MXPA04003954A - Benzimidazoles and analogues and their use as protein kinases inhibitors. - Google Patents

Benzimidazoles and analogues and their use as protein kinases inhibitors.

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Publication number
MXPA04003954A
MXPA04003954A MXPA04003954A MXPA04003954A MXPA04003954A MX PA04003954 A MXPA04003954 A MX PA04003954A MX PA04003954 A MXPA04003954 A MX PA04003954A MX PA04003954 A MXPA04003954 A MX PA04003954A MX PA04003954 A MXPA04003954 A MX PA04003954A
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Mexico
Prior art keywords
benzoimidazol
carboxylic acid
pyrazol
benzoimidazole
indazol
Prior art date
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MXPA04003954A
Other languages
Spanish (es)
Inventor
Cherry Michael
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Aventis Pharma Inc
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Publication date
Priority claimed from FR0113868A external-priority patent/FR2831537B1/en
Priority claimed from GB0206895A external-priority patent/GB0206895D0/en
Priority claimed from GB0206893A external-priority patent/GB0206893D0/en
Application filed by Aventis Pharma Inc filed Critical Aventis Pharma Inc
Publication of MXPA04003954A publication Critical patent/MXPA04003954A/en

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Abstract

The invention is directed to physiologically active compounds of the general formula (Ix) and compositions containing such compounds, and their prodrugs, and pharmaceutically acceptable salts and solvates of such compounds and their prodrugs, as well as to novel compounds within the scope of formula (Ix), and to processes for their preparation. Such compounds and compositions have valuable pharmaceutical properties, in particular the ability to inhibit kinases.

Description

BENCIMIDAZOLÉS This application is subject to the rights of the previously filed French application No. 0113868 filed on October 26, 2001, British application No. 0206893.0 filed on March 22, 2002, British application No. 0206895.5 filed on March 22, 2002 , US privisional application No. 60 / 395,060 filed July 1, 2002 and US provisional application. No. 60 / 395,151 filed July 11, 2002. This invention is directed to benzimidazoles of formula (Ix), their preparation, pharmaceutical compositions containing these compounds and their pharmaceutical use in the treatment of disease states capable of being modulated by inhibition of protein kinases. These protein kinases belong especially to the following group: EGFR, Fak, FLK-1, FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2, VEGFR, ITK and SYK. Protein kinases are a family of enzymes that participate in signaling events that control the activation, growth and differentiation of cells in response to extracellular mediators and changes in the environment. In general, these kinases fall into several groups; those which preferentially catalyze the phosphorylation of hydroxy groups of serine and / or threonine residues and those which preferentially catalyze the phosphorylation of hydroxy groups of tyrosine residues [S.K.Hanks and T.Hunter, FASEB. J., 1995, 9, pages 576-596]. These phosphorylations can modify conside- the function of proteins; therefore, protein kinases play an important role in the regulation of a wide variety of cellular procedures including, especially, metabolism, cell proliferation, cell differentiation or cell survival. Among the various cellular functions in which the activity of a protein kinase is involved, some procedures represent attractive targets for treating certain diseases. As an example, mention may be made especially of angiogenesis and cell cycle control, in which protein kinases may play an essential role. These procedures are essential for the growth of solid tumors and also for other diseases. Angiogenesis or the formation of new blood vessels by branching the previously existing vasculature is of crucial importance for embryonic development and organogenesis. In case it is necessary, the vascular system has the potential to generate a network of new vessels in order to maintain the proper functioning of tissues and organs. Angiogenesis is a complex multi-stage procedure that includes the activation, migration, proliferation and survival of endothelial cells. In adults, angiogenesis is quite limited, appearing only in repair procedures after a wound or vascularization of the endometrium. (Merenmies et al., Cell Growth &Differentiation, 8, 3-10, 1997). However, uncontrolled angiogenesis is found in certain pathologies such as retinopathy, psoriasis, rheumatoid arthritis of, diabetes, muscle degeneration or cancer (solid tumors) (Folkman, Natu-re Med., 1, 27-31, 1995). Protein kinases whose intervention has been possible to demonstrate in the angiogenesis procedure include three members of the family of growth factor receptor tyrosine kinases: VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR, receptor-like domain of insertion of kinases, or FLK-1), FGF-R (fibroblast growth factor receptor) and TEK (also known as Tie-2). In conjunction with other systems, vascular endothelial growth factor (VEGFRs) receptors transmit signals related to the migration, proliferation and survival of endothelial cells. The VEGFR family includes VEGFR-1 (Flt-1), VEGFR-2 (KDR) and VEGFR3 (Flt4). The VEGF-R2 receptor, which is expressed only in endothelial cells, binds to the angiogenic growth factor VEGF, and thus serves as a mediator of transduction signals through the activation of its intracellular kinase domain. Therefore, direct inhibition of the quinase activity of VEGF-R2 makes it possible to reduce the phenomenon of engiogenesis in the presence of exogenous VEGF (Strawn et al., Cancer Research, 56, 3540-3545, 1996), being demonstrated this procedure especially with the aid of VEGF-R2 mutants (Miliauer et al., Cancer Research, 56, 1615-1620, 1996). The VEGF-R2 receptor seems to have no other function in adults than that associated with the angiogenic activity of VEGF. Therefore, an Selective hybrid of VEGF-R2 kinase activity should show only low toxicity. In addition to its crucial role in the dynamic angiogenic process, recent studies suggest that VEGF expression contributes to the survival of tumor cells after chemotherapy and radiotherapy, accentuating the potential synergism of KDR inhibitors with other agents (Lee CG, Heijn M. et al., (2000), Cancer Research, 60 (19), 5565-70). The KDR inhibitors, therefore, are especially anti-angiogenic agents and these agents can be used as a first linear treatment against the appearance of new growth of malignant tumors. The inhibition or regulation of VEGFR-2 (KDR) therefore provides a new and powerful mechanism of action for the treatment of a large number of solid tumors. Extensive studies in the field of tumor angiogenesis in the last two decades have identified a number of therapeutic targets that include kinases, proteases and integrins that lead to the discovery of many new anti-angiogenic agents, including KDR inhibitors of which some they are currently under clinical evaluation (Je-kunen, et al Cancer Treatment Rev. 1997, 23, pages 263-286.). The present patent application thus relates in particular to new inhibitors of VEGFR-2 receptor (KDR) that can be used especially for the anti-angiogenic treatment in oncology.
Protein kinases that preferentially catalyze the phosphorylation of hydroxy groups of serine and / or threonine residues include, for example, protein kinase C isoforms [A.C. Newton, J. Biol. Chem., 1995, 270, pages 28495-28498] and a group of cyclin-dependent kinases such as cdk2 [J.Pines, Trends in Biochemical Sciences, 1995, 18, pages 195-197]. Protein kinases that preferentially catalyze the phosphorylation of hydroxy groups of serine and / or threonine residues include membrane extension growth factor receptors as epidermal growth factor receptor [S. lwashita and M. Kobayashi, Cellular Signaling, 1992, 4, pages 123-132], and cytosolic non-receptor kinases such as p56lck, p59fYn, ZAP-70 and csk kinases [C.Chan et. ai., Ann. Rev. Immunol., 1994, 12, pages 555-592]. Improperly elevated protein kinase activity has been implicated in many diseases resulting from abnormal cell function. This can arise directly or indirectly, for example, by a failure of the proper mechanisms of control for the kinase, related for example with mutation, overexpression or inappropriate activation of the enzyme; or by over- or under-production of cytokines or growth factors that also participate in signal transduction upstream or downstream of the kinase. In all these cases, the selective inhibition of the action of the kinase can be expected to have an advantageous effect. SYK (spleen tyrosine kinase) is a 72 kDa cytoplasmic protein tyrosine kinase that is expressed in a variety of cells. hematopoietic and is an essential element in various cascades that attach antigen receptors to cellular responses. Therefore, SYK plays a pivotal role in the signaling of the high affinity IgE receptor, FcsR1, in mast cells and in the signaling of receptor antigens in T and B lymphocytes. The signal transduction pathways present in mast cells, T and B have common characteristics. The ligand binding domain of the receptor lacks intrinsic tyrosine kinase activity. However, they can interact with transducing subunits containing tyrosine-based immunoreceptor activation motifs (ITAMs) [M. Ret, Nature, 1989, 338, pages 383-384J. These motifs are present in the subunits both ß and? of the FcsR1, in the subunits? of the T cell receptor (TCR) and in the IgGoc and IgG subunits of the B cell receptor (BCR). [N.S.van Oers and A.Weiss, Seminars in Immunology, 1995, 7, pages 227-236]. After antigen binding and multimerization, the ITA residues are phosphorylated by protein tyrosine kinases of the Src family. SYK belongs to a unique class of tyrosine kinases that have two domains of Src tandem homology 2 (SH2) and a C terminal catalytic domain. These SH2 domains bind with high affinity to ITAMs and this association. SH2 mediated by SYK with an activated receptor stimulates SYK kinase activity and localizes SYK to the plasma membrane. In mice with SYK deficiency, degranulation of mast cells is inhibited, suggesting that this is an important target for the development of mast cell stabilizing agents [P.S.CostelIo, Oncoge- Ne, 1996, 13, pages 2595-2605]. Similar studies have demonstrated a critical function for SYK in BCR and TCR signaling [AMCheng, Natu-re, 1995, 378, pages 303-306, (1995) and DHChu et al., Immunological Re-views, 1998, 165, pages 167-180]. SYK also seems to be involved in the survival of eosinophils in response to IL-5 and GM-CSF [S. Yousefi et al., J. Exp. Med., 1996, 183, pages 1407-1414]. Despite the key function of SYK in the signaling of mast cells, BCR and T cells, little is known about the mechanism by which SYK transmits downstream effectors. Two adapter proteins, BLNK (B cell connecting protein, SLP-65) and SLP-76 have been shown to be substrates for SYK in B cells and mast cells respectively, and it has been proposed that they establish an interfacial relationship of SYK with downstream effectors [M.lshiai et al., Immunity, 1999, 10, pages 17-125 and LRHendricks-Tailor et al., J. Biol. Chem, 1997, 272, pages 1363-1367]. In addition, SYK appears to play an important role in the CD40 signaling pathway, which plays an important role in the proliferation of B cells [M.Faris et al., J.Exp. Med., 1994, 179, pages 1923-1931]. SYK is additionally involved in the activation of platelets stimulated through the low affinity IgG receptor (Fe gamma-RIIA) or stimulated by collagen [F.Yanaga et al., Biochem. J., 1995, 311, (Pt. 2) pages 471-478]. ITK is a T-cell specific tyrosine kinase of the Tec family that is referred to normal Th2 function. Asthma is a disease characterized by an increased production of Th2 cytokines including IL-4. An inhibitor of ITK, therefore, would have an impact on the progress of the disease in asthma through the inhibition of Th2 cytokine production. A new group of benzimidazoles has been found, which have advantageous pharmaceutical properties, in particular, the ability to inhibit protein kinases, more particularly, the ability to inhibit SYK protein kinase, KDR protein kinase, protein kinase tie2 or protein kinase. ITK Therefore, in one aspect, the present invention is directed to pharmaceutical compositions comprising compounds of general formula (Ix): in which, for the purposes of (Ix): X represents C-R2 and W, Y and Z, which may be the same or different, represent CH or CR3 or W represents CH, X represents N, Y represents CH or CR ^, and Z represents CH or CR ^; or W represents N, X represents CH or CR2, Y represents CH and CR3, and Z represents CH or CR3; or W represents N, X represents CH or CR2, Y represents N, and Z is CH or CR3; or W represents N, X represents CH or CR2, Y represents CH or CR3, and Z represents N; or W represents N, X represents N, Y represents CH or CR3, and Z represents CH or CR3; A5 represents H or alkyl; R1 represents aryl or heteroaryl, each optionally substituted with one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -0 (= 0) ???? , -C (= 0) OR4, -N (R6) C (= 0) R4 -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4 -N (R6) S02R4, -N (R6) S02NY1Y2, - ???? , -OR4 -OCF2H, -OCF3, -OC (= 0) R4, - 0C (= 0) NY1 Y2, -OS (0) nR4, -S (0) nR4 -S (0) nNYlY2 and -S (0) ) nOR4; R2 and R3 are such that: R2 and R3, which may be the same or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4 -C (= 0) NY Y2 , -C (= 0) OR4, - ???? 2, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1 Y2, -N (R6) C (= 0) OR4 -N (R6) S02R4, -N (R6) S02NY1Y2, -OR4, -OCF2H, -OCF3, -OC (= 0) R4, -OC (= 0) NY1 Y2, -S (0) nR4, -S (0) nNYl Y2 or -S (0) nOR4; or R2 represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -C (= 0) NY Y2, -C (= 0) OR4, -NY1Y2 -N (R6) C (= 0) R4,. N (R6) C (= 0) NY1Y2j -N (R6) C (= 0) 0R4, -N (R6) S02R4, -N (R6) S02NY Y2, - OR4, -OCF2H, -OCF3, -OC (= 0) R4, _0C (= 0) NY1 Y2, -S (0) nR4, -S (0) nNYlY2 or -S (0) nOR4 and R3 represents alkyl, haloalkyl, halogen and OR6; or groups R2 and R3 in adjacent carbon atoms can form a ring based on 5 to 6 member carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, and which may be optionally being substituted with alkyl [examples include those in which R2 and R3 form a group selected from -0-CH2-0-, -0-CH2-CH2-0-; -CH2-0-CH2-, -CH2-N (R14) -CH2-, '-CH2-CH2-CH2-, -CH2-C (CH3) 2-CH2-! -CH2-0-CH2-CH2-, -CH2-N (R14) -CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C (CH3) 2 -CH2-CH2-, -CH = CH-CH = CH-, -N = CH-CH = CH-, -CH = N-CH = CH-, -CH = CH-N = CH- or - CH = CH-CH = N, in which R 14 is H or alkyl]; R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more sustituyeles selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -0 (= 0)? ? 3? 4, -C (= b) OR6, - N (R6) C (= 0) NY1Y2 - ???? 2. -C-R5 O alkyl substituted with -NY3Y4; R5 is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R6 is chosen from the values of R5; n is zero or an integer 1 or 2; Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocicloafquilalquilo or alkyl optionally substituted with one or more selected entr cyano, aryl, heteroaryl, hydroxy, -C (= 0) OR6 groups, -0 (=? )??3? -??3? or _QR5 0 e | group - ??? 2 can form a cyclic amine; Y3 and Y4 are independently hydrogen, alkynyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY3Y4 can form a cyclic amine; all alkyl radicals (or alk, representing alkyl), -alk-nile, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl present in the above radicals are optionally further substituted with one or more radicals chosen from halogen atoms and hydroxyl radicals , cyano, alkyl, alkoxy, acylamino (NH-COalk), -C ^ OJOR ^, -C (= 0) R6, hydroxyalkyl, carboxyalkyl, S (0) n-alk, S (0) N-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, NO2, aryl, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3Y4 and ?? 3? 4 , these latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free carboxylic radicals, salified or esterified radicals and acrylamino NH-C (0) R5 radicals; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of these compounds and their N-oxides and their prodrugs, and their acid bioisoesters; together with one or more pharmaceutically acceptable carriers or excipients. In another aspect, the invention relates to compounds of formula (Ix) as defined above wherein R 1 is a pyrozalyl moiety wherein R7 is hydrogen or alkyl, and R8 and R9 are selected independently between hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4, -C (= 0) R 4 -C (= 0) NY 1 Y 2 -C (= 0) OR 4 -N (R 6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N (R6) S02NY1Y2, - ???? 2, -OR4, -OC (= 0) R4, -OC (= 0) NY1 Y2 -S (0) NR4 V -S (0) 2NY Y2; or R8 and R9 together with the carbon atoms to which they are attached form (i) a 5- to 8-membered carbocyclic ring optionally substituted with one or more carbocyclic ring substituents; (ii) a phenyl ring optionally substituted with one or more substituents of aryl groups; (iii) a 5- or 6-membered heteroaromatic ring in which one or more members of! ring is / are nitro-gen, oxygen or sulfur (examples of these groups include furyl groups, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pirazoli-lo piridiio, pyrimidinyl, pyrrolyl, 1, 3,4-thiadiazolyl, thiazolyl, thienyl and triazolyl) and which are optionally substituted with one or more groups selected from haloalkyl, hydroxy, halo, cyano, nitro, R4 -0 (= 0) ???? 2, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) S02R4, -NY Y2 and -OR5; or (iv) a 5- or 6-membered heterocyclic ring optionally substituted with alkyl or oxo, and containing a group containing heteroatoms selected from O, S, S02 or NY5 (wherein Y5 is hydrogen, f¾4 -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) OR4 or -SO2 4); but excluding the compounds: 2- (2H-pyrazol-3-yl) -1-hibenzoimidazole; 2- (5-methyl-2H-pyrazol-3-yl) -1 H -benzoimidazole; 5-methyl-6- [2- (2H-pyrazol-3-yl) -3H-benzoimidazol-5-yl] -4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6- [2- (2H-pyrazol-3-yl) -1 H -benzoimidazol-4-yl] -4,5-dihydro-2H-pyridazin-3-one; 3,5-bis (benzimidazol-2-yl) -1 H-pyrazole; 5,6-dimethyl-2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-methyl-2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dichloro-2- (5-methyl-1H-pyrazol-3-yl) -1H-benzoimidazole; 5-nitro-2- (5-methyl-1H-pyrazol-3-yl) -1H-benzoimidazole; 2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (5-phenyl-1H-pyrazol-3-yl) -1H-benzoimidazole; 5,6-dimethyl-2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5-methyl-2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-chloro-2- (5-methyl-1 H -pyrazol-3-yl) -1H-benzoimidazole; 5-chloro-2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dichloro-2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; N- [2- (5-isoquinolin-4-yl-1 H -indazol-3-yl) -3H-benzoimidazol-5-yl] -methanesulfonamide; 3- (1H-benzoimidazol-2-yl) -5- (1 H-indazol-4-yl) -1 H-indazole, 3- [3- (1 H -benzoimidazol-2-yl) -1 H-indazole -5- il] -2-methoxyphenol; 4- [3- (1 H-b6nzoimidazol-2-yl) -1 H -indazol-5-yl] isoquinoline; 4-. { 3- [6- (4-Methy! -piperazin-1 H-benzoimidazoi-2-yl] -1 H -indazol-5-yl} -isoquinoline; 4- [3- (4-chloro-1 H- benzoimidazol-2-yl) -1 H -indazol-5-yl] -isoquinoline; 4- [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenol; 3- [5- (4-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -1 H-indazole; 3- [5- (4-methoxy-phenyl) -1 H -benzoimidazol-2-ii] -1 H-indazoI; 3- [5- (3-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -1 H-indazole; 3- (1 H-benzoimidazol-2-yl) -5-phenyl-1 H-indazole; 2- (4-bromo-1-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (5-ierc-butyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 3- (1 H-benzoimidazol-2-yl) -6- (3-methoxy-phenyl) -1 H -indazole; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid; 5- methyl acid ester. { [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -amino} -2-hydroxy-benzoic; acid methyl ester 5- . { [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl!] - amino} -furan-2-carboxylic; 3- (1H-benzoimidazole-2-H-indazole-6-carboxylic acid (3-hydroxy-4-methoxy-phenyl) -amide; (5-hydroxy-1H-pyrazol-3-yl) -amide of acid 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (1H-pyrazol-3-yl) -amide 3- (1 H-benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid; [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] - [4- (2-hydroxy-ethyl) -piperidin-1-yl] -methanone; 3- (1 H -benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (9H-purin-6-yl) -amide; dimethylamide of 3- (1 H -benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid; [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-yl] -morpholin-4-yl-methanone; 3- (1H-benzoimidazol-2-yl) -1 H-indazoy-6-carboxylic acid pyrazin-2-ylamide; 3- (1 H-benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid cyclohexylamide; (1 H-indazol-5-yl) -amide of 3- (1 H -benzoimidazoI-2-yl) -1 H -indazole-6-carboxylic acid; [3- (1 H- benzoimidazol-2-yl) -1 H -indazol-6-yl] -pyrrolidin-1-yl-methanone; (1 H-indazol-5-yl) -amide of 3- (1 H -benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid; [3- (1 H -benzoimidazoi-2-yl) -1 H -indazol-6-yl] - [4- (furan-2-carbonyl) -piperazin-1-yl] -methanone; [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] - (4-methyl-piperazin-1-yl) -methanone; 1-. { 4- [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -piperazin-1-yl} -etanone; 3- (1 H -benzoimidazoi-2-yl) -1 H -indazole-6-carboxylic acid (6-methoxy-pyridin-3-yl) -amide; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (3-hydroxy-phenyl) -amide; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid pyridin-4-ylamide; 3- (1 H -benzoimidazol-2-yl) -H-indazole-6-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid (2-hydroxy-etiI) -methyl-amide; 3- ethyl ester. { [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -amino} -butyric; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (3-hydroxy-propyl) -amide.; 3- (1H-benzoimidazol-2-yl) -1H-indazoI-6-carboxylic acid phenylamide; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid pyridin-3-ylamide; 3- (6-Methoxy-1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1 H-benzoimidazol-2-yl) -6-pyridin-4-yl-1H-indazole; 3- (5-Chloro-1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-Dimethoxy-1 H-benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (4-hydroxy-pheny1) -amide; 3- (5-Fluoro-1 H -benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (6-Trifluoromethyl-1 H-benzoimidazole-2-ii) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; (4-hydroxy-phenyl) -amide of acid 3- (6-Ierc-butyl-1 H-benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid; 3- (6,7-Dimethyl-1 H-benzoimidazol-2-yl) -1H-indazoy-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-Dichloro-1H-benzoimidazol-2-yl) -1H-indazoI-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-difluoro-1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-idroxy-phenyl) -amide; (3-fluoro-4-hydroxy-fenii) -amide 3- (1H-benzo¡midazol-2-yl) -1 H-indazoi-6-carboxílico¡ amide 3- (1 H-benzoimidazol-2 acid -l) -1 H-indazole-6-carboxylic acid; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (4-hydroxy-2,3-dimethyl-phenyl) -amide; 3- (1 H -benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-2-methyl-phenyl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H-indazoy-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid cyclopropylamide; 2- [6- (4-hydroxy-2-methoxy-phenyl) -1H-indazol-3-ii] -3H-benzoimidazole-5-sulfonic acid amide; 4- [3- (6-dimethylamino-1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -3-methoxy-phenol; 2- [6- (4-hydroxy-2-methoxy-phenyl) -1 H -indazol-3-yl] -3H-benzoimidazole-5-carboxylic acid methylamide; 3-methoxy-4-. { 3- [6- (4-metii-piperazin-1 -yl) -1 H -benzoimidazol-2-yl] -1 H -indazol-6-yl} -phenol; 2- [6- (4-Hydroxy-2-methoxy-phenyl) -1 H -indazoI-3-yl] -3H-benzo.imidazole- (2-morpholin-4-yl-ethyl) -amide. 5-carboxylic; 4- [3- (1 H -imidazo [4,5-c] pyridin-2-yl) -1 H -indazol-6-yl] -3-methoxy-phenol; 3- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -2-methoxy-phenol; 3- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -phenol; 4- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -3,5-d-methyl-phene !; 4- [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-yl] -3-phenoxy-phenol; 4- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -benzene-1,3-diol; 4- [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-yl] -3-methoxy- phenol; 4- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -2-methoxy-phenol; N-. { 3- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -phenyl} -benzamide; 6- [2- (1, 5-dimethyl-1 H -pyrazol-3-yl) -3H-benzoimidazol-5-yl] -5-methyW ^ 5-metii-6- [2- (1-methyl-1 H-pyrazol-3-yl) -3H-benzoimidazol-5-yl] -4,5-dihydro-2H pyridazin-3-one; 8- (1, 5-dimethyl-1 H -pyrazol-3-yl) -7H-purine; 2- (1, 5-dimethyl-1 H -pyrazol-3-yl) -1 H -imidazo [4,5-b] pyridine and 2- (5-methyl-1 H -pyrazol-3-yl) -1 H- imidazo [4,5-b] pyridine. In the present specification, the term "compounds of the invention", and equivalent expressions, are meant to embrace compounds of general formula (Ix) as defined above, which expression includes the prodrugs, the pharmaceutically acceptable salts and solvates , for example hydrates, when the context allows it. Analogously, the reference to intermediates, whether or not they are claimed in themselves, is intended to cover their salts and solvates, when the context permits. For reasons of clarity, particular cases are sometimes indicated in the text when the context permits, but these cases are purely illustrative and are not expected to exclude other cases when the allow it. As used above for the compounds of formula - (Ix) and throughout the entire description of the invention in the following, the following terms and expressions, unless otherwise indicated, are to be understood as having the following meanings: "Patient" includes both humans and other mammals.
"Bioisoéster acid" means a group which has chemical and physical similarities producing broadly similar biological properties to a carboxy group (see Lipinski, Annual Reports in Medicinal Chemis-try, 1986.21, P283"Bioisosterism In Drug Design"; Yun, Hwahak Sekye, 1993, 33, pages 576-579"Application Of Bioisosterism To New Drug Design"; Zhao, Huaxue Tongbao, 1995, pages 34-38"Bioisosteric Replacement and De-velopment Of Lead Compounds In Drug Design"; Graham, Theochem , 1995, 343, pages 105-109"Theoretical Studies Applied To Drug Desigmab initio Electronic Distributions In Bioisosteres"). Examples of bioisoesters of suitable acids include: -C (= 0) -NHOH, -C (= 0) -CH2OH, -C (= 0) -CH2SH, -C (= 0) -NH-CN, sulfo, phosphono, alkylsulfonylcarbamoyl, tetrazolyl, arylsulfonyl-carbamoyl, heteroarylsulfonylcarbamoyl, N-methoxycarbamoyl, 3- hydroxy-3-cyclobutene-1,2-dione, 3,5-dioxo-1, 2,4-oxadiazolidinyl or heterocyclic phenols such as 3-hydroxyisoxazolyl and 3-hydoxy-1-methylpyrazolyl. "Acyl" denotes a radical R-C (= 0) - wherein R represents a radical selected from a hydrogen atom, linear or branched alkyl radicals containing not more than 6 carbon atoms; optionally substituted amino; aryl, hete'roaryl, cycloalkyl or heterocycloalkyl radicals, for example phenyl or pyrroidinyl radicals: the term "acyl" therefore especially indicates, for example, formyl radicals and acetyl, propionium, butanoyl, pentaoyl, hexanoyl, benzoyl and pyrrolidinylcarbonyl radicals.
"Acylamino" indicates the radicals -C (= 0) -NH2, -C (0) -NH (alk) and -C (0) -N (alk) (alk): in these radicals, NH (alk) and N (alk) (alk) have the meanings that are defined later. "Alkenyl" means an aliphatic group that contains a carbon-carbon double bond and can be linear! or branched and has about 2 to about 15 carbon atoms in the chain and containing one or more double bonds. Preferred alkenyl groups have 2 to about 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (eg, 2 to 4 carbon atoms) in the chain. "Branched", as used herein and throughout the text, means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a straight chain; in this case a linear alkenyl chain. "Lower alkenyl" means about 2 to about 4 carbon atoms in the chain, which may be linear or branched. Examples of alkenyl groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, cyclohexylbutenyl, decenyl, and 3,7-dimethyl-octa-2, 6-dienyl. "Alkoxy" means an alkyl-O- group in which the alkyl group is as described herein described. Examples of alkoxy groups include difluoromethoxy, methoxy, trifluoromethoxy, ethoxy, n-propoxy, i- 'propoxy, n-butoxy, s-butoxy, t-butoxy, pentoxy, hexoxy and heptoxy, and also their linear or branched positional isomers.
"Alkoxycarbonyl" means an alkyl-O-CO- group in which the alkyl group is as described herein. Examples of alkoxycarbonyl groups include methoxy- and ethoxycarbonyl. "Alkyl" means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain and has about 1 to about 15 carbon atoms in the chain, optionally substituted with one or more halogen atoms. Particular alkyl groups have from 1 to about 6 carbon atoms. "Lower alkyl" as a group or a part of a lower akoxy group, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl means, unless otherwise specified, an aliphatic hydrocarbon group which may be straight or branched chain and has 1 to about 4 carbon atoms in the chain. Examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, 3-pentyl, hexyl, isohexyloyl, heptyl, octyl, nonyl, decyl and dodecyl, and also their linear or branched positional isomers. Examples of alkyl groups substituted with one or more halogen atoms include trifluoromethyl, difluoromethyl, trifluoroethyl and difluoroethyl. "Alkylene" means an aliphatic bivalent radical derived from a linear or branched alkyl group, wherein the alkyl group is as described herein. Examples of alkylene radicals include methylene, ethylene and trimethylene.
"Alkylenedioxy" means an O-alkylene-O- group in which alkylen is as defined above. Examples of alkylenedioxy groups include, methylenedioxy and ethylenedioxy. "Alkylsulfinyl" means an alkyl-SO- group in which the alkyl group is as previously described. Preferred alkylsulfinyl groups are those in which the alkyl group is Ci_4 alkyl. "Alkylsulfonyl" means an alkyl-S02- group in which the alkyl group is as previously described. Preferred alkylsulfonyl groups are those in which the alkyl group is Ci-4 alkyl. "Alkylsulfonylcarbamoyl" means an alkyl-S02-NH-C (= 0) - group in which the alkyl group is as previously described. Preferred alkylsulfonylcarbamoyl groups are those in which the alkyl group is C 1 - alkyl. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Examples of alkylthio groups include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentyl thio, isopentylthio, hexylthio, isohexylthio and heptylthyl, and also their linear or branched positional isomers. Preferred alkylthio groups have not more than 4 carbon atoms. "Alkynyl" means an aliphatic hydrocarbon group containing a triple carbon-carbon bond, which group can be straight or branched chain and has about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have 2 to approximately you 12 carbon atoms in the chain; and more preferably 2 to about 6 carbon atoms (eg, 2 to 4 carbon atoms) in the chain. Examples of alkynyl groups include ethynyl, propynyl, n-butynyl, i-butynyl, 3-methylbut-2-ynyl, and n-pentynyl. "Aroyl" means an aryl-CO- group in which the aryl group is as described herein. Examples of aroyl groups include benzoyl and 1- and 2-naphthoyl. "Aroylamino" is an aroyl-NH- group in which aroyl is as previously defined. "Aryl" as a group or part of a group indicates: (i) an optionally substituted monocyclic or multicyclic aromatic carbocyclic moiety of from about 6 to about 14 carbon atoms, such as phenyl or naphthyl; or (ii) a partially saturated multicyclic aromatic carbocyclic moiety, and opcionamlente substituted in which an aromatic carbocyclic moiety monocí-colic and a cycloalkyl or cycloalkenyl group are jointly condensed-two to form a cyclic structure, as a stetrahidronaftilo ring inde-nile or indanilo. Except where otherwise defined, aryl groups may be substituted with one or more aryl group substituents which may be the same or different, where "aryl group substituent" includes, for exam-cheep, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulphinyl, al-quilsulfonilo, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arilalquiloxicarboni-lo, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an bioisoéster acid), cyano, cycloalkyl, halo , heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, -C (= 0) NY1 Y2, -NY -C (= 0) alqu¡lo, -NY1S02alquilo, - -NY Y2, -S02NY1Y2 O alkyl, or aiquenilo alkynyl, each optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C (= 0) OR6, -C (= 0) NY1 Y2 -NY1 Y2 or -OR5. "Arylalkyl" means an aryl-alkyl group in which the aryl and alkyl moieties are as previously described. Preferred arylalkyl groups contain a C 1-4 alkyl moiety. Examples of arylalkyl groups include benzyl, 2-phenethyl and naphthienomethyl. "Arylalkyloxy" means an arylalkyl-O-group in which the arylalkyl group is as previously described. Examples of arylalkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. "Arylalkyloxycarbonyl" means an arylalkyl-O-CO- group in which the arylalkyl group is as previously described. An example of an arylalkyloxycarbonyl group is benzyloxycarbonyl. "Arylalkylthio" means an arylalkyl-S- group in which the arylalkyl group is as previously described. An example of an arylakylthio group is benzylthio. "Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Examples of aryloxy groups include phenoxy and naphthoxy, each optionally substituted.
"Aryloxycarbonyl" means an aryl-0-C (= 0) - group in which the aryl group is as previously described. Examples of aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. "Arylsulfinyl" means an aryl-SO- group in which the aryl group is as previously described. "Arylsulfonyl" means an aryl-S02- group in which the aryl group is as previously described. "Arylsulfonylcarbamoyl" means an aryl-S02-NH-C- (= 0) - group in which the aryl group is as previously described. "Arylthio" means an aryl-S- group in which the aryl group is as previously described. Examples of arylthio groups include phenylthio and naphthylthio. "Carbocyclic" means a saturated ring system comprising carbon atoms. "Carbocyclic group substituent" includes, for example, acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid-tert bioisoés), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarilalqui-Loxi, heteroaroylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, -C (= 0) NY1Y2, -NY1-C (= 0) alky, -NY1 S02alkyl, -NY1Y2, - SC ^ NY ^ Y2 or alkyl, alkenyl or alkynyl, each optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C (= 0) OR6, -C (= 0) NY1Y2, -NY1Y2 or -OR5.
