyl group and phenyl is optionally substituted by one or more of the following: to be substituted with hydroxy or (as described here, R _h and R _j are as defined above), the formula NR _h R _j of the group, i) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, , 4 or 5, R _g is hydroxy or a group of the formula NR _d R _e , wherein R _d and R _e are as defined above, or R _g is _a group of the formula COR _a wherein R _a represents the same meaning as defined above), m is 1, 2, 3, 4 or 5), j) nitro, k) optionally substituted phenyl C _1-6 alkyl, l) optionally substituted phenyl C _{1- 6} alkoxy or o) phenyl optionally substituted by one or more of C _1-6 alkyl, C _1-6 alkoxy or halo, Hwandoen C _2-4 alkenyl or C _2-4 alkynyl group represents a group, with the proviso that, R _3, R _4, R ₅ and R ₆ on the one or more of the substituents R ₂ or represents me next Medium: a) the formula O (CH ₂ ) _m R _g wherein m is 2, 3, 4 or 5 and R _g represents hydroxy or a group of the formula NR _d R _e wherein R _d and R _e are as defined above, Lt; / RTI &gt; R _g represents _a group of the formula COR _a wherein R _a is as defined above and m is 1, 2, 3, 4 or 5, b) C _1-6 substituted by one or more of Alkyl group: hydroxy or an amino group of the formula NR _h R _j , wherein R _h and R _j are as defined above, c) a C _1-6 alkoxy group optionally substituted by one or more of the following: hydroxy, or The 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 bound to the carbon bound to the oxygen of the alkoxy group; Or halo d) _a group of the formula COR _a wherein R _a is hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are as defined above, E) a group of the formula NR _d R _e wherein R _d and R _e are as defined above. Wherein R &lt; ₂ &gt; is selected from the group consisting of optionally substituted phenyl, naphthyl, optionally substituted thienyl, optionally substituted pyridyl, optionally substituted furyl or optionally substituted pyrrolyl compound. 50. The compound of claim 49, wherein R &lt; ₂ &gt; is each optionally substituted 2-thienyl, 3-thienyl, 2- furyl, 3- furyl, 2- pyridyl, 3- pyridyl or 4- Optionally substituted phenyl, wherein the substituents are optionally substituted alkoxy (especially methoxy, 3-morpholinoproxy, 2-morpholinoethoxy, 3-carboxypropoxy, 2-piperidino-ethoxy, 2- (piperazin-1-yl) -methoxy, ethoxy, Ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2-dimethylamino-ethoxy, 2- (perhydro- 3- (perhydrothiazin-4-yl) propoxy), lower (tertiary) amines, Alkyl (especially methyl), halo (especially fluoro and chloro), aryl (especially phenyl), hydroxy, aryloxy (Especially benzyloxy), di-lower-alkylamino (especially dimethylamino), polyhalo-lower-alkyl, polyhalo-lower-alkoxy (especially difluoromethoxy), nitro, cyano (Especially methylthio), carboxy, lower-alkoxycarbonyl (especially methoxycarbonyl), amido (especially acetamido and benzamido) and optionally substituted carbamoyl (especially carbamoyl, N-methylcarbamoyl, N-phenylcarbamoyl) and a pyridyloxy or pyridylthio group optionally substituted by one or more of pyridine rings, trifluoromethyl or nitro. 50. The compound of claim 49, wherein R ₂ is selected from the group consisting of 4-pyridyl, 2-formamidomethyl-4-pyridyl, 2-aminomethyl-4- pyridyl, 2- (hydroxyamidino) Pyridyl, 4-pyridyl-N-oxide, 2-chloro-4-pyridyl, 2-cyano- 2-yl, phenyl, 4-methoxyphenyl, 3-methoxyphenyl, 2-methoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5- (3-carboxy-propoxy) phenyl, 4-carboxymethoxyphenyl, 4- (2-morpholinoethoxy) Propoxy) phenyl, 3- (2-morpholino-ethoxy) phenyl, 3- 3-hydroxyphenyl, 3-hydroxyphenyl, 4-carboxymethoxyphenyl, 3- (3-carbamoylpropoxy) Hydroxyphenyl, 3-hydroxy-4-methoxyphenyl, 4-hydro 3-methoxyphenyl, 4-difluoromethoxyphenyl, 3-nitrophenyl, 4-nitrophenyl, 3,5-di- tert -butyl-4-hydroxyphenyl, 2-chlorophenyl, 4-methylthiophenyl, 4-fluorophenyl, 4-fluorophenyl, 4-benzyloxyphenyl, 4-dimethylaminophenyl, 4-diethyl-aminophenyl, 4-methoxycarbonylphenyl, 4-carbamoyl 4-acetamido-phenyl, 4-benzamidophenyl, 4-carboxyphenyl, 4- [N 3- (2-diethylamino) -carbamoyl] phenyl, 4- (prop-1-enyloxy) Phenyl) phenyl, 4- (N- (2-diethylaminoethyl) carbamoyl) phenyl, 3- Mile-me (Trifluoromethyl) phenyl] - (4-methylphenyl) - phenyl, 4- [3- (N- (2-diethylaminoethyl) 2-furyl, 3-bromo-2-thienyl, 5-methoxy-2-furyl, 5- (2-nitro-4-trifluoromethylphenyl) Phenyl), 4- (N- (2-morpholinoethyl) -carbamoylmethoxy) phenyl, 3- [3- Phenyl) -4- (3- (N- (2-morpholinoethyl) carbamoyl) propoxy] phenyl. Wherein R ₃ , R ₄ , R ₅ and R ₆ are independently selected from the group consisting of hydrogen, halo (especially fluoro), optionally substituted lower alkoxy (especially methoxy, 3-morpholinopropoxy, 2- Carboxy-methoxy, 2-carboxyethoxy, 2-carbamoylethoxy, 3-carbamoylpropoxy, 2-piperidinoethoxy, 2- (piperazin- 1-yl) ethoxy, 2- (pyrrolidin-1-yl) ethoxy, 2- dimethylaminoethoxy, 2- (perhydrothiazin- 3- (piperidin-1-yl) propoxy, 3- (pyrrolidin-1-yl) propoxy, 3- ), Carbamoylmethoxy, hydroxypropyloxy, hydroxyethoxy, (3-morpholino) propoxy and (2-morpholino) ethoxy), amido (especially acetamido and benzamido) , Optionally substituted carbamoyl (especially carbamoyl, N-methyl-carbamoyl and N-phenylcarbamoyl ), The compound characterized in that represents a carboxy, nitro and amino. 50. The compound of claim 49, wherein R ₃ , R ₄ , R ₅ and R ₆ are selected from the group consisting of 6,7-dimethoxy, 6,7,8-trimethoxy, 6-fluoro, 6- (2-morpholino) ethoxy, methoxy, 6-carbamoyl, 6- (N-methylcarbamoyl), 6- . 