"Cyclic amine" means a 3- to 8-membered monocyclic carbocyclic ring system in which one of the ring carbon atoms is substituted with nitrogen and which (i) may also contain an additional group containing heteroatoms selected from O, S, S02 or NY6 (where Y6 is hydrogen, alkyl, aryl, arylalkyl, -C (= 0) R5, -C (= 0) OR5, -0 (= 0) ???? 2 0 -SC ^ R ^); and (i) may be fused to additional aryl rings (eg, phenyl), heteroaryl (eg, pyridyl), heterocycloalkyl or cycloalkyl to form a bicyclic or tricyclic ring system. Examples of cyclic amines include pyrrolidine, piperidine, morpholine, piperazine, indoline, pyrindoline, tetrahydroquinoline and the like groups. "Cycloalkenyl" means a non-aromatic monocyclic or multicyclic ring system containing at least one carbon-carbon double bond and having about 3 to about 10 carbon atoms. Examples of monocyclic cycloalkenyl rings include cyclo-pentenyl, cyclohexenyl and cycloheptenyl. "Cycloalkyl" means a saturated monocyclic or bicyclic ring system of about 3 to about 10 carbon atoms, optionally substituted with oxo. Examples of monocyclic cycloalkyl rings include C3-8 cycloalkyl rings such as cyclopropyl, cyclopentyl, cyclohexyloyl and cydoheptyl. "Cycloalkylalkyl" means a cycloalkyl-alkyl group in which the cycloalkyl and alkyl moieties are as previously described. Examples of monocyclic cycloalkyl groups include cyclopropylmethyl, diclope- Tylmethyl, cyclohexylmethyl and cycloheptylmethyl. "Halo" or "halogen" means fluorine, chlorine, bromine or iodine. Fluorine, bromine and chlorine are preferred. "Haloalkyl" means an alkyl group having about 1 to about 6 carbon atoms in the chain and substituted with one or more halo atoms. Examples of haloalkyl groups include tri-fluoromethyl. "Heteroaroyl" means a heteroaryl-C (= 0) - group in which the heteroaryl group is as described herein. Examples of heteroaryl groups include pyridylcarbonyl. "Heteroaroylamino" means a heteroaroyl-NH- group in which the heteroaryl moiety is as previously described. "Heteroaryl" as a group or part of a group indicates: (i) an aromatic and optionally substituted monocyclic or multicyclic organic moiety, of about 5 to about 10 members in the ring, wherein one or more of the ring members is / are different carbon element (s), for example, nitrogen, oxygen or sulfur (examples of these groups include benzoimidazolyl, benzothiazolyl, furyl, imidazolyl, indazoyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl groups , oxadiazolyl, pi-razinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quino-iinyl, 1,4-thiadiazolyl, thiazolyl, thienyl and triazolyl, optionally substituted with one or more substituents of aryl groups as defined previously except when defining something else); (ii) a heterocyclic, multicyclic, partially saturated and optionally substituted moiety in which a moiety monocyclic heteroaromatics and a cycloalkyl, cycloalkenyl or heterocycloalkyl group are fused together to form a cyclic structure (examples of these groups include tetrahydro-indazole, tetrahydro-pyrazolopyridine, 5-oxo-1, 4,5,6,7,8, 9,9a-octahydro-1, 2,4,5a-tetraza-cydopenta [a] naphthyl, optionally substituted with one or more "substituents of aryl groups" as defined above, except where otherwise defined). Optional substituents include one or more "substituents of aryl groups" as defined above, except where otherwise defined. When R1 is heteroarylThis may particularly represent pyre-zolilo, triazolyl, isoxazolyl, isothiazolyl, thiazolyl, oxazolyl, imidazolyl, pyrrolyl, furanyl, thiophenyl, phenyl, pyridinyl, oxodihydropyridinyl, pyrimidinyl, indolyl, indazolyl, tienopirazolilo, tetrahydroindazolyl, tetrahidrociclopentapirazolilo, dihidrofuropirazolilo, oxodihidropiridazinilo, tetrahidropirrolopirazolilo , oxotetrahydropyrrolopyrazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazophyl, or oxodihydropyridinopyrazolyl. "Heteroarylalkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl moieties are as previously described. Preferred heteroarylalkyl groups contain a d-4 alkyl moiety. Examples of heteroarylalkyl groups include pyridylmethyl. "Heteroarylalkyloxy" means a hetaroarylalkyl-O- group in which the heteroarylalkyl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridylmethoxy.
"Heteroaryloxy" means a heteroaryl-O- group in which the heteroaryl group is as previously described. Examples of heteroaryloxy groups include optionally substituted pyridyloxy. "Heteroarylsulfonylcarbamoyl" means a heteroaryl-S02-NH-C (= 0) - group in which the heteroaryl group is as previously described. "Heterocycloalkyl" means: (i) a cycloalkyl group of about 3 to 10 members in the ring containing 1 or more heteroatoms or heteroatom-containing groups selected from O, S and NY6 and may be optionally substituted with oxo (examples of these groups include hexahydropyran, pyrrolidinyl, piperidinyl, tetrahydropyranyl and octahydro-pyrido [1,2-c] pyrimidin-1-one); (ii) a partially saturated heterocyclic cyclic moiety in which an aryl ring (or heteroaryl), each optionally substituted with one or more "aryl group substituents", and a heterocycloalkyl group are co-condensed to form a cyclic structure (examples of these groups include the chromanyl, dihydro-benzofuranyl, idolinyl and pirindolinyl groups). "Heterocycloalkylalkyl" means a heterocycloalkyl-alkyl group in which the heterocycloalkyl and alkyl moieties are as previously described. "Hydroxyalkyl" means an alkyl group substituted with one or more hydroxy groups. "NH (alk)" and "M (alk) (alk)" denotes an amino radical substituted, respectively, with one or two alkyl radicals, and these alkyl radicals are linear or branched and chosen from alkyl radicals as defined above, preferably containing not more than 4 carbon atoms. "Prodrug" means a compound that is convertible in vivo by metabolic means (eg, by hydrolysis) to a compound of formula (Ix) that includes its N-oxides. For example, an ester of a compound of formula (Ix) containing a hydroxy group can be converted by hydrolysis in vivo into the parent molecule. Alternatively, an ester of a compound of formula (Ix) containing a carboxy group can be converted by hydrolysis in vivo into the parent molecule. Suitable esters of the compounds of formula (Ix) containing a hydroxy group are, for example, acetates, citrates, lactates, tartrates, malonates, oxalates, salicylates, propionates, succinates, fumarates, maleates, methylene bis. - -hydroxynaphthoates, gentisatos, isethionates, di-p-toluoyltartrates, methanesulfonates, ethanesulfonates, benzenesulphonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. Suitable esters of the compounds of formula (Ix) containing a carboxy group are, for example, those described by F.J. Leinweber, Drug Metab. Res., 1987, 18, page 379. An especially useful class of compounds of formula (Ix) containing a hydroxy group can be formed from acid moieties selected from those described by Bundgaard et. al., J. Med. Chem., 989, 32, pages 2503-2507, and include substituted (aminomethyl) -benzoates, for example. pio dialkylamino-methylbenzoates in which the two alkyl groups can be joined together and / or interrupted by an oxygen atom or by an optionally substituted nitrogen atom, for example, an alkylated nitrogen atom, more especially (morpholino-methyl) benzoates , for example, 3- or 4- (morpholinomethyl) -benzoates, and (4-alkylpiperazin-1-yl) -benzoates, eg 3- or 4- (4-alkylpiperazin-1-yl) benzoates. When the compound of the invention of formula (Ix) contains a carboxy group, or a sufficiently acidic bioisoester, salts can be formed by addition of bases and are simply a more convenient form to be used; in practice, the use of the salt form inherently assumes the use of the free acid form. The bases which can be used to prepare the salts by addition of bases preferably include those which produce, when combined with the free acid, pharmaceutically acceptable salts., that is, salts whose cations are non-toxic to the patient in the pharmaceutical doses of the salts, so that the advantageous inhibitory effects inherent to the free base are not vitiated by side effects attributable to the cations. Pharmaceutically acceptable salts, including those derived from alkali metal and alkaline earth metal salts, within the scope of the invention, include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide , aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine, arginine, ornithine, choline,?,? '- dibenzylethylene diamine, chloroprocaine, diethanolamine, procaine, N- benzylphenethylamine, diethylamine, piperazine, tris (hydroxyethyl) am'inomethane, tetramethylammonium hydroxide and the like. Some of the compounds of the present invention of formula (Ix) are basic, and these compounds are useful in the form of the free base or in the form of a salt by the addition of pharmaceutically acceptable acids thereof. Acid addition salts are a more convenient way to be used and, in practice, the use of the salt form inherently involves the use of the free base form. Acids which can be used to prepare the acid addition salts preferably include those which, when combined with the free base, produce pharmaceutically acceptable salts, ie salts whose anions are non-toxic to the patient at the pharmaceutical doses of the salts, so that the advantageous inhibitory effects inherent to the free base are not vitiated by side effects attributable to the anions. Although pharmaceutically acceptable salts of said basic compounds are preferred, all acid addition salts are useful as a source of the free base even if the particular salt by itself is desired only as an intermediate product as, for example, when the salt it is formed only for purification and identification purposes, or when it is used as an intermediate in the preparation of a pharmaceutically acceptable salt by ion exchange processes. Pharmaceutically acceptable salts within the scope of the invention include those derived from mineral acids and organic acids, and include hydrohalides, for example, hydrochlorides and hydrobromides, sulphates, phosphates, nitrates, sulphamates, acetates, citrates, lactates, tartrates, malonates, oxalates, salates, propionates, succinates, fumarates, maleates, methylene-bis-b-hydroxynaphthates, gentisatos, isethionates , di-p-toluiltartratos, methano-sulfonates, ethanesuiponates, benzenesulfonates, p-toluenesulfonates, cyclohexyl sulfamates and kinatos. In addition to being useful in themselves as active compounds, the salts of the compounds of the invention of compounds of formula (Ix) are useful for the purification purposes of the compounds, for example, by exploiting differences in solubility between the salts and the parent compounds, by-products and / or starting materials by techniques well known to those skilled in the art. It will be appreciated that the compounds of the present invention of formula (Ix) may contain asymmetric centers. These asymmetric centers may be independently in any of the R or S configurations. It will be apparent to those skilled in the art that certain compounds of the invention may also exhibit geometric isomerism. It is to be understood that the present invention includes the individual geometric isomers and stereoisomers and mixtures thereof, including racemic mixtures, of the above-mentioned compounds of formula (Ix). These isomers can be separated from their mixtures, by the apption or adaptation of known methods, for example, chromatographic techniques and recrystallization techniques, or are prepared separately from the appropriate isomers of their intermediate Additionally, tautomers of the compounds of formula (ix) are possible, and the present invention is intended to include all forms tautomers of the compounds. An object of the present invention is therefore the compounds of formula (I): A5 in which: X represents C-R2 and V, Y and Z, which may be the same or different, represent CH or CR3; R represents aryl or heteroaryl chosen from the radicals pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, tienopirazolilo, tetrahidroin-dazolilo, tetrahidrociclopentapirazolilo, dihidrofuropirazolilo, oxodihidropiridazi-nile tetrahidropirrolopirazolilo, oxotetrahidropirrolopirazolilo, tetrahidropiranopi-razolilo, tetrahidropiridinopirazolilo and oxodihidropiridinopirazolilo being optionally substituted all these radicals with one or more radicals X1, X2 or X3 chosen from H, halogen, haloalkyl, OH, R4, NO2, CN, S (O) nR4, OR4, NY1Y2, COR4, -C (= 0) NY1Y2, -C (= O) OR4, -C (= 0) OH, -N (R6) C (= O) R4, -N (R6) SO2R4, - N (R6) C (= O) NY Y2, -N (R6) C (= 0) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, -OS (O ) nR 4, -OC (= O) R 4 and optionally substituted thienyl, R 2 and R 3 are such that: any of R2 and R3, which may be the same or different, represent H, R4, halogen, haloalkyl, OH, N02, CN, OR4, COR4, S (0) nR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, -NY Y2, -N (R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N ( R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY Y2, -OC (= 0) NY1Y2 and -OC (= 0) R4 or R2 represents H, R4, halogen, haloalkyl, OH, N02, CN, OR4, COR4, S (0) nR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, -NY1Y2, -N (R5) C ( = 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY Y2 and -OC (= 0) R4 and R3 represents alkyl, haloalkyl, halogen and OR6, or R2 and R3 together form a ring based on 5 to 6 membered carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, R4 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkio, heterocycloalkyl, heteroarylalkyl and arylalkyl, all of these radicals being optionally substituted with one or more lies chosen from aryl (optionally substituted), halogen, alkyl, hydroxyalkyl, OH, OR5, C (= 0) NY3Y4, NY3Y4, alk-NY3Y4 and C (= 0) OR6 ,; R 5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkio, heteroarylalkyl and heterocyanoalkyl-alkyl. Y1 and Y2 are such that: any of Y1 and Y2, which may be the same or different, represents H and optionally substituted alkyl, alkenyl so, cycloalkyl, heterocycloalicylic, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or Y1 and Y2 form, together with the nitrogen atom to which they are attached, a cyclic radical, Y3 and Y4 are such that: any of Y3 and Y4, which may be the same or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y3 and Y4 form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical, A5 represents H or alkyl, R6 is chosen from the values of R5, all the alkyl (or alk, representing alkyl), alkenyl, cycloalkyl, heterocyclealkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are further optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl radicals, cyano, alkyl, alkoxy, acylamino (NH-COalk), -C (= 0) OR6, acyl -C (= 0) R6, hydroxyalkyl, carboxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, N02, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3Y4 and NY3Y4, the latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more radicals chosen from halogen atoms and alkyl radicals, free carboxyl radicals, salified or esterified and acylamino radicals NH-C (0) R5, the phenyl radicals are further optionally substituted with a dioxol radical, n represents an integer from 0 to 2, it being understood that when R represents an inda-zolyl radical to provide the compounds of formula (F) below: (F) · wherein X represents H, R2 or R3 as defined above, then W necessarily represents H or unsubstituted alkyl, and said compounds of formula (I) are in any possible racemic, enantiomeric or diastereomeric isomeric form , and also the salts by the addition of mineral and organic acids or mineral bases. An object of the present invention is therefore the compounds of formula (I) as defined above corresponding to formula (la): (la) in which Xa represents C-R2a and Wa, Ya and 2a, which may be the same or different, represent CH or CR3a; R-a represents aryl or heteroaryl selected from pyrazolyl, triazolyl and indazolyl radicals, and all these radicals are optionally substituted with one or more radicals X1a, X2a or X3a selected from H, halogen, OH, R4a, OR4a, NY1aY2a, S (0) nR4a, -C (= 0) NY aY2a, -C (= 0) OR4a, - N (R6a) C (= 0) R a, -N (R6a) S02R a -N (R6a) C (= 0) NY aY2a, -N (R6a) C (= 0) 0R4a, -OC (= 0) NY1aY2a, -OC (= 0) R4a, -OS (0) nR and thienyl optionally substituted with an alkyl radical, R2a and R3a are such that: any of R a and R3a, which may be the same or different, represent H, R4a, halogen, OH, OR4a, C (= 0) NY1aY2a, -C (= 0) OR4a and -C (= 0) OH, 'and R3a represents alkyl, halogen and OR6a, or R2a represents H, R4a, halogen, OH, OR a, C (= 0) NY1aY2a, -C (= 0) OR4a and -C (= 0) OH, and R3a represents alkyl, halogen and OR6a, or R2a and R3a together form a ring -O-CH2-O- or -0-CH2-CH2-0-, R 4a represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl, all of these radicals being optionally substituted with one or more radicals selected from aryl (optionally substituted), halogen, alkyl, hydroxyalkyl, OH, OR 5a , C (= 0) NY3aY4a, NY3aY4a, alk-NY3aY4a and C (= 0) OR6a, R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, and all of these radicals are optionally substituted, Y1a and Y2a are such that: any of Y1a and Y2a, which may be the same or different, represent H, alkyl, alkoxyalkyl, aryloxyalkyl, arylalkyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, aryl and heteroaryl, and all of these radicals are optionally substituted, or Y and Y2a form, together with the nitrogen atom to which they are attached, an optionally optional amino radical substituted organism, Y3a and Y4a are such: either Y3a and Y4a, which may be the same or different, represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y3a and Y4a form, together with the nitrogen atom which are attached, a cyclic amino radical, A5 represents H or alkyl, all the alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are further optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH-C (0) R6a), -C (= 0) OR6a, acyl -C (= 0) R6a, hydroxyalkyl, carboxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3aY4a and NY3aY4a, these latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more radicals selected from halogen atoms and alkyl radicals, alkoxy radicals, free carboxyl radicals, salified or esterified radicals and acylamino NH-C (0) R6a, the phenyl radicals are further optionally substituted with a dioxole radical R6a is chosen from the values of R5a, n represents an integer from 0 to 2, said compounds of formula ( ) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or ba Minerals An object of the present invention is therefore the compounds of formula (I): wherein: X represents C-R2 and W, Y and Z, which may be the same or different, represent CH or CR3; R represents aryl or heteroaryl radical chosen from pyrazolyl, triazolyl, imidazolyl, indolyl, indazolyl, tienopirazolilo, tetrahidroindazo-Lilo, tetrahidrociclopentapirazolilo, dihidrofuropirazolilo, oxodihidropiridazinilo, tetrahidropirrolopirazolilo, oxotetrahidropirrolopirazolilo, tetrahydropyran-pyrazolyl, tetrahidropiridinopirazolilo ,. and oxodihydro-pyridinopyrazolyl, and all these radicals are optionally substituted with one or more radicals X1, X2 or X3 selected from H, halogen, haloaikyl, OH, R4, NO2, CN, S (O) nR4, OR4, NY1Y2, COR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= 0) OH, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C ( = O) NY1Y2 -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2, -OS (O) nR4, -OC (= O R4 and optionally substituted thienyl, R2 and R3 are such that: any of R2 and R3, which may be the same or different, represent H, R4, halogen, haloaikyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= O) OH, -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1 Y2, -N (R6) C (= O) OR4, -S (O) nOR4, -S (O) nNY1Y2, -OC (= O) NY1Y2 and -OC (= O ) R4 or R2 represents R4, halogen, haloaikyl, OH, NO2, CN, OR4, COR4, S (O) nR4, -C (= O) NY1Y2, -C (= O) OR4, -C (= 0) OH , -NY1Y2, -N (R6) C (= O) R4, -N (R6) SO2R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= O) OR4, - S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2 and -OC (= 0) R4 and R3 represent alkyl, haloalkyl, halogen and OR6, or R2 and R3 together form a ring based on atoms carbon of 5 to 6 members containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, R4 represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, hetero-arylalkyl and arylalkyl , and all these radicals are optionally substituted with one or more radicals selected from aryl, OH, OR5, C (= 0) NY3Y4, NY3Y4 and C (= 0) OR6, R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl , arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, R6 represents H and alkyl Ci-C, n represents an integer from 0 to 2, Y1 and Y2 are such that: either of Y1 and Y2, which may be the same or different, represents H, alkyl, alkenyl, cycloalkyl, aryl, arylalkyl, heteroaryl or heteroaryl ilalkyl, and all these radicals are optionally substituted with one or more radicals chosen from hydroxyl, -C (= 0) -NY3Y4, -C (= 0) OR6 and NY3Y4, or Y1 and Y2 form, together with the nitrogen atom at which are attached, a cyclic amino radical, Y3 and Y4 are such that: any of Y3 and Y4, which may be the same or different, represents hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y3 and Y4 form, together with the nitrogen atom to which they are attached, a cyclic amino radical, A5 represents H or alkyl, it being understood that when R1 represents an inda-zolyl radical to provide the compounds of formula (F) below: (F) wherein X represents H, R2 or R3 as defined above, then W necessarily represents H or unsubstituted alkyl, and said compounds of formula (F) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts per addition of mineral and organic acids or mineral bases. It is evident that, according to the ring represented by R and its number of members, R1 may comprise one, two or three substituents represented by X1, X2 and X3.