3- (3,4,5-trimethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 3- (1, 4-dihydroindeno [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- 3- (2-thienyl) -1H- [1] benzothieno [3,2-c] pyrazole, 3-phenylindeno [1,2-c] pyrazole-4 (1H) -one oxime, Dimethoxyphenyl) indeno [1,2-c] pyrazole-4 (1H) -one oxime, (3-methylphenyl) indeno [1,2-c] pyrazole-4 (1H) (2-thienyl) indeno [1,2-c] pyrazole-4 (1H) 3-phenyl-1H-benzofuro [3,2-c] pyrazole, Dihydro-3-phenylpyrazolo [4,3-b] indole, 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, Methyl 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzoate, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -3 -morpholinopropionanilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) morpholinoacetanilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide, 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, 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N-methyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzanilide, (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl) 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenol, 3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole, 3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazol- 6- (2-morpholinoethoxy) -3- (2-thienyl) -1,4-dihydroindeno [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, Ethyl 3- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetate, 3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide, Dihydroindeno [1,2-c] pyrazol-3-yl) phenoxyacetamide, N- Dihydroindeno [l, 2-c] pyrazol-3-yl) phenoxyacetamide, N- (2-morpholinoethyl) Dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butyric acid, Ethyl 4- {3- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) phenoxy} 4- {3- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} butyramide, Dihydroindeno [1,2-c] pyrazol-3-yl) phenoxy} -butyramide, N- (2- Dihydroindeno [l, 2-c] pyrazol-3-yl) phenoxy} -butyramide, N- (2-morpholinoethyl) -4- {3- 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, (2-morpholinoethyl) -3-phenyl-1,4-dihydroindeno [1,2-c] pyrazole-6-carboxamide, 3- (2-thienyl) -1,4-dihydroindeno [1,2-c] pyrazole-6-carboxyanilide; N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide, 3-phenyl-1,4-dihydroindeno [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-lH-benzo [g] indazol-3-yl) pyridine 1-oxide, 3- (2-chloro-4-pyridyl) -4,5-dihydro-1H-benzo [g] Benzo [g] indazol-3-yl) -2-pyridinecarbonitrile, 4- (4,5- Benzo [g] indazol-3-yl) -2-pyridinecarboxamide oxime, 4- Benzo [g] indazol-3-yl) -2-pyridinecarboxamide, 4- (4,5-dihydro- Benzo [g] indazol-3-yl) -2-pyridyl] methyl} ammonium chloride, Benzo [g] -indazol-3-yl) -2-pyridyl] methyl} formamide, N - {[4- (4,5- 2- [3- (1, 4-dihydroindeno [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-thiomethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 3- (2-naphthyl) -1,4-dihydroindeno [1,2-c] pyrazole, 3- (4-difluoromethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole, 3- (4-acetamidophenyl) -4,5-dihydro-2H-benz [g] Dihydroindeno [l, 2-c] pyrazole, l- (4-bromo-2-thienyl) 3- (4-benzyloxyphenyl) -4,5-dihydro-2H-benz [g] 6,7-dimethoxy-3- (3-phenoxyphenyl) -1,4-dihydroindeno- [1,2- c] pyrazole, Pyridyloxy) phenyl] -1,4-dihydroindeno [1,2-c] pyrazole, 6,7,8-triethoxy-3- (2,3,4-trimethoxyphenyl) -1,4-dihydroindeno [1,2-c] pyrazole, Dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxymethyl) phenol, 2-methoxy-5- (1, 4-dihydroindeno [1,2-c] pyrazol- 2-chloro-4- (1, 4-dihydroindeno [1,2-c] pyrazol- 2-methoxy-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) 4-dihydroindeno [l, 2-c] pyrazol-3-yl) phenol, 2- [4- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) phenoxy] acetamide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) diethylamino-acetanilide, 4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) benzamide, 3- (4-aminophenyl) -1H- [1] benzothieno [3,2-c] pyrazole, 3- (4-methoxyphenyl) -1H-benzothieno [3,2-c] pyrazole, 3- (4-hydroxyphenyl) -1H- [1] benzothieno [3,2-c] pyrazole, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl) 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzonitrile, 7-methoxy-3- (4-methylsulfonylphenyl) -4,5-dihydro-2H-benz [g] Methyl-3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (N- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (N, N- dimethylamino) ethyl] -4- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (N, Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (N, N- di- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N- dimethylamino) Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (N, (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N- di- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-piperidinoethyl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-piperidinopropyl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinoethyl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-morpholinopropyl) Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (piperazin- Propyl] -4- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) benzamide, N- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (pyrrolidin- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (pyrrolidin- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (4-methylpiperazin- Propyl] -4- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (thiomorpholin- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (thiomorpholin- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (homopiperazin- Propyl] -4- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (1,4-dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (perhydro- Propyl] -4- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (perhydro- N-isopropyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) Yl-4- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) benzamide, N-methyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) N-ethyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-bromoethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) 1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3,3,3-trifluoro- N- (Cyclopropylmethyl) -4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) N-cyclopentyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (cyclohexylmethyl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-chlorocyclopentyl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N-dimethylamino) Propyl] -4- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) benzamide, N- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-methylbut- Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [2- (pyrrolidin- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [3- (N, N-dimethylamino) prop- Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-hexyl) N-tert-butyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [7- (N, N- dimethylamino) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2-methylbut- 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- N-tert-butyl-4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3,3-dimethylbutyl) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2,2,3,3,3-pentafluoropropyl) -4- 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (2,5-dichloropentyl) Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- (2,2-difluoroethyl) 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- [2- (N, N- dimethylamino) Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-morpholinopropyl) Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, N- [3- (pyrrolidin- 