An object of the present invention is therefore the compounds of formula (I) as defined above corresponding to formula (la): TO, (la) in which: Xa represents C-R2a and Wa, Ya and Za, which may be the same or different, represent CH or CR3a; R1a represents aryl or heteroaryl selected from pyrazolyl, triazolyl or indazolyl radicals, and all these radicals are optionally substituted with one or more radicals X1a, X2a or X3a selected from H, halogen, OH, R a, OR4a, NY1aY2a, S (0) nR4a, -C (= 0) NY1aY2a, -C (= 0) OR4a, -N (R6a) C (= 0) R4a, -N (R6a) S02R4a, -N (R6a) C (= 0) ) NY1aY2a, -N (R6a) C (= 0) OR4a, -OC (= 0) NY1aY2a and -OC (= 0) R4a, -OS (0) nR4a and thienyl optionally substituted with an alkyl radical, R2a and R3a are such that: any of R2a and R3a, which may be the same or different, represents H, R4a, halogen, OH, OR4a, C (= 0) NY aY2a, -C (= 0) OR a, -C (= 0) OH and R3a represents alkyl, halogen and OR6a, or R2a represents H, R a, halogen, OH, OR a, C (= O) NY1 aY2a, -C (= 0) OR4a, -C (= O) OH and R3a represent alkyl, halogen and OR6, or R2a and R3a together form a ring an -O-CH2-0 or -0- CH2-CH2-O-, R4a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, and all these radicals are optionally substituted with one or more radicals chosen from aryl, OH, OR5a, C (= 0) NY3aY4a, NY3aY4a and C (= 0) OR6a, R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, R6a represents H and alkyl CrC4, n represents an integer from 0 to 2, Y to Y2a are such that: any of Y to Y2a, which may be the same or different, represents H, alkyl, cycloalkyl, aryl and heteroaryl, and all these radicals are optionally substituted with one or more radicals chosen from hydroxyl, -C (= 0) -NY3Y4, -C (= O) OR6 and NY3Y4, or Y1 to Y2a form, together with the nitrogen atom to which they are attached, a cyclic amino radical, Y3a and Y4a are such: either of Y3a and Y a, which may be the same or different, represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y3a and Y4a form, together with the nitrogen atom to which they are attached, a cyclic amino radical, A5 represents H or alkyl, and said compounds of formula (Ia) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or mineral bases.An object of the present invention is therefore the compounds of formula (1) as defined above corresponding to formula (IA): (IA) wherein A represents a saturated heterocyclic radical which is a 5- or 6-membered monocyclic radical or a bicyclic radical having no more than 10 members, and these members are such that at least two of them represent a nitrogen atom and the others, which may be identical or different, represent a carbonized member or a heteroatom selected from O, N and S, and this heterocycle A is optionally substituted with one or more radicals XA1, XA2 or XA3 chosen from the values indicated above for the radicals X1, X2 or X3, ???, A2, A3 and A4, which may be the same or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy radicals, a radical -boxyl which is free, salified, esterified with an alkyl radical or amidated with a radical NA6A7 so that any of A6 and A7, which may be the same or different, is chosen from optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl radicals , cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl radicals, or A6 and A7 form, together with the nitrogen atom to which they are attached, an optionally substituted 5 or 6-membered cyclic radical, it being understood that two consecutive radicals between , A2, A3 and A4 can form, with the benzimidazole radical to which they are attached, a ring based on carbon atoms of 5 to 6 members containing one or more heteroatoms, which can be in being the same or different, chosen from O, N and S, A5 represents a hydrogen atom or an alkyl radical, R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl, and cycloalkylalkyl, all the alkyl, alkenyl, aryl radicals , heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl present in the above radicals are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino ( NH-COR6), -C (= 0) OR6b, acyl -C (= 0) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, N02, CN, phenyl, substituted by itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2, all the above alkyl, alkenyl, alkoxy and alkyloxy radicals are linear or branched and contain no more than 4 carbon atoms, all the phenyl radicals of the above radicals are further optionally substituted with a dioxole radical, n represents an integer from 0 to 2, and said compounds of formula (IA) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or mineral bases and organic of said compounds of formula (IA). An object of the present invention is therefore the compounds of formula (I) as defined above, corresponding to the formula (the A): (the A) wherein Aa represents a pyrazolyl, triazolyl or indazolyl radical, and this heterocycle Aa is optionally substituted with one or more radicals XA1, XA2 or XA3 selected from the values indicated above for radicals X1, X2 or X3, A- ia, A2a, A3a and A- ^ a, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical which it's free, salified or esterified with an alkyl radical or amidated with a radical NA6aA7a so that any of A6a and A7a, which may be the same or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl radicals , furylalkyl, thienylalkyl and pyridylalkyl, or A6a and A7a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, pyrazoliniin, piperidyl, morpholino or piperazinyl radical, optionally substituted on the second nitrogen atom with a alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals between A-ia, A2a, A3a and A4a can form, with the benzimidazole radical to which they are attached, a ring based on carbon atoms of to 6 members optionally substituted containing one or two oxygen atoms, A5a represents a hydrogen atom or an alkyl radical, and the phenyl radicals the foregoing phenoxy and phenoxy are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino radicals, alkylamine, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl and dioxole, and all of the above alkyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 6 carbon atoms, and said compounds of formula (Ia) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (Ia). The substituents X1, X2 and X3 as defined above are in particular such that one represents a hydrogen atom and the other two, which may be the same or different, are chosen from halogen atoms and OH, radicals R4a, OR a, CF3 , OCF3, N02, CN, NY1aY2a, acylamino (NH-COR5b), S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk ) 2, -C (= 0) -NH2 > -C (= 0) -NH (alk), C (= 0) -N (alk) 2, -C (= 0) OR4a, -N (R6b) C (= 0) R4a, -N (R6b) S02R4a , -N (R6b) C (= 0) NY1aY2a, -N (R6b) C (= 0) OR4a, -OC (= 0) NY1aY2a and thienyl, so that the thienyl radical is optionally substituted with an alkyl radical, R4a , Y1a, Y2a and R6b, having the values defined above, and alk representing a linear or branched alkyl radical including no more than 6 carbon atoms and is optionally substituted as indicated above.
All the alkylthio radicals are such that the sulfur atom is optionally oxidized to sulfone or sulfoxide with one or two oxygen atoms. Tables I, II and III described below provide examples of compounds illustrating the present invention, and particular substituents are chosen from the values of X1, X2 and X3 as defined above. TABLE I X represents hydrogen, halogen or alkoxy as defined above.
TABLE wherein NR'R represents NY1Y2 ran was previously defined. TABLE III wherein X represents hydrogen, alkynyl or NHCOCH2Ph which is optionally substituted. The object of the present invention is therefore the compounds of formula (I) as defined above in which the substituents of said compounds of formula (I) have any of the indicated values as defined above and in which the radicals aryl represent the phenyl and naphthyl radicals; the heteroaryl radicals represent the furyl, thienyl, benzothienyl, thiantrenyl, pyridyl, pyrazolyl, benzimidazolyl, benzofuran, sobenzofuran and dihydrobenzofuran radicals; the cycloalkyl radicals represent a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl radical; the heterocycloalkyl radicals represent the hexahydropyran, piperidyl or morpholino radicals; the heterocycloalkylalkyl radicals represent the hexahydropyranylalkyl, piperidylalkyl and morpholinoalkyl radicals; the aryl radicals The radicals represent phenylalkyl, ethylenedioxyphenylalkyl and naphthylalkyl radicals; the heteroarylalkyl radicals represent the thienylalkyl, pyridylalkyl, furylalkyl, pyrazolylalkyl, benzothienylalkyl, dihydrobenzofuranoyl-alkyl and benzimidazolylalkyl radicals; the aryloxy radicals represent the phenoxy and naphthyloxy radicals; the arylalkoxy radicals represent the phenylalkoxy and naphthialkoxy radicals; and the aryloxyalkyl radicals represent the phenoxyalkyl radical; and all of these radicals are optionally substituted as indicated above. An object of the present invention is, more particularly, the compounds of formula (I) as defined above corresponding to formula (IA): (IA) in which A represents a saturated heterocyclic radical which is a 5- or 6-membered monocyclic radical or a bicyclic radical having no more than 10 members, and these members are such that at least two of them represent an atom of nitrogen and the others, which may be the same or different, represent a carbon member or a heteroatom member chosen from O, N and S, and this heterocycle A is optionally substituted with one or more XA1, XA2 or 33 radicals selected from halogen atoms, alkyl, alkoxy or alkylthio radicals or thionyl radicals optionally substituted with an alkyl radical, Ai, A2, A3 and A4, which may be the same or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, a carboxy radical that is free, salified or esterified with an alkyl or amidated radical with a radical NA6A7 so that A6 and A7, which may be the same or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroarylalkyl radicals, or A6 and A7 form, together with the nitrogen atom to which they are attached, a cyclic radical of 5 or 6 members, it being understood that two consecutive radicals between Ai, A2, A3 and A4 can form, with the radical ben cimidazole to which they are attached, a ring based on 5 to 6 membered carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and s, represents a hydrogen atom or an alkyl radical, all the phenyl, phenoxy, cycloalkyl and heteroarylalkyl radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethyl, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkyl-mino radicals , free carboxyl, salified or esterified and dioxol, and all of the above alkyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 6 carbon atoms, and said compounds of formula (IA) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (IA). An object of the present invention is also, more particularly, the compounds of formula (1) as defined above, corresponding to formula (Iab): (lAb) wherein Ab represents an optionally substituted pyrazolyl or indazolyl radical with one or two radicals selected from halogen atoms and OH, alkyl, alkynyl, -OR6b (including alkoxy), --COR6b, -0-COR6b, radicals, -OS (0) nR6b, -0 (CH2) n-CO-R6b, phenyl, phenylalkyl, CF3, OCF3, N02, CN, NY1bY2b, -NH-C (= 0) NY1bY2b, acylamino (NH-CO-R6b) , S (0) n-alk, S (0) n-NY1bY2b, -C (= 0) -NY1bY¾, -C (= 0) OR6b, -NH-C (= 0) R6b, -NH-S (0 ) nR6b, -NH- C (= 0) OR6b, -N (R6b) C (= 0) NY1bY2b, -OC (= 0) NY1bY2b and thienyl, and all of these radicals are optionally substituted, NY1bY2b is such that either of Y1b and Y2b, which can be same or different, it is chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y 1b and Y 2b form, together with the nitrogen atom to which they are attached, a radical piperidyl, hexahydrofuran, morpholinyl or morpholinyl alkyl, Aib, Aa, A3b and A4b, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, -OR6b radicals (including alkoxy) ), -CO-R¾, -0-COR6b, -OS (0) nR6b, -0 (CH2) n -CO-R6b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thiantrenyl, phenyl and phenoxy and a radical carboxyl which is free, salified, esterified with an alkyl radical or amidified with a radical NA6bA7b so that A6b and A7b, which ueden be identical or different, they are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthyl, thienylalkyl, piperidyl, pyridyl, benzotienilalquilo, pyrazolylalkyl, dihidrobenzofuranoilalquilo, hexa-hidropiranilalquilo, etilenedioxifenilalquilo and bencimidazolilalquilo, and all of these radicals are optionally substituted, or A6b and A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholinyl or piperazinyl radical, and the piperazinyl radical is optionally substituted on the second nitrogen atom with an alkyl radical which are itself optionally substituted, it being understood that two consecutive radicals between A1b, A2b, A3b and A b can form, with the benzimidazo radical; to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole radical or an optionally substituted 4,5-methylenedioxybenzimidazole radical, A5b represents a hydrogen atom, and all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl , piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dial-quiamino, phenylamino, phenylalkylamino, acylamino (NH-COR6b), -C (= 0) OR6b, acyl -C (= 0) R6b, hydroxyalkyo, carboxyalkyl, phenoxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, N02, CN, phenyl, optionally substituted by itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2, n represents an integer from 0 to 2, and R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pi Ridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinoline, -NH-phenyl, phenylalkyl and cycloalkylalkyl, and all these radicals are optionally substituted with a morpholino, piperidyl or phenyl radical optionally substituted with one or more Radicals chosen from halogen atoms genos and the cyano radical, CF3, OCF3, alkyl, phenyl-S (0) n-alk-phenyl, alkoxy, NH2, NHalk, N (alk) 2, S02NH2, S02Nalk or S02N (alk) 2, and all radicals Previous alkyl, alkenyl, alkoxy and alkylthio are linear or branched and contain no more than 10 carbon atoms, and all phenyl radicals of the above radicals are further optionally substituted with a dioxole radical, and said compounds of formula (Iab) are any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (Iab). An object of the present invention is therefore, in particular, the compounds? of formula (1) as defined above corresponding to formula lAb) wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or two radicals selected from halogen atoms and OH, alkyl, alkynyl, alkoxy, phenyl radicals , phenylalkyl, CF3, OCF3 > N02, CN, NY1bY2b, -NH-C (= 0) NY1bY2b, acylamino (NH-CO-R6b), S (0) n -alk, S (0) n-NY1bY2b, -C (= 0) -NY1bY2b, -C (= 0) OR6b, -NH-C (= 0) R6b, -NH-S (0) nR6b, -NH-C (= 0) OR6b, -N (Rsb) C (= 0) NY1bY¾, - OC (= 0) NY1bY2b and thienyl which are optionally substituted, and NY1bY2b is such that any of Y1b and Y2b, which may be the same or different, are chosen from hydrogen and alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, optionally substituted phenylalkyl, phenylalkylthio and naphthylalkyl or Y1b and Yb form, together with the nitrogen atom, trógeno to which they are attached, a radical to piperidyl, hexahydrofuran, morpholini-lo or morpholinyl-alkyl, A-ib, A2b, Asb and A b, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, radicals hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrene, phenyl and phenoxy and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidified with a radical NA6bA7b that A6b and A7b, which may be the same or different, are selected from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenylamino, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranoylalkyl, hexahydropyranyl- lalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl, and all these radicals are optionally substituted, or A6b and A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical which is optionally substituted on the second nitrogen atom with an alkyl radical which is itself optionally substituted, it being understood that two consecutive radicals between A1b, A2b, A3b and A4b can form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazole radical or a radi-lime 4,5-methylenedioxybenzimidazole optionally substituted, A5b represents a hydrogen atom, and all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dial-quiamino, phenylamino, phenylalkylamino, acylamino (NH-COR6b), -C (= 0) OR6b, acyl -C (= 0) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2 , CF3, OCF3, N02, CN, phenyl, optionally substituted in itself with one or more halogen atoms, thienyl, phenoxy, phenylaloxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2, n represents an integer from 0 to 2, and R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl, and all alkyl, alkenyl, alkoxy and The above alkylthio are linear or branched and contain not more than 10 carbon atoms, and all the phenyl radicals of the above radicals are further optionally substituted with a dioxole radical, and said compounds of formula (Iab) are in which any possible racemic, enantiomeric or diastereomeric isomer form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (Ab). An object of the present invention is therefore, in particular, the compounds of formula (I) as defined above corresponding to formula (Iab) in which Ab represents a pyrazolyl radical substituted with one or two radicals so that one is chosen from hydrogen, halogen atoms and alkyl, alkynyl, -COR6b, phenyl, phenylalkyl, CF3, N02, CN radicals, NY1bY2b, -NH-C (= 0) NY bY2b, NH-CO-R6b, S (0) n-alk, S (0) n-NY bY2b, -C (= 0) -NY1bY¾, -C (= 0 ) OR6b, -NH-C (= 0) R6b, -NH, and all these radicals are optionally substituted, and the other is chosen from OH radicals, -OR6b, -0-COR6b, -OS (0) nR6b, - 0 (CH2) n-CO-R6b and -OC (= 0) NY1bY2b, and these radicals are optionally substituted, NY1bY2b is such that Y be Y b, which may be the same or different, are chosen from hydrogen and alkyl, cycloalkyl, optionally substituted cycloalkylalkyl, phenol, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl, or Y 1b and Y 2b form, together with the nitrogen atom to which they are attached, a radical to piperidyl, hexahydrofuran, morpholinyl or morpholinyl-chyl, Aib, A2b, Aab and A4b, which may be the same or different, are such that two of them represent hydrogen and the other two, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl radicals, alkyl, alkenyl, -O R6b (including alkoxy), -CO-R6b, -0-COR6b, -OS (0) nR6b, -0 (CH2) n -CO-R6b, nitro, cyano, furyl, thienyl, benzothienium, naphthyl, thiantrenyl, phenyl and phenoxy and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA6bA7b so that any of A6b and A7b, which may be the same or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl radicals chyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, thienylalkyl, piperidylalkyl, pyridylalkyl, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranoylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl, and all of these radicals are optionally substituted, or A6b and A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical which is optionally substituted on the second atom of nitrogen with an alkyl radical which is itself optionally substituted, A5b represents a hydrogen atom, and all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acyamino (NH-COR6b) radicals, -C (= 0) OR6b, acyl -C (= 0) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk) , S (0) nN (alk) 2, CF3, OCF3, N02, CN, phenyl, which is optionally substituted by itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2, n represents an integer from 0 to 2, and R6b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl , pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihi-droquinolone, -NH-phenyl, phenylalkyl and cycloalkylalkyl, and all these radicals are optionally substituted with a morpholino, piperidyl or phenyl radical optionally substituted by itself with one or more radicals chosen in- three halogen atoms and the cyano radical, CF3, OCF3, alkyl, phenyls (0) n-alk-phenyl, alkoxy, NH2I NHalk, N (alk) 2, S02NH2, S02Nalk or S02N (alk) 2, and all the above alkyl, alkenyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 10 carbon atoms, and all of the phenyl radicals of the above radicals are further optionally substituted with a dioxole radical, and said compounds of formula (lAb) they are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (Iab). An object of the present invention is therefore, in particular, the compounds of formula (I) as defined above corresponding to formula (IAb) wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals selected from halogen atoms and alkyl, alkoxy and thienyl radicals, Aib, A2b, A3b and A4b, which may be the same or different, are chosen from a hydrogen atom; halogen atoms; radicals of the following types: hydroxyl, alkyl, alkenyl optionally substituted with phenyl itself optionally substituted with one or more halogen atom, alkoxy, nitro, cyano, furium, thienyl optionally substituted by acyl COalk, benzothienyl, naphthyl, thiantrenyl , phenyl and phenoxy which are optionally substituted; and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidified with a radical NA6bA7b so that any of A6b and A7b, which may be the same or different, are chosen from hydrogen and radicals of the following types: alkyl, alkoxyalkyl containing no more than 6 carbon atoms, phenoxyalkyl optionally substituted with acylamino, NH-C (0) alk, phenyl optionally substituted phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl optionally substituted with one or more alkyl, naphthylalkyl, thienylalkyl radicals optionally substituted with alkyl or thienyl, pyridylalkyl optionally substituted with a carboxyl radical that is free, salified or esterified with a radical alkyl, pyridylalkyl optionally substituted with one or more radicals chosen from halogen and CF3, benzothienylalkyl, pyrazolylalkyl optionally substituted with one or more alkyl radicals, dihydrobenzofuranylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl optionally substituted with one or more alkyl radicals, or A6b and A7b form, jointly e with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, and the piperazinyl radical is optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals between Aib, A2, A3b and A4b can form, with the benzimidazole radical to which they are attached, a radical 4,5-ethylenedioxybenzimidazole! optionally substituted or an optionally substituted 4,5-methylenedioxybenzimidazole radiolyal, A5a represents a hydrogen atom, and the above phenyl, phenoxy and phenylalkyl radicals are optionally substituted with one or more radicals selected from the group consisting of halogens, hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and -NH-COalk radicals, a carboxyl radical that is free, salified or esterified with an alkyl radical and hydroxyalkyl, carboxyalkyl, phenoxyalkyl, alkylthio, S02alk, S02NH2, S02-NH (alk), S02-N (alk) 2, CF3, OCF3, N02, CN, phenyl, optionally substituted by itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk), C (= 0) -N (alk) 2 and C (0) CH3, and all the alkyl or alk, alkenyl radicals , alkoxy and lower alkylthio are linear or branched and contain no more than 4 carbon atoms, and all the phenyl radicals of the above radicals are further optionally substituted with a dioxol radical, and said compounds of formula (Ia) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (Ia). An object of the present invention is therefore, in particular, the compounds of formula (I) as defined above corresponding to formula (Iab) in which Ab, A1b, A2b, A3b, A4b and A5b have any of the meanings above, and when one of A b, A2b, A3b and A4b represents a carboxyl radical amidated with a radical NA6bA7b, then either of A6b and A7b represents a hydrogen atom or an alkyl radical and the other of A6b and A7b represents choose between the values defined for A6b and A7b, or A6b and A7b form, together with the nitrogen atom to which they are attached, a cyclic radical of 5 or 6 members, and the other substituents of said compounds of formula (I) have any of the values indicated above, and said compounds of formula (Ia) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula ( lAb). An object of the present invention is therefore, in particular, the compounds of formula (I) as defined above in which X, W, Y and Z are such that two or three of them represent CH and the others are chosen from the values of CR2 or CR3 and, if appropriate, that is, when two of them represent CH and CR2 and CR3 are adjacent to each other, can form a radical dioxol, R2, R3 and the other substituents of said compounds of formula (I) have any of the values defined above, and said compounds of formula (I) are in any possible racemic, enantiomeric or diastereomeric isomeric form, and also the salts by the addition of mineral and organic acids or mineral bases and organic compounds of said compounds of formula (I). The present invention thus relates, in particular, to the compounds of formula (IA) as defined above in which Ai, A2, A3 and A4 are such that two or three of them represent a hydrogen atom and the others are chosen between the values of Ai, A2, A3 and A4 and, if appropriate, that is, when two of them represent a hydrogen atom and the other two are adjacent carbon atoms, can form a dioxol radical, the other substituents of the compounds of formula (IA) have any of the values defined above, and said compounds of formula (IA) are in any racemic isomeric form possible , enantiomer or diastereoisomer and also the salts by addition of mineral and organic acids or mineral and organic bases of said compounds of formula (IA). An object of the present invention is also, more particularly, the compounds of formula (I) as defined above, corresponding to formula (Ia): OAa) wherein Aa represents a pyrazolyl, triazolyl or indazolyl radical, and this heterocycle Aa is optionally substituted with one or more radicals XA1, XA2 or XA3 chosen from halogen atoms, alkyl, alkoxy or alkylthio radicals and thienyl radicals optionally substituted with an alkyl radical, A-i'a, A2a, A3a and A- ^ a, which may be identical or different are selected from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidated with a radical NA6aA7a so that any of A6a and A7a, which may be the same or different, is chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A6a and A7a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinium, pyrazolinyl, piperidyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl or phenyl radical, which is in themselves optionally substituted, it being understood that two consecutive radicals between A-ia, A2a, A3a and A4a can form, with the benzimidazole radical to which they are attached, a ring based on optionally substituted 5 to 6 membered carbon atoms containing one or two oxygen atoms, A5a represents a hydrogen atom or an alkyl radical, - the above phenyl and phenoxy radicals are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino radicals, Quilamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl and dioxole, all the above alkyl, alkoxy and alkylthio radicals are straight branched and contain no more than 6 carbon atoms, said compounds of formula (Ia) are in any isomeric possible racemic, enantiomeric or diastereoisomeric form, and also the salts by addition of organic and mineral acids or of mineral and organic bases of said compounds of formula (Ia). An object of the present invention is, more particularly, the compounds of formula (I) as defined above in which R 1 represents a pyrazolyl or indazolyl radical and the other substituents have the values indicated above or subsequently. Among the preferred compounds which are particularly indicated are the compounds of formula (I) wherein Aa represents an optionally substituted pyrazolyl or indazolyl radical as indicated above or subsequently, Aia, A2a, A3a and * a are selected from the following values: - A-ia represents hydrogen or carboxyl or forms a ring with the adjacent member A2a-A a represents hydrogen or carboxyl or forms a ring with the adjacent member A3a A2a represents a carboxyl radical which is free, salified, esterified with an optionally substituted alkyl radical or an amidated carboxyl as indicated above or subsequently, - A2a and A3a represent two optionally substituted alkyl radicals, - A5a represents hydrogen. An object of the present invention is, even more particularly, the compounds of formula (I) as defined above, corresponding to formula (Iab): (lAb) wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals selected from halogen atoms and alkyl, alkoxy and thienyl radicals, A- | b, A2b, As and A4b, which may be the same or different, are chosen between a hydrogen atom, halogen atoms, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy radicals and a carboxyl radical which is free It is selected from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl radicals, or A6b and A6b radicals, salified, esterified with an alkyl radical or amidated with a radical NA6bA7b so that any of A6b and A7b can be the same or different. A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals between A-ib, A2b, A3b and A4b they can form, with the benzimidazole radical to which they are attached, an optionally substituted 4,5-ethylenedioxybenzimidazoi radical or a 4,5-methylenedioxybenzimidazole radical, Asb represents a hydrogen atom, and the above phenyl and phenoxy radicals are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino radicals , phenylamino, phenylalkylamino and free carboxyl, salified or esterified, and all the above alkyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 4 carbon atoms, and said compounds of formula (Iab) are in any isomeric form possible racemic, enantiomeric or diastereomeric, and also the salts by addition of mineral and organic acids or of mineral and organic bases of said compounds of formula (Iab).
With reference to formula (Ix) above, the following are particular and preferred groupings: R may represent particularly optionally substituted heteroaryl. Examples of optionally substituted heteroaryl groups include dihidrofuropirazolilo, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihidropiri-dazinilo, oxodihidropiridinopirazolilo, oxodihydropyridinyl, oxotetrahidropirrolopi-razolilo, pyrazolyl, thiazolyl, tienopirazolilo, tetrahidrociclopentapirazolilo, te-trahidroindazolilo, tetrahidropiranopirazolilo, tetahidropiridinopirazolilo, tetrahi-dropirrolopirazolilo or triazolyl . Optional substituents include one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4 -C (= 0) R 4, -C (= 0) NY 1 Y 2 -C (= 0) OR 4, -N. { R6) C (= 0) R4, - N (R6) C (= 0) NY1 Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N (R6) S02NY1 Y2, -NY1 Y2, -OR4, -OCF2H, -OCF3L -OC (= 0) R4, -OC (= 0) NY1 Y2, -S (0) NR and -S (0) 2 Y '' Y. R1 represents more particularly a heteroaryl radical wherein R7, R8 and R9 are as defined above.
It will be appreciated that the compounds of formula (Ix) wherein R 1 represents a heteroaryl radical and R7 is hydrogen can exist in the more tautomers W can represent particularly CH when X is CR2, Y is CH or CR3 and Z is CH or CR3. W can also represent particularly CH when X is N, Y is CH or CR3 and Z is CH or CR3. W may also particularly represent N when X is CH or CR2, Y is CH or CR3 and Z is CH or CR3. W may also particularly represent N when X is CH or CR2, Y is CH or CR3 and Z is N.
It should be understood that this invention encompasses all appropriate combinations of the particular and preferred groupings cited in the present specification. A particular group of compounds of the invention is formed by the compounds of formula (Ixa): (Ixa) wherein W, X, Y, Z and R7 are as defined above for the compounds of formula (Ix) and R8 and R9 are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, 4 - C (= 0) R4 -C (= 0) NY1Y2, -C (= 0) OR4 -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) 0R4, -N (R6) S02R4 - ???? 2, -OR4, -OC (= 0) R4 -OC (= 0) NY1Y2, -S (0) NR4 and -S (0) 2NY1Y2; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (e.g. hydrates) of the compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bio-iso esters.
The compounds of formula (Ixa) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH3 are preferred. The compounds of formula (Ixa) in which W represents CH, X represents CH, Z represents CH and Y represents: (i) C-C 1-4 alkyl [e.g. C-CH3, C-CH2CH3. C-CH2CH2CH3 0 C- CH (CH3) 2]; (ii) (iü) C-CN; (V) C-N02; (v) C-halo [e.g. C-Br, C-CI or C-F]; (vi) C-haloalkyl [e.g. C-CF3]; (vii) C-heteroaryl [e.g.
OR4 [p.e. C-OCH,, C-OCBLCEL, C-OCHF2, C-OCF, C-C = 0) NY1Y2 [e.g. CC (= 0) -NH-CH3, CC (= 0) -N (CH3) 2, C-C (= 0) -NH-CH2CH3, CC (= 0) -NH-CH (CH3) 2, CC ( = 0) - HC (CH3) 2-CH2OH, CC (= 0) -NH-CH2CH2CN, C-C (= 0) - H- (CH) 2 -N ^ 0, C-C (= 0) -NH- (0¾)? (xi) C-C (= 0) 0R4 [p.e. C-C (= 0) OH or C-C (= 0) OCH3]; (xii) C-NHC (= 0) R4 [p.e. C-NHC (= 0) CH3, C-NHC (= 0) CH (CH3) 2, (xv) C-S (0) nR4 [p.e. C-S02CH3]; they are also preferred. The compounds of formula (Ixa) in which W represents CH, X represents C-CH3, C-CH2CH3, C-CH (GH3) 2, C-OCH3, C-OCH2CH3, C-Br 0 C-CI, Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-CI, C-F, C (and o and Z represents CH are also well-liked The compounds of formula (Ixa) in which W represents CH, X represents CH, Y represents C-CH3 and Z represents C-CH3 are also preferred. The compounds of formula (Ixa) in which W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-0-CH2-, and Z represents CH are also preferred. The compounds of formula (Ixa) in which W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2-CH2-CH2-, and Z represents CH are also preferred. The compounds of formula (Ixa) in which R7 represents hydrogen are preferred. The compounds of formula (Ixa) wherein R8 represents: (i) hydrogen; (ii) C1-4 alkyl p.e. CH 3, CH 2 CH 3, CH (CH 3) 2 or CH (CH 3) CH 2 CH 3]; (Üi) -SR4 [p.e. - S - CH3, -S- CH2CH3 -S- CBLj-, (v) -0R5 [e.g. -OCH2CH3]; they are preferred. The compounds of formula (Ixa) in which R9 represents: (i) hydrogen; (ii) C1-7 alkyl [e.g. -CH3, -CH2CH2CH3, -CH (CH3) 2 or -CH2-CH2-CH (CH3) 2]; (Ii) aryl [e.g. phenyl]; (iv) -C (= 0) NY1Y2 [e.g. - C (= 0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2CH3, - C (= 0) - H-CH2CH (CH3) 2, - C (= 0) -NH-CH (C¾) 2, - C (= 0) -NH-C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - CCK ^ -NH-CI ^ CE ^ OCHj, - C (= 0) -N (CH3),, C (= 0) -N (CH2CH3) 2, - C (= 0) - H- | , - C (= 0) (v) -N (R6) C (= 0) R4, particularly -NHC (= 0) R4 wherein (a) R4 * is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NYl Y2 or _OR5 [e.g. - H-C (= 0) -CH3, - H-C (= 0) - (CH2) 2CH3, - H-C (= 0) -CH (CH3) 2, - NH-C (= 0) -C (CH3) 3, C (= 0) -CH2CH (CH3) 2, - NH-C (= 0) -CH (CH3) C¾CH3 .
] O (e) heterocycloalkyl [e.g.
-N (R6) C (= 0) NY1Y2, particularly -NHC (= 0) NY1Y2 [p.e. - NH-C (= 0) -NHCH3, - NH-C (= 0) -NHCH2CH3, - NH-C (= 0) -NHCH (CH3) 2 | - NH-C (= 0) -NHCH2CH (CH3) 2 > - H-C (= 0) - HC (CH3) 3 | - NH-C (= 0) -N (CH3) 2.
-NH-C (= 0) -N (CH2CH3) 2, -NH-C (= 0) -NH (vii) - ??? ? 2 [p.e. -NH2]; or (viii) alkyl substituted with -N (R6) C (= 0) NY Y2 [e.g. -CH2-NH-C (= 0) - CH (CH3) 2 O - CH2 - NH - C (= 0) - N? ] they are preferred. A preferred group of compounds of the invention are the compounds of formula (Ixa) in which: W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen, R8 represents (i) hydrogen, (ii) Ci-4 alkyl [e.g. CH3, CH2CH3, CH (CH3) 2 or CH (CH3) CH2CH3], (iii) -SR4 [e.g. -s- CH3, -S- CH2CH3 or NY1Y2 [e.g. - N o] o (v) -OR5 [p.e. -OCH2CH3]; represents (i) hydrogen; (I) alkyl C < \ _j [p.e. -CH3, -CH2CH2CH3, -CH (CH3) 2 or -CH2-CH2-CH (CH3) 2]; O'ü) aryl [e.g. phenyl]; (iv) -C (= 0) NY1Y2 [e.g.
- C (= 0) - H-CH2CH3, - C (= 0) -NH-CH2CH2CH3, - C (= 0) -NH-CH2CH (CH3),, - C (= 0) -NH-CH (CH3) 2, - C (= 0) -NH-C (CH3) 3, - C (= O) - HC (CH3) 2CH, 0H, - C (= 0) -NH-CH2CH2OCH3, - C (= 0) - N (CH3) 2, C (= 0) -N (CH2CH3),, - C (= 0) C (= 0) -NH (v) -N (R6) C (= 0) R4, particularly -NHC (= 0) R4, wherein (a) R4 is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NY Y2 0 -OR5 [pe - HC (= 0) -C¾ | 3 '- NH-C (= 0) - (CH 2) 2CH 3, - NH-C (= 0) -CH (CH 3) 2, - NH-C (= 0) -C (CH3) 3, - NH-C (= 0) -CH2CH (CH3) 2, - NH-C (= 0) -CH (CH3) CH2CH3, , (b) R4 is aryl [e.g. . heteroaryl [e.g. (vi) -N (R6) C (= 0) NY1Y2, particularly -NHC (= 0) NY1Y2 [p.e. - H-C (= 0) -NHCH3, - NH-C (= 0) -NHCH2CH3, - NH-C (= 0) -NHCH (CH 3) 2 - - NH - C (= 0) - NHCH 2 CH (CH 3) 2 > - NH-C (= 0) - HC (CH 3) 3 - - NH - C (= 0) - N (CH 3) 2, - NH - C (= 0) - N (CH 2 CH 3), -NH-C (= 0) -NH -NH-C (= 0) - H-CH. alkyl susti with -N (R6) C (= 0) NY1 Y2 [p.e. -CH2-NH-C (= 0) -CH (CH3) 2 or and their corresponding N-oxides and their prodrugs, and their acid bioisoesters; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (IXa) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixa) in which: W represents CH; X represents CH; Z represents CH; Y represents (i) C-alkyl C- (vi) -N (R6) C (= 0) NY Y2, particularly -NHC (= 0) NY1Y2 [p.e. - NH-C (= 0) -NHCH3, - NH-C (= 0) - HCH2CH3, - NH-C (= 0) - HCH (CH 2. - NH-C (= 0) - HCH 2 CH (CH 3) 2 . - NH-C (= 0) -NHC (CH - - MH-C (= 0) - N (CH 3) 2. - H-C (= 0) -N (CH 2 CH 3) 2, - H-C (= 0) -Mí -Mí-C (= 0) - H-CH: substitute alkyl with -N (R6) C (= 0) NY1 Y2 [P E. -CH2-N H-C (= 0) -CH (CH3) 2 or - CHrMI-C (= 0) -N or]; (v) -N (R6) C (= 0) R4 particularly -NHC (= 0) R4, wherein (a) R4 is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocyc-cloaikyl, NY Y2 or .OR5 [e.g. - HC (= 0) -CH3, - NH ~ C (= 0) - (CH2) 2CH3, - NII-C (= 0) -CH (CH3) 2, - NH-C (= 0) -C (CH3 ) 3, - NH-C (= 0) -CH2CH (CH3),, - NH-C (= 0) -CH (CH3) CH2CH3, - H-C (= 0) -CH2C (CH3) 3, -NH-C (= O) -C¾0CH3], (b) R4 is aryl [e.g. [p.e. - - (vi) -N (R6) C (= 0) NYY2, particularly -NHC (= 0) NY1Y2 [p.e. - H-C (= 0) -NHCH3, - H-C (= 0) -NHCH2CH3, - NH-C (= 0) -NHCH (CH3) 2. - NH-C (= 0) -NHCH2CH (CH3) 2 > - H-C (= 0) ~ NHC (CH 3) 3 - - NH - C (= 0) - N (CH 3) 2 > - H-C (= 0) -N (CH2CH3) 2 - NH-C (= 0) -NH - H-C (= 0) -NH-CH alkyl susti with -N (R6) C (= 0) NYl y2 [p.e. -CH2-NH-C (= 0) -CH (CH3) 2 or - CH- ?? - C (= 0) -? ]; and their corresponding N-oxides and their profár¬ macos, and their acid bioisoesters; and salts and solvates (for example, hydrates) pharmaceutically acceptable of the compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bio-esters.