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) piperidinoacetanilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -4-methylpiperazin- 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -4-methyl 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) 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-difluorobenzyl anilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4-fluorobenzyl anilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -2-fluorobenzyl anilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -3-fluorobenzyl anilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,4-difluorobenzyl anilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,5-difluorobenzyl anilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) -2,3-difluorobenzyl anilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -4-nitrobenzanilide, 4 '- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) -3-nitrobenzanilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -3,3,3- trifluoropropanilide, 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- methylpentanilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -2- ethylbutananilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) neopentanilide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) -4,4-dimethylpentanilide, 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) pentafluoropropan- Fluoro-N- (3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol-6-yl) acetamide, (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide, 4-dihydroindeno [l, 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-1,4-dihydroindeno [1,2- c] pyrazol-6- yl) benzylamide, 2,4-dihydroindeno [1,2-c] pyrazol-6-yl) benzylamide, 2,5-difluoro- 4-dihydroindeno [l, 2-c] pyrazol-6-yl) benzylamide, 3-Nitro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol- 6- yl) benzylamide, 3,3,3-trifluoro-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) isobutanamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) isopentanamide, Methyl-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) Methyl-N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) pentanamide, 2-ethyl-N- (3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol-6-yl) N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) neopentanamide, 4-dihydroindeno [1,2-c] pyrazol-6-yl) pentanamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) cyclohexanecarboxamide, (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) acetamide, (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) propanamide, 4 '- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) acetanilide, Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, 2-hydroxy- 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (pyrrolidin-1-yl) ethyl] -5- (1,4- Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, Dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxybenzamide, N- [2- (N, N-diethylamino) ethyl] Dihydroindeno [1,2-c] pyrazol-3-yl) -2-hydroxybenzamide, N- [3- (N, Dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (N, N- dimethylamino) ethyl] (1,4-dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (N, N-dipropylamino) ethyl] -5- (1,4- dihydroindeno [ Dihydroindeno [l, 2-c] pyrazol-3-yl) benzene (hereinafter referred to as &quot; amides, (1,4-dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzene amides, 2-hydroxy-N- (2-piperidinoethyl) -5- (1,4-dihydroindeno [1,2- c] pyrazol- 2-hydroxy-N- (2-piperidinopropyl) -5- (1,4-dihydroindeno [1,2- c] pyrazol- (1,4-dihydroindeno [l, 2-c] pyrazol-3-yl) benzamide, Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, Dihydroindeno [l, 2-c] pyrazol-3-yl) benzene (hereinafter referred to as &quot; amides, Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzene amides, Ethyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, Propyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, Ethyl] -5- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, 2-hydroxy-N- [2- (perhydroazepin-1-yl) ethyl] -5- , Propyl] -5- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide , Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2-morpholinoethyl) aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2 -morpholinopropyl) aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2-piperidinoethyl) Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (2-piperidinopropyl) aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (thiomorphyrin 1-yl) ethyl] aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (thiomorpholin-1- yl) propyl] aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (piperazin- 1- yl) ethyl] aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (piperazin- 1-yl) propyl] aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin- 1- yl) ethyl] aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (4-methylpiperazin- 1- yl) propyl] aniline, Dihydroindeno [1,2-c] pyrazol-3-yl) aniline, N- [2- (N, N- Dihydroindeno [1,2-c] pyrazol-3-yl) aniline, N- [3- (N, Dihydroindeno [1,2-c] pyrazol-3-yl) -N- [2- (N, N-dipropylamino) ethyl] aniline, N- (3- (N, N-dipropylamino) propyl] aniline, Dihydroindeno [l, 2-c] pyrazol-3-yl) -N- [2- (N, N- dimethylamino) ethyl] aniline, N- [3- (N, N-dimethylamino) propyl] aniline, Methyl 4- (6-acetamido-1,4-dihydroindeno [1,2-c] pyrazol-3- yl) benzoate, Dihydroindeno [1,2-c] pyrazol-3-yl) benzamide, N- (3-methoxypropyl) Dihydroindeno [1,2-c] pyrazol-3-yl) -N- (4-nitrophenyl) Dihydroindeno [1,2-c] pyrazol-6-yl) morpholinoacetamide, N- (3-phenyl- Dihydroindeno [1,2-c] pyrazol-6-yl) morpholinoacetamide, N- (3-phenyl- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) piperidino acetamide, N- (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) thiomorpholinoacetamide, Dihydroindeno [1,2-c] pyrazol-6-yl) -4-methylpiperazin-1-ylacetamide, N- Dihydroindeno [1,2-c] pyrazol-6-yl) piperazin-1-ylacetamide, N- (3-phenyl- Dihydroindeno [1,2-c] pyrazol-6-yl) pyrrolidin-1-ylacetamide, N- 2- (N, N-diethylamino) -N- (3-phenyl-1,4-dihydroindeno [1,2- c] pyrazol- 6- yl) acetamide, (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2- (dimethylamino) acetamide, (3-phenyl-1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2- (dipropylamino) acetamide, N, N-diethylamino) ethyl] - &lt; RTI ID = 0.0 &gt; benzamide, &lt; 3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydroindeno [1,2c] pyrazole, 3- [3- (2-morpholinoethoxy) phenyl] -1,4-dihydroindeno [1,2c] pyrazole, 3- [3- (3-morpholinoproxy) phenyl] -1,4-dihydroindeno [1,2c] pyrazole, 3- [3- (2-piperidinoethoxy) phenyl] -1,4-dihydroindeno [1,2c] pyrazole, 3- [3- (3-piperidinopropoxy) phenyl] -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (piperazin-1-yl) ethoxy] phenyl} -1,4-dihydroindeno [1,2 c] 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 [1,2 c] 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 [1,2 c] pyrazole, 3- {3- [3- (4-methylhomopiperazin-1-yl) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [2- (N, N-diethylamino) ethoxy] phenyl} -1,4-dihydroindeno [1,2 c] pyrazole, 3- {3- [3- (N, N-diethylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2 c] pyrazole, 3- {3- [2- (N, N-dimethylamino) ethoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, 3- {3- [3- (N, N-dimethylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2c] pyrazole, Phenyl] -1,4-dihydroindeno [1,2 c] pyrazole and 3- {3- [3- (N, N-dipropylamino) Propylamino) propoxy] phenyl} -1,4-dihydroindeno [1,2 c] pyrazole, and pharmaceutically acceptable salts and tautomers thereof. Compounds selected from the following formulas and their pharmaceutically acceptable salts and tautomers thereof: In this formula, X is (CH _{2) n,} R ₂ is ego, Definitions for the remaining groups are given in Table 1: Table 1 Compounds selected from the following formulas and their pharmaceutically acceptable salts and tautomers thereof: In this formula, X is (CH _{2) n,} Definitions for the remaining groups are given in Table 2: Table 2 Compounds selected from the following formulas and their pharmaceutically acceptable salts and tautomers thereof: In this formula, The definition is given in Table 3: Table 3 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) as defined in claim 1 which is used as a medicament. A compound of formula (I) as defined in claim 1 used as a medicament for inhibiting protein kinase activity. Use of a compound of formula I as defined in claim 1 in the manufacture of a medicament for use in inhibiting protein kinase activity. The compound according to claim 1, characterized in that the compound is present in enantiomeric form, in the form of a mixture with one or more other compounds, or in the form of an enantiomeric form and a mixture with one or more other compounds Way. 2. The method of claim 1, wherein the protein kinase is a serine kinase. 2. The method of claim 1, wherein the protein kinase is a threonine kinase. 3. The method of claim 2, wherein the tyrosine kinase is KDR. Dihydroxy 4- (4H-indeno- [1,2-c] -pyrazol-3-yl) phenylborane, 4- (1H- [1] benzothieno [3,2-c] pyrazol-3-yl) benzaldehyde, Yl) -N- [3- (imidazol-1-yl) propyl] benzylamine trihydrochloride, Methyl 4- (4-oxo-1,4-dihydroindeno [1,2-c] pyrazol-3- yl) benzoate, 4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) benzamide oxime, Phenyl] -1,4-dihydroindeno [1,2-c] pyrazole trihydrochloride, 3- {4 - [(2- diethylaminoethyl) aminomethyl] Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] benzenesulfonamide, N- [4- Dihydroindeno [l, 2-c] pyrazol-3-ylaniline dihydrochloride, N- (2-morpholinoethyl) N- (1,4-dihydroindeno [1,2-c] pyrazol-6-yl) -2-morpholinoacetamide, Dihydroindeno [1,2-c] pyrazol-6-ylamine trihydrochloride, N- (2-morpholinoethyl) 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, 4-pyridyl] -4,5-dihydro-2H-benzo [g] indazole, 3- (4-isocyanatophenyl) -1,4-dihydroindeno [1,2-c] pyrazole, Dihydroindeno [l, 2-c] pyrazol-3-yl) phenyl] carbamate, 2- (diethylamino) ethyl N- [4- 2-morpholinoethyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] carbamate, (Dibenzylamino) propyl N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] carbamate, (2-hydroxyethyl) amino] ethyl N- [4- (1, 4-dihydroindeno [1,2- c] pyrazol-3- yl) phenyl] carbamate, 2-c] pyrazol-3-yl) phenyl] carbamate &lt; / RTI &gt; , Methyl-2-propoxyethyl N- [4- (1, 4-dihydroindeno [1,2- c] pyrazol-3- yl) phenyl] carbamate, Yl) phenyl] carbamate, &lt; RTI ID = 0.0 &gt; 2- (1-methyltetrahydro-lH- 2- [2- (dimethylamino) ethoxy] ethyl N- [4- (1,4-dihydroindeno [1,2- c] pyrazol-3- yl) phenyl] carbamate, Methyl] ethyl] -N- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] carbamate, Yl] phenyl] urea, &lt; / RTI &gt; &lt; RTI ID = 0.0 & Yl] phenyl] -N'- (2-morpholinoethyl) urea, &lt; / RTI &gt; N1- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -1- piperidinecarboxamide, N '- [2- (dimethylamino) -1-methylethyl] urea, &lt; / RTI &gt; Yl] phenyl] -N ' -tetrahydro-2-furanylmethyl &lt; / RTI &gt; Yl] phenyl] -N '- (2-furylmethyl) urea, N- [4- Phenyl] urea, &lt; / RTI &gt; &lt; RTI ID = 0.0 & N-cyclohexyl-N '- [4- (1, 4-dihydroindeno [1,2- c] pyrazol- Yl] phenyl] -N '- (2-piperidinoethyl) urea [0157] N-benzyl-N '- [4- (1,4-dihydroindeno [1,2- c] pyrazol- Dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] urea, N- [4- (diethylamino) N '- [2- (2-thienyl) ethyl] urea, &lt; / RTI &gt; Phenyl] urea, &lt; / RTI &gt; &lt; RTI ID = 0.0 & Yl] phenyl] -N '- [(1-ethyltetrahydro-1H-2-pyrrolyl) methyl] ]Element, Phenyl] urea, &lt; / RTI &gt; &lt; RTI ID = 0.0 & N '- [2- (2-hydroxyethoxy) ethyl] urea, &lt; / RTI &gt; - [2-hydroxy-1-hydroxymethyl] ethyl] urea, &lt; / RTI &gt; Yl] phenyl] -N '- (2,3-dihydroxypropyl) urea, N- [4- (1,4-dihydroindeno [ Yl) phenyl] -4- (2-pyridyl) -1-piperazinecarboxamide, N1- [4- (1,4-dihydroindeno [1,2- c] pyrazol- N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] -N- [3- (dimethylamino) propyl] N1- [4- (1, 4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] -1- azetanecarboxamide, Yl) phenyl] -4- (4-fluorophenyl) -1-piperazinecarboxamide, N1- [4- (1,4- dihydroindeno [1,2- c] pyrazol- Yl] phenyl] -N-methyl urea, &lt; / RTI &gt; N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] Yl) phenyl] -4- (2-methoxyphenyl) -1-piperazinecarboxamide, N1- [4- (1,4- dihydroindeno [1,2- c] pyrazol- N, N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] -N- [2- (dimethylamino) ethyl] Yl] phenyl] -4-methyl-1-piperazinecarboxamide, N1- [4- (1,4- (4-hydroxyphenyl) -1-piperazinecarboxamide, N1- [4- (1,4-dihydroindeno [1,2- c] pyrazol- Phenyl] -4 - [(E) -3-phenyl-2-propenyl] -l- [4- (1,4- dihydroindeno [1,2- c] pyrazol- Piperazine carboxamide, N1- [4- (1, 4-dihydroindeno [1,2-c] pyrazol-3-yl) phenyl] -4- phenyl- 1- piperazinecarboxamide, N, N-di (2-methoxyethyl) urea, N '- [4- (1,4- dihydroindeno [ N '- [4- (1,4-dihydroindeno [1,2-c] pyrazol-3- yl) phenyl] -N- (2,3- dihydroxypropyl) N, N-di [2- (diethylamino) ethyl] -N '- [4- (1,4- dihydroindeno [1,2- c] pyrazol- Yl] phenyl] -N '- (2-pyridylmethyl) urea, N- [4- Yl] phenyl] -N '- (3-pyridylmethyl) urea, N- [4- (1,4-dihydroindeno [ Yl] phenyl] -N '- (4-pyridylmethyl) urea, Phenyl] -N '- (2-hydroxyethyl) urea, &lt; / RTI &gt; Yl] phenyl] -N '- [7- (dimethylamino) heptyl] urea. A compound selected from the following formula: In this formula, R &lt; ₁ &gt; is H, The definitions of the remaining groups are as follows: A compound selected from the following formula: In this formula, The definition is as follows: A compound selected from the following formula: In this formula, The definition is as follows: Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula S (O) _p , wherein p represents 0, 1 or 2; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a represents a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl is optionally substituted with one or more of the following substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, by one or more it is optionally substituted with hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- ( C ₁ -C ₆ ) alkyl-hydroxy, a C _3-12 cycloalkyl group or an amino group of the formula NR _h R _j ; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered, 5-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or heterocycle , 6-membered or 7-membered heterocyclic ring, R _b and R _c together with the nitrogen atom to which they are attached form an optionally substituted 4-membered, 5-membered, 6-membered or 7-membered ring optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, Br, Cl, F, I, hydroxy, nitro, amino, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl and (C ₁ -C ₆₎ alkoxy group consisting of &Lt; / RTI &gt; g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, hydroxy, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, di - (C ₁ -C ₆₎ alkyl-amino - (C ₁ -C ₆ ), Or an amino group of the formula NR _h R _j , wherein R _h and R _j are as defined above, optionally substituted by hydroxy, alkoxy, (C ₁ -C ₆ ) alkyl, h) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the formula COR _a 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 alkoxy, l) cyano, m) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h is an amino group of R _j , wherein R _h and R _j are as defined below, provided that said groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy , g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are independently represent hydrogen, C _1-6 alkyl or phenyl, the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxyl Or an amino group of formula NR _h R _j (wherein, R _h and R _j are independently hydrogen or C _1-6 alkyl, (C ₃ -C ₆₎ heterocycloalkyl - (C ₀ -C ₆₎ alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j together with the nitrogen atom to which they are attached optionally contain an additional heteroatom selected from O, S or N and C _{1- 6} or 7 membered saturated heterocyclic ring optionally substituted by a C1-6 alkyl group, h) a group of formula NR _d R _e , wherein R _d and R _e are independently hydrogen, C _1-12 alkyl group, C _3-12 cycloalkyl group or phenyl, or a group of the formula COR _f wherein R _f is hydrogen, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 An alkyl group or a phenyl group, in each case, an alkyl group, a cycloalkyl group and a phenyl group, (I) reacting a compound of the formula O (CH ₂ ) _m R _{g with} a halo, hydroxy, nitro or an amino group of the formula NR _h R _j wherein R _h and R _j are as defined above, Wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e , wherein R _d and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group; Provided that 1) when R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen and X represents SO ₂ , R ₂ does not represent phenyl, 2) When X represents S and R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, then R ₂ does not represent 2,4-dichlorophenyl. Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents oxygen; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a represents a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Wherein the alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl is optionally substituted with one or more of the following substituents selected from the group consisting of methyl, ethyl, propyl, isopropyl, butyl, isobutyl, by one or more it is optionally substituted with hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- ( C ₁ -C ₆ ) alkyl-hydroxy, a C _3-12 cycloalkyl group or an amino group of the formula NR _h R _j ; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, 6, or 7 membered heterocyclic ring, 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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, part is Br, Cl, F, I, hydroxy, nitro, amino, mono-as (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl and (C ₁ -C ₆₎ alkoxy or di Lt; / RTI &gt; is optionally substituted by one or more moieties selected from the group consisting of; g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, hydroxy, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, di - (C ₁ -C ₆₎ alkyl-amino - (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆₎ an amino group (wherein, R _h and R _j of pyrrolidine, or the formula NR _h R _j are optionally substituted with an alkyl is as defined above), h) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h is an amino group of R _j , wherein R _h and R _j are as defined below, provided that said groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are independently C _1-6 alkyl group or phenyl, and the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy Or an amino group of the formula NR _h R _j wherein R _h and R _j are independently hydrogen or a C _1-6 alkyl group, a (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j optionally together with the nitrogen atom to which they are attached contain an additional heteroatom selected from O, S or N and C _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently a group selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _{1 -6} represents an alkyl group or phenyl) (in each case, an alkyl group, a cycloalkyl group and a phenyl of the following: One or more is optionally substituted by: halo, hydroxy, nitro, or (as described here, R _h and R _j are as defined above), formula group of NR _h R _j), i) the formula O (CH _{2) m} R _g Wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group, only, When R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, R ₂ does not represent phenyl, 2,4-dimethylphenyl or 2,4-dichlorophenyl. Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula NR ₈ ; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo or an amino group of the formula NR _h R _j , wherein R _h and R _j are as defined below, c) an amino group of a C _1-6 alkoxy group optionally substituted by one or more of the following: hydroxy, COOH, 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 bonded to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a represents a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl is optionally substituted with one of the following: halogen, alkyl, cycloalkyl, It is optionally substituted by or more: hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- (C ₁ -C ₆₎ alkyl-hydroxy, C _3-12 cycloalkyl group or an amino group of formula NR _h R _j; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, A 6-membered or 7-membered heterocyclic ring, 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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, Br, Cl, F, I, hydroxy, nitro, amino, mono- or di - (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl and (C ₁ -C ₆₎ alkoxy group consisting of &Lt; / RTI &gt; g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, hydroxy, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, di - (C ₁ -C ₆₎ alkyl-amino - (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆₎ an amino group (wherein, R _h and R _j of pyrrolidine, or the formula NR _h R _j are optionally substituted with an alkyl is as defined above), h) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h is an amino group of R _j , wherein R _h and R _j are as defined below, provided that said groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy , g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are independently represent hydrogen, C _1-6 alkyl or phenyl, the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxyl Or an amino group of formula NR _h R _j (wherein, R _h and R _j are independently hydrogen or C _1-6 alkyl, (C ₃ -C ₆₎ heterocycloalkyl - (C ₀ -C ₆₎ alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j optionally together with the nitrogen atom to which they are attached contain an additional heteroatom selected from O, S or N and C _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently a group selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _{1 -6} represents an alkyl group or phenyl) (in each case, an alkyl group, a cycloalkyl group and a phenyl of the following: One or more is optionally substituted by: halo, hydroxy, nitro, or (as described here, R _h and R _j are as defined above), formula group of NR _h R _j), i) the formula O (CH _{2) m} R _g Wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group. Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula -C = NOR ₇ , wherein R ₇ represents H or a C _1-4 alkyl group; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a is a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl is optionally substituted with one of the following: halogen, alkyl, cycloalkyl, It is optionally substituted by or more: hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- (C ₁ -C ₆₎ alkyl-hydroxy, C _3-12 cycloalkyl group or an amino group of formula NR _h R _j; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, A 6-membered or 7-membered heterocyclic ring, 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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, Is selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) Lt; / RTI &gt;group; g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, 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, wherein pyrrolidine 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 _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h is an amino group of R _j , wherein R _h and R _j are as defined below, provided that said groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy , g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are Independently represents hydrogen, a C _1-6 alkyl group, or phenyl, wherein the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy Or an amino group of the formula NR _h R _j wherein R _h and R _j are independently hydrogen or a C _1-6 alkyl group, a (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j optionally together with the nitrogen atom to which they are attached contain an additional heteroatom selected from O, S or N and C _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently a group selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _{1 -6} represents an alkyl group or phenyl) (in each case, an alkyl group, a cycloalkyl group and a phenyl of the following: One or more is optionally substituted by: halo, hydroxy, nitro, or (as described here, R _h and R _j are as defined above), formula group of NR _h R _j), i) the formula O (CH _{2) m} R _g Wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group; Provided that when R ₁ , R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen and X represents C═NOH, then R ₂ does not represent 4-methylphenyl or 3,4-dimethoxyphenyl. Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a substituted methylene or carbonyl group; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a is a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) represents one or more of the following groups: (a) an alkyl group, a cycloalkyl group, a heterocyclyl group, optionally substituted by: hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- (C ₁ - C ₆ ) alkyl-hydroxy, a C _3-12 cycloalkyl group or an amino group of the formula NR _h R _j ; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, A 6-membered or 7-membered heterocyclic ring, 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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, Is selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) Lt; / RTI &gt; is optionally substituted by one or more moieties selected from the group consisting of: g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, 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 (wherein, pyrrolidine is (C ₁ -C ₆₎ is optionally substituted with alkyl), or an amino group (wherein R _h and R _j in the formula NR _h R _j are as defined above same), h) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h R _j , wherein R _h and R _j are as