A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixa) in which: W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br O C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-CI, C-F, ; Z represents CH; R7 represent ta hydrogen; R represents (i) hydrogen, (ii) C 1-4 alkyl [e.g. CH3, CH2CH3, CH (CH3) 2 or CH (CH3) CH2CH3], (iii) -SR4 [e.g. -S-CH3, -S-CH2CH3 NY1 Y2 [e.g. -] or (v) -OR5 [p.e. -OCH2CH3]; m R9 represents (i) hydrogen; (ii) C1-7 alkyl [e.g. -CH3, -CH2CH2CH3, -CH (CH3) 2 or -CH2-CH2- CH (CH3) 2l; (iii) aryl [e.g. phenyl]; (iv) -C (= 0) NY1Y2 [e.g. - C (-0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2CH3, - C (= 0) -NH-CH2CH (CH3) 2, - C (= 0) -NH-CH (CH3) 2, - C (= 0) -NH-C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) - H-CH2CH2OCH3, - C (= 0) - N (CH3) 2, C (= 0) -N (CH2CH3) 2, -C (= 0) - H- J, - C (= 0) - C (= Q) -NH- ^ O]; (v) -N (R6) C (= 0) R4, particularly -NHC (= 0) R4, wherein (a) R4 is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NY1Y2 0 -OR5 [e.g. - i-C (= 0) -CH3, - HC (= 0) - (CH2) 2CH3, - HC (= 0) -CH (CHj) 2, - HC (= 0) -C (CH3) 3, - HC (= 0) - CE ^ CHCC ^),, - NH-C (= 0) -CH (CH3) CH2CH3, - NH-C (= 0) -CH N O or - NH-C (= 0) -CH.OCHj], (b) R4 is aryl [e.g. (vi) -N (R6) C (= 0) NY1Y2, particularly -NHC (= 0) NY1Y2 [e.g. - H-C (= 0) - HCH3, - H-C (= 0) -NHCH2CH3, - NH-C (= 0) -NHCH (CH3) 2. - NH-C (= 0) -NHCH2CH (CH3) 2 NH-C (= 0) - H ^] f - NH-C (= 0) - H-CH2- I rent their substituted with -N (R6) C (= 0) NY1Y2 [p.e. -CH2-NH-C (= 0) -CH (CH3) 2 or And its corresponding N-oxides, and their pro drugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixa) in which: W represents CH, X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; R8 represents (i) hydrogen, (ii) alkyl C-j_4 [e.g. CH3, CH2CH3, CH (CH3) 2 or CH (CH3) CH2CH3], (iii) -SR4 [e.g. -S-CH3, -S-CH2CH3 (V) ???? 2 [p.e. ] or (v) -OR5 [p.e. -OCH2CH3]; R9 represents (i) hydrogen; (I) C7-alkyl [e.g. -CH3, -CH2CH2CH3, -CH (CH3) 2 or -CH2-CH2CH (CH3) 2]; (iii) aryl [e.g. phenyl]; (iv) -C (= 0) NV Y2 [e.g. - C (= 0) -NH-CH2CH3, - C (= 0) - H-CH2CH2CH3, - C (= 0) -NH-CH2CH (CH3) 2, - C (= 0) -NH-CH (CH3) 2, - C ^ -Mi-CCCH ^ ^ C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) -NH-CH2CH2OCH3, - C (= 0) -N (CH3) 2 C (= 0) -N (CH2CH3) 2, -C (= 0) - H- | , - C (= 0) OR (v) -N (R6) C (= 0) R4, wherein (a) R4 is optionally substituted alkyl aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NY ^ Y2 or _OR5 [e.g. - NH-C (= 0) -CH3, - H-C (= 0) - (CiyjCHj, - NH-C (= 0) -CH (CH3) 2, - HC (= 0) -C (CH3) 3, - NH-C (= 0) -CH2CH (CH3) 2, - NH-C (= 0) -CH (CH3) CH2CH3, - NH-C (= 0 ) -CH2C (CH3) 3, ), -NH-C (= 0) -CH2OCH3], (b) R4 is aryl [p. . (vi) -N (R6) C (= 0) NY1Y2, particularly - ??? (= 0) ???? 2 [p.e. - NH-C (= 0) -NHCH3, - NH-C (= 0) -NHCH, CH3, - NH-C (= 0) -NHCH (CH3) 2 - - NH-C (= 0) - HCH2CH (CH3) 2 - - H-C (= 0) -NHC (CH 3) 3 - - NH - C (= 0) - N (CH 3) 2. - NH-C (= 0) -N (CH2CH3) 2 -NH-C (= 0) -NH -NH-C (= 0) -NH-CH.
- NH-C (= 0) - N 0], (vii) - ?? 1? 2 [p.e. -NH2] or (viii) alkyl substituted with -N (R6) C (= 0) NY1Y2 [p.e. -CH2-NH-C (= 0) -CH (CH3) 2 or ; and their corresponding N-oxides, and their drugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixa) in which: W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; R7 represents hydrogen; R8 represents (i) hydrogen, (ii) alkyl C-j_4 [e.g. CH3, CH2CH3, CH (CH3) 2 or CH (CH3) CH2CH3], (iii) -SR4 [e.g. -S-CH3, -S-CH2CH3 - ] (V) " NY1 Y2 [e.g. - N O] or (v) -OR5 [p.e. -OCH2CH3]; R9 represents (i) hydrogen; (ii) alkyl Q, [e.g. -CH3, -CH2CH2CH3, -CH (CH3) 2 or -CH2-CH2-CH (CH3) 2]; (iii) aryl [e.g. phenyl];. (V) -C (= 0) NY1Y2 [e.g. - C (= 0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2CH3, - C (= 0) -NH-CH2CH (C¾) 2, - C (= 0) -NH-CH (CH3) 2, - C (= 0) - HC (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (-0) -NH-CH2CH2OCH3, - C (= 0) -N (CH3) 2 -C (= 0) -N (CH7CH3) 2, - C (= 0) -NH C (= 0) -NH O (v) -N (R6) C (= 0) R4, particularly'-NHC (= 0) R4, wherein (a) R4 is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocycloalkyl, < RTI ID = 0.0 > O _OR5 [eg - H-C (= 0) -CH3, - NH-C (= 0) - (CH2) 2CH3, - NH-C (= 0) -CH (CH 3) 2, - NH-C (= 0) -C (CH 3) 3, - NH-C (= 0) -CH 2 CH (CH 3) 2 - NH-C (= 0) -CH (CH3) CH2CH3, - NH-C (= 0) -CH2C (CH3) 3, - H-C (= 0) -CIi, 0CH3], (b) R4 is aryl [e.g.
(VÍ) -N (R6) C (= 0) NY1 Y2, particularly -NHC (= 0) NY Y2 [p.e-NH-C (= 0) -NHCH3, -NH-C (= 0) -NHCH2CH3, - NH-C (= 0) -NHCH (CH3) 2. - H-C (= 0) -NHCH2CH (CH3) 2 > - NH-C (= 0) - HC (CH3) 3. - H-C (= 0) -N (CH3) 2. - NH-C (= 0) -N (CH2CH3), - H-C (= 0) -NH- < ^ I - H-C (= 0) - H-CH- alkyl susti with -N (R6) C (= 0) NY1Y2 [p.e. -CH2-NH-C (= 0) -CH (CH3) 2 or and its corresponding N-oxides, and their prof macos, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixa) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixa) in which: W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2- CH2-CH2-; Z represents CH; R7 represents hydrogen; R8 represents (i) hydro- geno, (i) C1-4 alkyl [e.g. CH3, CH2CH3, CH (CH3) 2 or CH (CH3) CH2CH3], (üi) - OCH2CH3]; R9 represents (i) hydrogen; (ii) C1-7 alkyl [e.g. -CH3, -CH2CH2CH3, -CH (CH3) 2 or -CH2-CH2-CH (CH3) 2]; (üi) aryl [e.g. phenyl]; (iv) -C (= 0) NY1Y2 [e.g. - C (= 0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2CH3, C (= 0) -NH-CH2CH (CH3) 2, - C (= 0) -NH-CH (CH3) 2 , - 0 (= 0) - ?? - ^? ¾, C (= 0) - H-C (CH3) 2CH2OH, - C (= 0) -NH-CH2CH2OCH3, - C (= 0) -N (CH3) 2, C (= 0) -N (CH2CH3) 2, - C (= 0) -NH -C (= 0) -NH-CHL (v) -N (R6) C (= 0) R4, wherein (a) R4 is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocycloalkyl, NY ^ Y ^ -OR ^ [p.e. - NH-C (= 0) -CH3, - H-C (= 0) - (CH2) 2CH3, - NH-C (= 0) -CH (CH3) 2, - NH-C (= 0) ~ C (CH3) 3, - NH-C (= 0) -CH2CH (CH3) 2 > - H-C (= 0) -CH (CH3) CH2CH3, - NH-C (= 0) ~ CH2C (CH3) 3, -NH-C (= 0) -CH2OCH3], (b) R4 is aryl [e.g.
-NH-C (= 0) - < or]; (vi) -N (R6) C (= 0) NY1 Y2, particularly -NHC (= 0) NY1Y2 [e.g. - NH-C (= 0) -NHCH3, - H-C (= 0) - HC¾CH3, - NH-C (= 0) -NHCH (CH3) 2. - NH-C (= 0) -NHCH2CH (CH3) 2 > - H-C (= 0) -NHC (CH3) 3. - NH-C (= 0) -N (CH3) 2. - NH-C (= 0) -N (CH2CH3) 2, - NH-C (= 0) -NH- ^], - NH-C (= 0) ~ H-CH2- alkyl subs substituted with -N (R6) C (= 0) NY1Y2 [p.e. -CH2-NH-C (= 0) -CH (CH3) 2 or i and its corresponding N-oxides, and its prodrugs, and its acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (IXa) and their N-oxides and their prodrugs and their acid bioisoesters. The compounds of formula (Ixa) wherein R8 is hydrogen or -CH3 and R9 is -CH2-CH2-CH (CH3) 2, - C (= 0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2CH3, - C (= 0) -NH-CH (CH3) 2, - C (= 0) -NH-C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) -NH- C (= 0) -NH-CH2CH2OCH3, - C (= 0) -N (CEL) 2, - C (= 0) -N (CH2CH3) 2, - NH-C (= 0) -CH (CH 3) 2, - H-C (= 0) -C (CH 3) 3, - NH-C (= 0) -CH 2 CH (CH 3) 2 NH-C (= 0) -CH (CH3) CH2CH3, - H-C (= 0) -CH, C (CH3) 3, -NH-C (= 0) ^^ - CH3, - H-C (= 0) -NH-C (= 0) - NH-C (= 0) - HCH (CH3) 2. - NH-C (= 0) -MiC (CH3) 3 · NH-C (= 0) -N (CH3) 2, - NH-C (= 0) -N (CH2CH3) 2, - NH-C (= 0) - they are particularly preferred. The compounds of formula (Ixa) in which R9 represents hydrogen · and R8 represents -CH (CH3) 2, -S-CH3, -S- CH2CH3 -S- CH. they are particularly preferred.
The compounds of formula (Ixa) in which W is CH, X is CF C-O-CH- ([, C-C (-0) -NH-CH3, C-C (= 0) -NH-CH2CH3, C-C (= 0) -NH-CH (CH3) 2, C-C (= 0) - H-C (CH3) 2-CH2OH, C- C (= 0) -NH-CH2CH2CN, C-C (= 0) -NH-CH2CH2OCH3, C-C (= Q) -NH ^, C-C (= 0) OCH3 j C-C (= 0) OH > C-CH (OH) ^ C-SO2CH3 or C-SO-NH-CH2- y and Z is CH are particularly preferred. The compounds of formula (Ixa) in which W is CH, X is C-CH3 or C-CH2CH3, Y is C-CH3, C-CH2CH3, C-CH (CH3) 2, C-Br, C-CI, CF, C y, and Z is CH are also particu larly preferred. The compounds of formula (Ixa) wherein W is CH, X is C-OCH3, Y is CH, C-CH3, C-CH2CH3, C-CI or C-OCH3 and Z is CH are also particularly preferred. Compounds of formula (Ixa) wherein W is CH, X is C-OCH2CH3, Y is C-F and Z is CH are also particularly preferred.
Compounds of formula (Ixa) in which W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2- and Z represents CH are also particularly preferred. Compounds of formula (Ixa) in which W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2-O-CH2- and Z represents CH are also particularly preferred. The compounds of formula (Ixa) in which R8 is hydrogen or -CH3 and R9 is is -C (= O) -NH-CH2CH3, - C (= 0) -Mí-CH2C¾CH3, - C (= 0) -NH-CH (CH3) 2, - C (= 0) - H-CH2CH (CH3) 2, - C (= 0) -NH- C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) -N (CH2CH3) 2, - C (= 0) -NH- - NH-C (= 0) - (CH ^ CH,, - NH-C (= 0) -CH (CH3) 2, - NH-C (= 0) -C (CH3) 3, - H-C (= 0) -CH2CH (CH3) 2, - H-C (= 0) -CH (CH) CH, CH3, NH-C (= 0) -CH2C (CH3) 3, - NH-C (= 0) - NH-C (= 0) -NHC (CH3) 3, - NH-C (= 0) - N (CH3) 2, - NH-C (= 0) - N (CH2CH3) 2, - H-C (= 0) - H- < ], - H-C (= 0) - H-CH.
- H- C (= Q) - 0 are especially preferred.
The compounds of formula (Ixa) in which W is CH, X is CH, Y is C-OCH3, C-OCH2CH3, C-OCHF2, C-CF3, C- C (= 0) - H- CHj- > and Z is CH are especially preferred. or The compounds of formula (Ixa) in which W is CH, X is C-CH3 or C-CH2CH3, Y is C-CH3 or C-CH2CH3, C-CI or C-F and Z is CH are ta¬ also especially preferred. The compounds of formula (Ixa) in which W is CH, X is C-OCH3, Y is C-CH3, C-CH2CH3, C-CI, C-F or C-OCH3 and Z is CH are also especially preferred. The compounds of formula (Ixa) in which W is CH, X is C-OCH 2 CH 3, Y is C-CI or C-F and Z is CH are also especially preferred.
The compounds of formula (Ixa) in which W represents CH, X represents CR2 and Y represents CR3 where R2 and R3 form the group -CH2-CH2-CH2-, and Z represents CH are also especially preferred.
The compounds of formula (Ixa) in which W represents CH, X represents CR2 and Y represents CR3 where R2 and R3 form the group -CH2-O-CH2-, and Z represents CH are also especially preferred.
Another particular group of compounds of the invention is constituted by the compounds of formula (Ix) wherein R 1 is a heteroaryl moiety where R and R together with the carbon atoms to those which are attached form an optionally substituted phenyl ring, that is, compounds of formula (Ixb): (Ixb) wherein W, X, Y, Z and R7 are as defined above for the compounds of formula (Ix); R 10 is carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4 -C (= 0) R 4 -0 (= 0) 2, -C (= 0) OR 4, -N (R6) S02NY1Y2, -NY1 Y2, -OR, -OCF2H, -OCF3, -OC (= 0) R4, -00 (= 0) ???? 2, -S (0) nR4 or -S ( 0) 2NY1Y2; and p is zero or an integer 1; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) tabies of the compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisoesters. The compounds of formula (Ixb) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH3 are preferred. The compounds of formula (Ixb) in which W represents CH, X represents CH, Z represents CH and Y represents: (i) C-C 1-4 alkyl [p. C-CH3, C-CH2CH3. C-CH2CH2CH3 0 C- CH (CH3) 2]; (ii) (iii) C-CN; (iv) C-N02; (v) C-halo [e.g. C-Br, C-CI or C-F]; (vi) C-haloalkyl [e.g. C-CF3]; (vii) C-heteroaryl [e.g. ]; (Vi) C-OR4 [e.g. C-OCH3, C-OCH2CH3, C-OCHF2, C-OCF3, ? G C-0- (CH2) 2 -N w Pl; (x) C-C = 0) NY1Y2 [e.g. CC (= 0) -NH-CH3, CC (= 0) -N (CH3) 2, CC (= 0) -NH-CH2CH3, CC (= 0) -NH-CH (CH3) 2, CC (= 0) ) - HC (CH3) 2-CH2OH, CC (= 0) - H-CH2CH2CN, CC (= 0) -NE-CH2CH2OCH3. (xi) C-C (= 0) 0R4 [p.e. C-C (= 0) OH or C-C (= 0) OCH3]; (xii) C-NHC (= 0) R4 [p.e. C-NHC (= 0) CH3, C-NHC (= 0) CH (CH3) 2l (xiii) C-CH (OH) aryl [e.g. C-CH (OH) - -]; (xiv) C-S (0) 2NY1Y2 [p.e. ]; or (xv) C-S (0) NR4 [e.g. C-S02CH3]; they are also preferred. The compounds of formula (Ixb) in which W represents CH, X represents CH, Y represents C-CH3 and Z represents C-CH3 are also preferred. Compounds of formula (Ixb) in which W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-, and Z represents CH are also preferred.
The compounds of formula (Ixb) in which W represents CH, X represents CR ^ and Y represents CR3 wherein R ^ and R3 form the group -CH2-CH2-CH2-, and Z represents CH are also preferred. Compounds of formula (Ixb) in which R7 represents hydrogen are preferred. The compounds of formula (Ixb) wherein p is zero or one are preferred. The compounds of formula (Ixb) wherein R10 represents: (i) cyano (ii) halo [e.g. chlorine, fluorine]; (iii) alkyl C- | _4 [e.g. methyl, (iv) -OR4 [p.e. -OCH3, -OCH2CH3]; or (v) -C (= 0) NY1Y2 [e.g. -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2, -C (= 0) -N (CH3) 2 are preferred. A preferred group of compounds of the invention is constituted by the compounds of formula (Ixb) in which: W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; R 10 represents (i) cyano, (ii) halo [e.g., chloro or fluoro], (iii) C 1-4 alkyl [e.g. methyl], (iv) -OR4 [p.e. -OCH3 or -OCH2CH3] or (v) -C (= 0) NY1Y2 [p.e. -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2]; and their corresponding N-oxides and their prodrugs, and their bioisoesters of acid two; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixb) in which: W represents CH; X represents CH; Z represents CH; Y represents (i) C-C 1-4 alkyl [e.g. C-CH3, C-CN, (iv) C-NO2, (v) C-halo [e.g. C-Br, C-CI or C-F], (vi) C-haloalkyl [e.g.
C-CF3], (vii) C-heteroaryl [e.g. ], (viii) C-OR4 [p.e. C-OCH3, C-OCH2CH3, C-OCHF2, C-OCF3, C- O- // w [p.e. [p.e. C-C (= 0) -NH-CH3 C- C (= 0) -N (CH 3) 2, C-C (= 0) -NH-CH 2 CH 3, C-C (= 0) -NH-CH (CH 3) 2 C-C (= 0) -NH-C (CH 3) 2-CH 2 OH; C-C (= 0) - H-CH2CH2CN, C (= 0) OR4 [p.e. C-C (= 0) OH or C-C (= 0) OCH3], (xii) C-NHC (= 0) R4 [e.g. or [p.e.
C-CH (OH)], (xiv) C-S (0) 2NY1Y2 [e.g. ] or (xv) C-S (0) nR4 [p.e. C-S02CH3]; R7 represents hydrogen; p is zero or one; R10 represents (i) cyano, (ii) halo [e.g. chlorine, fluorine], (iii) Ci-4 alkyl [e.g. methyl], (iv) -O ^ [p.e. - OCH3 or -OCH2CH3] or (v) -0 (= 0) ?? "?? 2 [pe -C (= 0) -NH2, -C (= 0) - HCH (CH3) 2 or -C (= 0) -N (CH3) 2], and their corresponding N-oxides, and their prodrugs and their acid bioisoesters, and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixb) and their N oxides and their prodrugs, and their acid bioisoesters A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixb) in which: W represents CH, X represents C-CH3, C-CH2CH3, C -CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-CI, CF, I; Z represents CH; R7 represent ta hydrogen; p is zero or one; R10 represents (i) cyano, (ii) halo [e.g. chlorine, fluorine or], (ii) C1-4 alkyl [e.g. methyl], (iv) -OR4 [p.e. -OCH3 or -OCH2CH3] or (v) -C (= 0) NY1 Y2 [e.g. -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2]; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula Ixb) in which: W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; p is zero or one; R 0 represents (i) cyano, (ii) halo [e.g. chlorine, fluorine], (iii) C1-4 alkyl [e.g. methyl], (iv) -OR4 [p.e. -OCH3 or -OCH2CH3] or (v) -C (= 0) NY1Y2 [p.e. -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2]; and their corresponding N-oxides and their prodrugs, and their acid bio-esters; and pharmaceutically acceptable salts and solvates (for example, hydrates) of the compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula Ixb) in which: W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; R7 represents hydrogen, p is zero or one; R10 represents (i) cyano, (ii) halo [e.g. chlorine, fluorine], (iii) C ^ alkyl [p.e. methyl], (iv) -OR4 [p.e. -OCH3 or -OCH2QH3] or (v) -C (= 0) NY1Y2 [e.g. -C (= 0) -NH2, -C (= 0) -NHCH (CH 3) 2 ° -C (= 0) -N (CH 3) 2]; and their corresponding N-oxides and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and sovas (e.g. hydrates) of the compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixb) in which: W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R7 represents hydrogen; p is zero or one; R10 represents (i) cyano, (ii) halo [e.g. chlorine, fluorine], (iii) Ci-4 alkyl [e.g. methyl], (iv) -OR4 [p.e. -OCH3 or -OCH2CH3] or (v) -C (= 0) NY Y2 [e.g. -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) ¿l; and their corresponding N-oxides and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and sovas (e.g. hydrates) of the compounds of formula (Ixb) and their N-oxides and their prodrugs, and their acid bioisoesters. The compounds of formula (Ixb) in which R7 represents hydrogen and p is zero are particularly preferred. The compounds of formula (Ixb) wherein R7 represents hydrogen; p is one and R10 represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3, -C (= 0) - NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2 are also particularly preferred. The compounds of formula (Ixb) wherein R7 represents hydrogen; p is one and R10 represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3, -C (= 0) -NH 2, -C (= 0) -NHCH (CH 3) 2 0 -C (= 0) -N (CH 3) 2 are also particularly preferred. The compounds of formula (Ixb) in which W is CH, X is CH, C-C (= 0) - H-CH (CH | 33) h 'C-C (= 0) -NH-C (CH,) 2-CH, OH C-C (= 0) - H-CH2CH2CN, C-C (= 0) -NH-CH2CH2OCH3 - C-SO2CH3 or C-SO-NH-CH- // W CH are particularly preferred ridos. The compounds of formula (Ixb) wherein W is CH, X is C-OCH3, Y is CH, C-CH3, C-CH2CH3, C-CI or C-OCH3 and Z is CH are also * particularly preferred. The compounds of formula (Ixb) wherein W is CH, X is C-OCH 2 CH 3, Y is C-F and Z is CH are also particularly preferred. The compounds of formula (Ixb) in which W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-, and Z represents CH are also particularly preferred.
The compounds of formula (Ixb) in which W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-, and Z represents CH are also particularly preferred. The compounds of formula (Ixb) in which R7 represents hydrogen and p is zero are especially preferred. The compounds of formula (Ixb) in which R7 represents hydrogen; p is one and R10 represents -OCH3, -OCH3, -OCH2CH3 or ~ C (= 0) -NHCH (CH3) 2 linked to the 5-position of the indazolyl ring are also especially preferred. Compounds of formula (Ixb) wherein W is CH, X is C-CH3 or C-CH2CH3, Y is C-CH3 or C-CH2CH3 and Z is CH are also especially preferred. Another particular group of compounds of the invention is constituted by the compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9 together with the carbon atoms to those which are attached form an optionally substituted cycloalkyl ring C5-8, ie, compounds of formula (Ixc): (lxc) wherein W, X, Y, Z, X and p are as defined above for the compounds of formula (Ix), is a C5-8 cycloalkyl ring and R 12 is acyl, acylamino, alkoxy, alkoxycarbonyl, alkylenedioxy, alkylsulfinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy (or an acid bioisoester ), cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, -C (= 0) NY1Y2, -NY -C (= 0) alkyl, -NY1S02alkyl, - ???? 2, -SC ^ NYIY2 O alkyl, alkenyl or alkynyl; each of which is optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C (= 0) OR6, -C (= 0) NY Y2, -NY1Y2 or -OR5; or their corresponding N-oxides and their prodrugs, and their acid bioisoesters, and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (lxc) and their N-oxides and their prodrugs, and their bioisoesters of acids.
The compounds of formula (Ixc) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH3 are preferred. The compounds of formula (Ixc) in which W represents CH, X represents CH, Z represents CH and Y represents: (i) C-C 1-4 alkyl [p. C-CH3, C-CH2CH3 > C-CH2CH2CH3 0 C- CH (CH3) 2]; (i) (iii) C-CN; (iv) C-N02; (v) C- alo [p.e. C-Br, C-CI or C-F]; (vi) C-haloalkyl [e.g. C-CF3]; (vii) C-heteroaryl [e.g. c]; (vii) C-OR4 [p.e. C-OCH3, C-OCH2CH3, C-OCHF2, C-OCF3, O C-0- (CH2) RN p]; C-C = 0) NY1Y2 [e.g. C-C (= 0) -NH-CH3, C ~ C (= 0) -N (CH3) 2 C ^ C (= 0) -NH-CH2CH3, · C-C (= 0) - H-CH2CH2CN, C-C (= 0) -NH-CH2CH2OCH3, C-C (= 0) -NH-CH2 - ^^^ CH3, C-C (^ -mL-CH ^^ (xi) C-C (= 0) 0R4 [p.e. C-C (= 0) OH or C-C (= 0) OCH3]; (xii) C-NHC (= 0) R4 [p.e. C-NHC (= 0) CH3, C-NHC (= 0) CH (CH3) 2, (xiü) C-CH (OH) aryl [e.g. C-CH (OH) - (xiv) C-S (0) 2NY1Y2 [p.e. c-S02-NH-CH2? ]; (xv) C-S (0) nR4 [p.e. C-S02CH3]; they are also preferred. The compounds of formula (Ixc) in which W represents CH, X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br 0 C-CI, Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-CI, C-F, and Z represents CH are also preferred.
The compounds of formula (Ixc) in which W represents CH, X represents CH, Y represents C-CH3 and Z represents C-CH3 are also preferred. The compounds of formula (Ixc) in which W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-0-CH2- and Z represents CH are also preferred. The compounds of formula (Ixc). wherein W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2-CH2-CH2- and Z represents CH are also preferred. The compounds of formula (Ixc) in which R7 represents hydrogen are preferred.
The compounds of formula (Ixc) in which represents a cyclopentyl, cyclohexyl and cycloheptyl ring, especially cyclohexyl, are preferred. The compounds of formula (Ixc) in which q is zero are preferred. A preferred group of compounds of the invention are compounds of formula (Ixc) in which: W represents CH; X represents CH; And re¬ presents CH; Z represents CH or C-CH3; R7 represents hydrogen; represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides and their prodrugs, and their acid bioisoesters; Y pharmaceutically acceptable salts and solvates (for example, hydrates) of the compounds of formula Ixc) and their N-oxides and their prodrugs, and their acid bio-esters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixc) in which: W represents CH; X represents CH; Z represents CH; Y represents (i) C-C 1-4 alkyl [e.g. C-CH3, C-CN, (iv) C-NO2, (v) C-halo [e.g. C-Br, C-CI or C-F], (vi) C-haloalkyl [e.g. 4 .
C-C (0) -N (CH3) 2, C-C (= 0) -NH-CH2CH3, C-C (= 0) - H-CH (CH3) 2, C-C (= 0) -NH-C (CH3)? - CH2OH C-C (= 0) - H-CH2CH2CN, [p.e. C-C (= 0) OH or C-C (= 0) OCH3], (xii) C-NHC (= 0) R4 [e.g. C-NHC (= 0) CH3 sat a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; and their corresponding N-oxides and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of the compounds of the invention is constituted by the compounds of formula (Ixc) in which: W represents CH; X represents C-CH 3, C-CH 2 CH 3, C-CH (CH 3) 2, C-OCH 3, C-OCH 2 CH 3 1 C-Br 0 C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-; Z represents CH; R7 represents clopentyl, cyclohexyl or cycloheptyl; q is zero; and their corresponding N-oxides, and their prodrugs and its acid bio-esters; and pharmaceutically acceptable salts and solvates- (eg, hydrates) of the compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixc) in which W represents CH; X represents. CH; Y represents C-CH3; Z represents C-CH3; R7 represents¬ ta hydrogen; represents a cyclopentyl, cyclohexyl or cycloheptyl ring the; q is zero; and their corresponding N-oxides and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (xb) in which: W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-0- CH2-; Z represents CH; R7 represents hydrogen; represents a ring cyclopentyl, cyclohexyl or cycloheptyl; q is zero; and their corresponding N-oxides, and their prodrugs and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (eg, hydrates) of the compounds of formula (xc) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixb) in which: W presents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R7 represents hydrogen; represents a cyclopentyl, cyclohexyl or cycloheptyl ring; q is zero; Y their corresponding N-oxides, and their prodrugs and their acid bio-esters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixc) and their N-oxides and their prodrugs, and their acid bioisoesters. The compounds of formula (Ixc) in which R7 represents hydrogen and p is zero are particularly preferred. The compounds of formula (Ixc) wherein W is CH, X is C-CH3, Y is C-CH3 and Z is CH are also particularly preferred.
The compounds of formula (Ixc) in which is a ring cyclopentyl are particularly preferred. Another particular group of compounds of the invention is constituted by the compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9 together with the carbon atoms to those which are attached form an optionally substituted heterocycloalkyl ring, ie, compounds of formula (Ixd): (Ixd) wherein W, X, Y, Z and X are as defined above for compounds of formula (Ix), X1 is O, S, SO2, or NY5 (where? 5 is hydrogen, R4, -C (= 0) R4, -0 (= 0) ???? 2, -C (= 0) 0R4 or -S02R4), r is zero or a whole number one or two and R 3 is alkyl or two R 3 groups attached to the same carbon atom form an oxo group; and their corresponding N-oxides, and their prodrugs and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisoesters. Compounds of formula (Ixd) in which W represents CH, X represents CH, Y represents CH and Z represents CH or C-CH3 are preferred. The compounds of formula (Ixd) in which W represents CH, X represents CH, Z represents CH and Y represents: "(i) C 1-4 alkyl [eg C-CH 3, C-CH 2 CH 3 'C-CH 2 CH 2 CH 3 C-CH (CH3) 2]; (ii) (iii) C-CN; (iv) C-NO2; (v) C-halo [e.g. C-Br, C-CI 0 C-F]; (vi) C-haloalkyl [e.g. C-CF3]; (vii) C-heteroaryl [e.g. ]; (viii) C-OR4 [p.e. C-OCH3, C-OCH2CH3, C ~ OCHF2, C-OCF3 (x) C-C = 0) NY1 Y2 [e.g. C ~ C (= 0) -NH-CH3, C-C (= 0) -N (CH3) 2, C-C (= 0) -NH-CH2CH3, C-C (= 0) - H-CH (CH3) 2, C-C (= 0) - H-C (CH 3) 2-CH 2 OH, C-C 4 CO-N i i -CH 2 CN, (xi) C-C (= 0) OR4 [p.e. C-C (= 0) OH or C-C (= 0) OCH3]; (xii) C-NHC (= 0) R4 [p.e. C-NHC (= 0) CH3, C-NHC (= 0) CH (CH3) 2, (xiii) C-CH (OH) aryl [e.g. C-CH (OH) d? ]; (xiv) C-S (0) 2NY Y2 [e.g. or (xv) C-S (0) nR4 [p.e. C-S02CH3]; they are also preferred. The compounds of formula (Ixd) in which W represents CH, X represents C-CH 3, C-CH 2 CH 3, C-CH (CH 3) 2, C-OCH 3, C-OCH 2 CH 3, C-Br 0 C-Cl, Y represents C-CH3, C-CH2CH3,. C-OCH3, C-Br, C-CI, C-F, and Z represents CH are also preferred. The compounds of formula (Ixa) in which W represents CH, X represents CH, Y represents C-CH3 and Z represents C-CH3 are also preferred. Compounds of formula (Ixd) in which W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2-O-CH2- and Z represents CH are also preferred.
Compounds of formula (Ixd) in which W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2-CH2-CH2- and X represents CH are also preferred. Compounds of formula (Ixd) in which R7 represents hydrogen are preferred. The compounds of formula (Ixd) wherein X 1 is: (i) O; (ii) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N- C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 0 ]; N-C (= 0) NY1Y2 [e.g. N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2) (iv) N-C (= 0) OR4 [e.g. N-C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02R4 [p.e. N-S02CH3 or N-S02CH (CH3) 2]; they are preferred. Compounds of formula (Ixd) in which r is zero are preferred. A preferred group of compounds of the invention is constituted by the compounds of formula (Ixd) in which: W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen;; X1 is (i) O; (ii) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 0 N- (C = 0)]; (ii) N-C (= 0) NY1Y2 [e.g. N-C (= 0) N (CH3) 2, N- C (-0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N- (C = 0) -N [p.e. N- C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02R4 [p.e. N-S02CH3 or N-SÜ2CH (CH3) 2] and r is zero; and their corresponding N-oxides, and their prodrugs and their bioisoesters; and pharmaceutically acceptable salts and solvates (e.g., hydrate) of the compounds of formula (Ixd) and their N-oxides and their prodrugs and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixd) in which: W represents CH; X represents CH; Z represents CH, Y represents (i) C-C1- alkyl [p.s.