defined below, provided that these groups do not bind to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy, f) hydroxy, g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are independently is hydrogen, C _1-6 alkyl group, or represents a phenyl, an alkyl group and phenyl are optionally substituted by one or more of the following: hydroxy It is an amino group of formula NR _h R _j (wherein, R _h and R _j are independently hydrogen or C _1-6 alkyl, (C ₃ -C ₆₎ heterocycloalkyl - (C ₀ -C ₆₎ alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j optionally together with the nitrogen atom to which they are attached contain an additional heteroatom selected from O, S or N and C _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently a group selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _{1 -6} represents an alkyl group or phenyl) (in each case, an alkyl group, cycloalkyl group and phenyl are one of the following: From the above and is optionally substituted by: halo, hydroxy, nitro, or (as described here, R _h and R _j are as defined above), the formula NR group of _h R _j), i) the formula O (CH _{2) m} R _g Wherein m is 2, 3, 4 or 5 and R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group; Provided that when 1) X represents carbonyl or substituted methylene, R ₁ is hydrogen and R ₃ , R ₄ , R ₅ and R ₆ each represent hydrogen, R ₂ is pyridyl, 2-thienyl, 3 -Thienyl, phenyl or C _1-2 alkyl, not phenyl substituted by a halogen atom, a lower alkoxy group, a hydroxyl group or an amino group; 2) X represents a methylene, R ₁ is hydrogen and R _3, R _4, R ₅ and R ₆ two are independently hydrogen, halogen having an atomic weight of about 19 to 36, C _1-4 alkyl, C _1- of ₄ alkoxy or trifluoromethyl and the remaining two represent hydrogen, then R ₂ is selected from the group consisting of unsubstituted thienyl, unsubstituted furyl, unsubstituted pyrrolyl, unsubstituted pyridyl, or substituted groups having from about 19 to 36 with a halogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl with the atomic weight is not a phenol having a substituent of the following two more methyl; 3) when X represents a carbonyl group and R ₂ represents phenyl, 4-chlorophenyl or 4-methoxyphenyl, then R ₃ , R ₄ , R ₅ and R ₆ are not trifluoromethyl; 4) when X represents a carbonyl group, R ₂ represents phenyl, R ₃ represents bromo, R ₄ represents hydroxy and R ₅ represents methoxy, R ₆ is not hydrogen, 5) when X represents carbonyl and R ₃ , R ₄ , R ₅ and R ₆ represent hydrogen, then R ₆ is not aryl. Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a is a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) alkyl is optionally substituted with one of the following: halogen, alkyl, cycloalkyl, It is optionally substituted by or more: hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- (C ₁ -C ₆₎ alkyl-hydroxy, C _3-12 cycloalkyl group or an amino group of formula NR _h R _j; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, A 6-membered or 7-membered heterocyclic ring, 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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, Is selected from the group consisting of Br, Cl, F, I, hydroxy, nitro, amino, mono- or di- (C ₁ -C ₆ ) alkylamino, (C ₁ -C ₆ ) alkyl and (C ₁ -C ₆ ) Lt; / RTI &gt;group; g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, 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, wherein pyrrolidine 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 _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, with R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h is an amino group of R _j , wherein R _h and R _j are as defined below, provided that said groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy , g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are taemyeo independently represent the hydrogen, C _1-6 alkyl or phenyl, the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxyl Or an amino group of formula NR _h R _j (wherein, R _h and R _j are independently hydrogen or C _1-6 alkyl, (C ₃ -C ₆₎ heterocycloalkyl - (C ₀ -C ₆₎ alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j optionally together with the nitrogen atom to which they are attached contain an additional heteroatom selected from O, S or N and C _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently a group selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _{1 -6} represents an alkyl group or phenyl) (in each case, an alkyl group, cycloalkyl group or phenyl is: (I) a group of the formula O (CH ₂ ) _m R (where R _h and R _j are as defined above) optionally substituted by one or more of the following: halo, hydroxy, nitro or an amino group of the formula NR _h R _j , _g , wherein m is 2, 3, 4 or 5, R _g represents hydroxy or a group of the formula NR _d R _e , wherein R _d and R _e are as defined above; R _g is _a group of the 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, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally by phenyl substituted by one or more of the C _1-6 alkoxy group or halo An optionally substituted C _2-4 alkenyl group or a C _2-4 alkynyl group, With the proviso that when X is a group of the 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 are independently hydrogen, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl and the remaining two are hydrogen, R ₂ is unsubstituted thienyl, unsubstituted furyl, Unsubstituted pyrrolyl, unsubstituted pyridyl, or phenyl having up to two substituents wherein the substituents are halogen with an atomic weight of about 19 to 36, C _1-4 alkyl, C _1-4 alkoxy or trifluoromethyl, No, When n is 2 and R ₃ , R ₄ , R ₅ and R ₆ are each hydrogen or methoxy, then R ₂ is 3-carboxypyrid-2-yl, 3-methoxycarbonylpyrid- Carboxyphenyl. &Lt; / RTI &gt; Compounds of formula I and their pharmaceutically acceptable salts: In the formula (I) X represents a) substituted methylene, b) carbonyl, c) oxygen, d) a group of the formula -C = NOR ₇ (wherein, R ₇ represents H or C _1-4 alkyl group), e) of the formula NR ₈ F) a group of the formula (CH ₂ ) _n , wherein n is 1, 2 or 3, or a group of the formula (CH ₂ ) _n , wherein R ₈ represents H, an optionally substituted C _1-4 alkyl group or an optionally substituted phenyl; Or g) a group of the formula S (O) _p , wherein p is 0, 1 or 2; R ₁ represents H; R &lt; _{2 &gt;} is aryl, pyridyl, thienyl, furyl or pyrrolyl, a) halo, b) a C _1-6 alkyl group optionally substituted by one or more of the following: hydroxy, halo 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: hydroxy, 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 (With the proviso that these groups are not bound to the carbon bound to the oxygen of the alkoxy group); Or halo, d) optionally substituted phenoxy, e) hydroxy, f) a group of the formula COR _a or SO ₂ R _a wherein R _a is hydroxy, (C ₁ -C ₆ ) alkyl, (C ₁ -C ₆ ) alkoxy or R _a is a group of formula NR _b R _c ); Wherein R _b and R _c are independently selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl, phenyl (C ₀ -C ₆ ) alkyl or heterocyclyl- (C ₀ -C ₆ ) Alkyl, cycloalkyl, phenyl or heterocyclyl- (C ₀ -C ₆ ) represents one or more of the following groups: (a) an alkyl group, a cycloalkyl group, a cycloalkyl group, optionally substituted by: hydroxy, (C ₁ -C ₆₎ - hydroxyalkyl, halo, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, -O- (C ₁ - C ₆ ) alkyl-hydroxy, a C _3-12 cycloalkyl group or an amino group of the formula NR _h R _j ; Wherein R _h and R _j are independently selected from the group consisting of hydrogen, (C ₁ -C ₁₂ ) alkyl, (C ₃ -C ₆ ) cycloalkyl, (C ₃ -C ₆ ) heterocycloalkyl- (C ₀ -C ₆ ) (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 ₁ -C ₆ ) alkyl, C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl wherein the phenyl moiety is optionally substituted with halo, hydroxy, nitro, amino, mono- or di- ₁ -C ₆₎ alkyl, or represent (C ₁ -C ₆₎ alkoxy is optionally substituted by one or more moieties selected from the group consisting of a); R _h and R _j together with the nitrogen atom to which they are attached form a 4-membered ring optionally containing one or more additional heteroatoms selected from O, S and N and optionally substituted by a C _1-6 alkyl group or a heterocycle, A 6-membered or 7-membered heterocyclic ring, 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 optionally containing one or more additional heteroatoms selected from the group consisting of O, N and S, Wherein the ring is optionally substituted by (C ₁ -C ₆ ) alkyl, pyridinyl, phenyl (C ₀ -C ₆ ) alkyl, phenyl (C ₂ -C ₆ ) alkenyl, part is Br, Cl, F, I, hydroxy, nitro, amino, mono-as (C ₁ -C ₆₎ alkylamino, (C ₁ -C ₆₎ alkyl and (C ₁ -C ₆₎ alkoxy or di Lt; / RTI &gt; is optionally substituted by one or more moieties selected from the group consisting of; g) 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, S (O) ₂ -phenyl, phenyl, heterocycloalkyl- C ₁ -C ₆ ) alkyl, wherein heterocycloalkyl is a 4, 5, 6 or 7 membered heterocyclic ring having one or more heteroatoms selected from the group consisting of O, S and N, or , R _d and R _e are each independently a group of the formula COR _f ) Wherein, R _f is _{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 to 6} ) alkoxy, a C _1-12 alkyl group, a C _3-12 cycloalkyl group, a phenyl C _1-6 alkyl group or a phenyl group, and in each case, the alkoxy, alkyl group, cycloalkyl group and phenyl may be substituted with one or more optionally substituted by: halo, hydroxy, nitro, (C ₁ -C ₆₎ alkyl, (C ₁ -C ₆₎ alkoxy, di - (C ₁ -C ₆₎ alkyl-amino - (C ₁ -C ₆ ) alkoxy, (C ₁ -C ₆₎ an amino group (wherein, R _h and R _j of pyrrolidine, or the formula NR _h R _j are optionally substituted with an alkyl is as defined above), h) a group of the formula O (CH _{2) m} R _g (wherein, m is 2, 3, 4 or 5, R _g is a group of the hydroxyl or the formula NR _d R _e (wherein R _d and R _e are the R _g represents _a group of the 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) a C _3-6 alkenyloxy group, n) a pyridyloxy or pyridylthio group in which the pyridine ring is optionally substituted by one or more of trifluoromethyl or nitro, o) hydroxyamidino, p) aminomethyl, q) formamidomethyl, r) C _1-6 alkylthio group, s) phenyl, t) a C _2-4 alkenyl group or a C _2-4 alkynyl group, each of which is optionally substituted by a phenyl optionally substituted by one or more of C _1-6 alkyl groups, C _1-6 alkoxy groups or halo, u) CHO, v) dihydroxyborane, w) tetrazolyl; &lt; / RTI &gt; R _3, R _4, R ₅ and R ₆ are independently a) H, b) halo, c) by one or more of the following: optionally substituted C _1-6 alkyl group: hydroxy, halo or formula NR _h R _j of an amino group (wherein, R _h and R _j is as defined for), d) optionally substituted by one or more of the following: C _1-6 alkoxy group: hydroxyl, C _1-6 alkoxy, halo, or the formula NR _h is an amino group of R _j , wherein R _h and R _j are as defined below, provided that said groups are not bound to the carbon bound to the oxygen of the alkoxy group, e) optionally substituted phenoxy , g) _a group of formula COR _a wherein R _a represents hydroxy, a C _1-6 alkoxy group or R _a is _a group of the formula NR _b R _c wherein R _b and R _c are independently represent hydrogen, C _1-6 alkyl or phenyl, the alkyl group and phenyl are optionally substituted by one or more of the following: hydroxyl Or an amino group of formula NR _h R _j (wherein, R _h and R _j are independently hydrogen or C _1-6 alkyl, (C ₃ -C ₆₎ heterocycloalkyl - (C ₀ -C ₆₎ alkyl (heterocycloalkyl = Pyridine, morpholine, piperazine and N-methylpiperazine), or R _h and R _j together with the nitrogen atom to which they are attached optionally comprise an additional heteroatom selected from O, S or N and C _{A) a} group of the formula NR _d R _e , wherein R _d and R _e are independently a group selected from the group consisting of hydrogen, C _1-12 alkyl, C _3-12 is selected from a cycloalkyl group or phenyl) or a group of formula COR _f (wherein, R _f is hydrogen, C _1-12 alkyl, C _3-12 cycloalkyl group, a phenyl C _{1 -6} represents an alkyl group or phenyl) (in each case, an alkyl group, a cycloalkyl group and a phenyl of the following: From the above and is optionally substituted by: halo, hydroxy, nitro, or (as described here, R _h and R _j are as defined above), the formula NR group of _h R _j), i) the formula O (CH _{2) m} R _g Wherein m is 2, 3, 4 or 5, R _g is hydroxy or a group of the formula NR _d R _e wherein R _d and R _e are as defined above, or R _g is a group of the formula COR _a (wherein, R _a is as defined above) an represents, m is 1, 2, 3, 4 or 5), j) nitro, k) optionally substituted phenyl C _1-6 alkyl, l) optionally substituted phenyl C _1-6 alkoxy, m) cyano or o) C _1-6 alkyl, each optionally substituted by an optionally phenyl substituted by one or more of the C _1-6 alkoxy group or halo A substituted C _2-4 alkenyl group or a C _2-4 alkynyl group.