C-CH3, C-CH2CH3 > C-CH2CH2CH3 0 C-CH (CH3) 2], (ii) C-aryl [e.g. c- / X c- // ^ C- C (= 0) -NH-CH3, C-C (= 0) -N (CH3) 2, C-C (= 0) - H-CH2CH3, C-C (= 0) -NH-CH (CH3),, C-C (= 0) - H-C (CH3) 2-CH2OH: C-C (= 0) - H-CH2CH2CN, C-C (= 0) - H-CH2CH2OCH3 C (= 0) OCH3], (xii) C-NHC (= 0) R4 [e.g. C-NHC (= 0) CH3 or C- (xiii) C-CH (OH) aryl [e.g. C-CH (OH) - 1, fxiv) C-S (0) 2NY1Y2 [p.e. C-S02-NH-CH2- ^ ~ ^ > ] or '(XV) C-S (0) nR4 [p.e. C-S02CH3]; R7 represents hydrogen; X1 is (i) O; (ii) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N- C (= 0) CH2CH (CH3) 2. N-C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 N- (C = 0) N-C (= 0) NY Y2 [e.g. N-C (= 0) N (CH3) 2, C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N- (C = 0) -N C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02 4 [e.g. N-S02CH3 or N-S02CH (CH3) 2] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixd) in which: W represents CH, X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C -OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-Cl, C-F, C- // W Z represents CH; R7 repre sat hydrogen; X1 is (i) O; (ii) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 0 N- (C = 0)]; (iii) N-C (= 0) NY1Y2 [e.g. N-C (= 0) N (CH3) 2, N- - C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02R4 [p.e. N-S02CH3 or N-S02CH (CH3) 2] and r is zero; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and their pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisoesters. A preferred group adds! of compounds of the invention is constituted by the compounds of formula (Ixd) in which: W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; X1 is (i) O; (I) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 0 N - (C = 0)]; (iii) N-C (= 0) NYlY2 [e.g. N-C (= 0) N (CH3) 2, N- C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N- (C = 0) -N C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02R4 [p.e. N-S02CH3 or N-S02CH (CH3) 2] and r is zero; and their corresponding N-oxides, and their prodrugs cos and its acid bio-esters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixd) in which: W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; R7 represents hydrogen; X1 is (i) O; (ii) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N-C (-0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 or N- (O0) - < ]; (iii) N-C (= 0) NY1Y2 [e.g.
N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N- (C = 0) -N (ÍV) N- C (= 0) OR4 [p.e. N-C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02R4 [p.e. N- S02CH3 or N-S02CH (CH3) 2] and r is zero; and their corresponding N-oxides, and their prodrugs and their acid bioisoesters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixd.) and their N-oxides and their prodrugs, and their acid bioisoesters. A further preferred group of compounds of the invention is constituted by the compounds of formula (Ixd) in which: W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R7 represents hydrogen; X "1 is (i) O; (ii) N-C (= 0) R4 [e.g. N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, or N-C (= 0) C (CH3) 3 or [p.e.
N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2, N- (C = 0) -N ^ ol (iv) N-C (= 0) OR4 [p.e. N-C (= 0) OCH3 or N-C (= 0) OCH2CH3]; or (v) N-S02R4 [e.g., N-S02CH3 or N-S02CH (CH3) 2] and r is zero; and their corresponding N-oxides, and their prodrugs and their acid bio-iso esters; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of the compounds of formula (Ixd) and their N-oxides and their prodrugs, and their acid bioisoesters. The compounds of formula (Ixd) wherein X1 is N- C (= 0) CH (CH3) 2, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) C (CH3) 3; N- (O0) - N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2, N- (C = 0) -N. N- (O0) -t, N-C (= 0) OCH3 or N-C (= 0) OCH2CH3 and r is zero are particularly preferred. The compounds of formula (Ixd) in which W is CH, X is CH, CN Y is CH, C-CH CH3, C-CH2CH2CH3, c- // w C-C (= 0) -NH-CH (CH3) 2, C-CC ^ -NH-CC ^ J-CHJOH, C-C (= 0) - H-CH2CH2CN, C-C (= 0) -NH-CH2CH2OCH3, ridos. The compounds of formula (Ixd) wherein W is CH, X is C-CH3 or C-CH2CH3, Y is C-CH3, C-CH2CH3, C-CH (CH3) 2, C-Br, C-CI, CF, , and Z is CH are also particu larly preferred. The compounds of formula (Ixa) in which W is CH, X is C-OCH3, Y is CH, C-CH3, C-CH2CH3, C-CI or C-OCH3 and Z is CH are also particularly preferred. The compounds of formula (Ixd) wherein W is CH, X is C-OCH 2 CH 3, Y is C-F and Z is CH are also particularly preferred.
The compounds of formula (Ixd) in which W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2- CH2-CH2- and Z represents CH are also particularly preferred. The compounds of formula (Ixd) in which W represents CH, X represents CR2 and Y represents CR3, wherein R2 and R3 form the group -CH2-0-CH2- and Z represents CH are also particularly preferred. positions of formula (Ixd) in which X1 is N - (C = 0) N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2, - (O0) -N y j y is zero they are especially preferred.
The compounds of formula (Ixd) in which W represents CH, X represents C-CH3, Y represents C-CH3 or C-CI and Z represents CH are espe¬ cially preferred.
The particular compounds of the invention of formula (Ix) are selected from the compounds formed by the linking of the carbon (C *) of one of the fragments of benzoimidazole, imidazo [4,5- b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine (A1 to A110) two in Table 1 to the carbon atom at (* C) of the heteroaryl moiety of one of the fragments (B1 to B168) shown in Table 2.
The particular compounds of the invention of formula (lxa) are select between the compounds formed by the union of the atom of carbon (C *) of one of the fragments of benzoimidazole, imidazo [4,5-bjpyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine (A1 to A110) two in Table 1 to the carbon atom (* C) in the pyrazole ring of one of the fragments (B1 to B48, B74 to B107, B124 to B127, 130 to 142 or 144 to 150) shown in Table 2.
The particular compounds of the invention of formula (IXb) are also selected from the compounds formed by the attachment of the carbon atom (C *) of one of the benzoimidazole fragments, imidazo [4,5-b] pyridine. , imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine (A1 to A1 10) shown in Table 1 to the carbon atom (* C) in the five-membered ring of one of the fragments (B63 to B73, B108 to B114, B128 or B151) shown in Table 2. The particular compounds of the invention of formula (Ixc) are selected from the compounds formed by the carbon atom attachment (C *). ) of the fragments of behzoimidazole, imidazo [4,5-b] pyridine, imi-dazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine (A1 to A1 10) shown in Table 1 to carbon atom (* C) in the five-membered ring of one of the fragments (B56, B59 or B129) shown in Table 2. The particular compounds of the invention of formula (Ixd) are selected from the compounds formed by binding the carbon atom (C *) of one of the fragments of benzoimidazole, imidazo [4,5-b] pyridine, imidazo [4,5-c] pyridine or imidazo [4,5-b] pyrazine (A1 to A110) shown in Table 1 to the carbon atom (* C) of the five-membered ring of one of the fragments (B1 15 to B123 or B157) shown in Table 2.
TABLE 1 TABLE 2 639 Z29 929 S28 1-29 61-a Particular compounds of the invention of formula (Ix) indicate the product of the combination of group A1 to A110 in Table 1, and B 69 in Table 2, are illustrated below: A1-B1; A1-B2; A1-B3; A1-B4; A1-B5; A1-B6; A1-B7; A1-B8; A1-B9; A1-B10; A1-B11; A1-B12; A1-B13; A1-B14; A1-B15; A1-B16; A1-B17; A1-B18; A1-B19; A1-B20; A1-B21; A1-B22; A1-B23; A1-B24; A1-B25; A1-B26; A1-B27; A1-B28; A1-B29; A1-B30; A1-B31; A1-B32; A1-B33; A1-B34; A1-B35; A1-B36; A1-B37; A1-B38; A1-B39; A1-B40; A1-B41; A1-B42; A1-B43; A1-B44; A1-B45; A1-B46; A1-B47; A1-B48; A1-B49; A1-B50; A1-B51; A1-B52; A1-B53; A1-B54; A1-B55; A1-B56; A1-B57; A1-B58; A1-B59; A1-B60; A1-B61; A1-B62; A1-B63; A1-B64; A1-B65; A1-B66; A1-B67; A1-B68; A1-B69; A1-B70; A1-B71; A1-B72; A1-B73; A1-B74; A1-B75; A1-B76; A1-B77; A1-B78; A1-B79; A1-B80; A1-B81; A1-B82; A1-B83; A1-B84; A1-B85; A1-B86; A1-B87; A1-B88; A1-B89; A1-B90; A1-B91; A1-B92; A1-B93; A1-B94; A1-B95; A1-B96; A1-B97; A1-B98; A1-B99; A1-B100; A1-B101; A1-B102; A1-B103; A1-B104; 'A1-B105; A1-B106; A1-B107; A1-B108; A1-B109; A1-B110; A1-B111; A1-B112; A1-B113; A1-B114; A1-B115; A1-B116; A1-B117; A1-B118; A1-B119; A1-B120; A1-B121; A1-B122; A1-B123; A1-B124; A1-B125; A1-B126; A1-B127; A1-B128; A1-B129; A1 -B130; ? 1-? 131; ? 1- 132; A1-B133; A1-B134; A1-B135; ? 1-? 136; ? 1-? 137; ? 1-? 138; A1-B139; A1-B140; A1-B141; ? 1-? 142; ? 1-? 143; ? 1-? 144; A1-B145; A1-B146; A1-B147; ? 1-? 148; ?1-? 49; ? 1- 150; A1-B151; A1-B152; A1-B153; ? 1-? 154; ? 1-? 155; ? 1- 156; A1-B157; A1-B158; A1-B159; ? 1-? 160; ? 1-? 161; 1- 1- 162; A1-B163; A1-B164; A1-B165; ? 1-? 166; ? 1-? 167; ? 1-? 168; A1-B169; A2-B1; A2-B2; ? 2-? 3;,? 2-? 4; ? 2-? 5; A2-B6; A2-B7; A2-B8; ? 2-? 9; ? 2-? 10; ? 2-? 11; A2-B12; A2-B13; A2-B14; ? 2-? 15; ? 2-? 16; ? 2-? 17; A2-B18; A2-B19; A2-B20; ? 2-? 21; ? 2-? 22; ? 2-? 23; A2-B24; A2-B25; A2-B26; ? 2-? 27; ? 2-? 28; ? 2-? 29; A2-B30; A2-B31; A2-B32; ? 2-? 33; ? 2-? 34; ? 2-? 35; A2-B36; A2-B37; A2-B38; ? 2-? 39; ? 2-? 40; ? 2-? 41; A2-B42; A2-B43; A2-B44; ? 2-? 45; ? 2-? 46; ? 2-? 47; A2-B48; A2-B49; A2-B50; -? 2-? 51; ? 2-? 52; ? 2-? 53; A2-B54; A2-B55; A2-B56; ? 2-? 57; ? 2-? 58; ? 2-? 59; A2-B60; A2-B61; A2-B62; ' ? 2-? 63; ? 2-? 64; ? 2-? 65; A2-B66; A2-B67; A2-B68; ? 2-? 69; ? 2-? 70; ? 2-? 71; A2-B72; A2-B73; A2-B74; ? 2-? 75; ? 2-? 76; ? 2-? 77; A2-B78; A2-B79; A2-B80; ? 2-? 81; ? 2-? 82; ? 2-? 83; A2-B84; A2-B85; A2-B86; ? 2-? 87; ? 2-? 88; ? 2-? 89; A2-B90; A2-B91; A2-B92; ? 2-? 93; 2- 2- 94; ? 2-? 95; A2-B96; A2-B97; ? 2-? 9¾ ·? 2-? 99; ? 2-? 100; ? 2- 101; A2-B102; A2-B103; 2- 2- 104; 2- 2- 105; ? 2-? 106; ? 2-? 107; A2-B108; A2-B109; A2-B110; A2-B11 1; A2-B1 12; A2-B1 13; A2-B114; A2-B115; A2-B116; A2-B117; A2-B118; A2-B119; A2-B120; A2-B121; A2-B122; A2-B123; A2-B124; A2-B125; A2-B126; A2-B127; A2-B128; A2-B129; A2-B130; A2-B131; A2-B132; A2-B133; A2-B134; . A2-B135; A2-B136; A2-B137; A2-B138; A2-B139; A2-B140; A2-B141; A2-B142; A2-B143; A2-B144; A2-B145; A2-B146- A2-B147; A2-B148; A2-B149; A2-B150; A2-B151; A2-B152; A2-B153; A2-B154; A2-B155; A2-B156; A2-B157; A2-B158; A2-B159; A2-B160; A2-.B161; A2-B162; A2-B163; A2-B164; A2-B165; A2-B166; A2-B167; A2-B168; A2-B169; A3-B1; . A3-B2; A3-B3; A3-B4; A3-B5; A3-B6; A3-B7; A3-B8; A3-B9; A3-B10; A3-B11; A3-B12; A3-B13; A3-B14; A3-B15; A3-B16; A3-B17; A3-B18; A3-B19; A3-B20; A3-B21; A3-B22; A3-B23; A3-B24; A3-B25; A3-B26; A3-B27; A3-B28; A3-B29; A3-B30; A3-B31; A3-B32; A3-B33; A3-B34; A3-B35; A3-B36; A3-B37; A3-B38; A3-B39; A3-B40; A3-B41; A3-B42; A3-B43; . A3-B44; A3-B45; A3-B46; A3-B47; A3-B48; A3-B49; A3-B50; A3-B51; A3-B52; A3-B53; A3-B54; A3-B55; A3-B56; A3-B57; A3-B58; A3-B59; A3-B60; A3-B61; A3-B62; A3-B63; A3-B64; A3-B65; A3-B66; A3-B67; A3-B68; A3-B69; A3-B70; A3-B71; A3-B72; A3-B73; A3-B74; A3-B75; A3-B76; A3-B77; A3-B78; A3-B79; A3-B80; A3-B81; A3-B82; A3-B83; A3-B84; A3-B85; A3-B86; A3-B87; A3-B88; A3-B89; A3-B90; A3-B91; A3-B92; A3-B93; A3-B94; A3-B95; A3-B96; A3-B97; A3-B98; A3-B99; A3-B100; A3-B101; A3-B102; A3-B103; A3-B104; A3-B105; A3-B106; A3-B107; A3-B108; A3-B109; A3-B110; A3-B111; A3-B112; A3-B113; A3-B114; A3-B115; A3-B1 6; A3-B117; A3-B118; A3-B 19; A3-B120; A3-B121; A3-B122; A3-B123; A3-B124; A3-B125; A3-B126; A3-B127; A3-B128; A3-B129; A3-B130; A3-B131; A3-B132; A3-B133; A3-B134; A3-B135; A3-B136; A3-B137; A3-B138; A3-B139; A3-B140; A3-B141; A3-B142; A3-B143; A3-B144; A3-B145; A3-B146; A3-B147; A3-B148; A3-B149; A3-B150; A3-B151; A3-B152; A3-B153; A3-B154; A3-B155; A3-B156; A3-B157; A3-B158; A3-B159; A3-B160; A3-B161; A3-B162; A3-B163; A3-B164; A3-B165; A3-B166; A3-B167; A3-B168; A3-B169; A4-B1; A4-B2; A4-B3; A4-B4; A4-B5; A4-B6; A4-B7; A4-B8; A4-B9; A4-B10; A4-B11; A4-B12; A4-B13; A4-B14; A4-B15; A4-B16; A4-B17; A4-B18; A4-B19; A4-B20; A4-B21; A4-B22; A4-B23; A4-B24; A4-B25; A4-B26; A4-B27; A4-B28; A4-B29; A4-B30; A4-B31; A4-B32; A4-B33; A4-B34; A4-B35; A4-B36; A4-B37; A4-B38; A4-B39; A4-B40; A4-B41; A4-B42; A4-B43; A4-B44; A4-B45; A4-B46; A4-B47; A4-B48; A4-B49; A4-B50; A4-B51; A4-B52; A4-B53; A4-B54; A4-B55; A4-B56; A4-B57; A4-B58; A4-B59; A4-B60; A4-B61; A4-B62; A4-B63; A4-B64; A4-B65; A4-B66-; A4-B67; A4-B68; A4-B69; A4-B70; A4-B71; A4-B72; A4-B73; A4-B74; A4-B75; A4-B76; A4-B77; A4-B78; A4-B79; A4-B80; A4-B81: A4-B82; A4-B83; A4-B84; A4-B85; A4-B86; A4-B87; A4-B88; A4-B89; A4-B90; A4-B91; A4-B92; A4-B93; A4-B94; A4-B95; A4-B96; A4-B97; A4-B98; A4-B99; A4-B100; A4-B101; A4-B102; A4-B103; A4-B104; A4-B105; A4-B106; A4-B107; A4-B108; A4-B109; A4-B110; A4-B111; A4-B112; A4-B113; A4-B114; A4-B1 15; A4-B116; A4-B117; A4-B118; A4-B119; A4-B120; A4-B121; A4-B122; A4-B123; A4-B124; A4-B125; A4-B126; A4-B127; A4-B128; A4-B129; A4-B130; A4-B131; A4-B132; A4-B133; A4-B134; A4-B135; A4-B136; A4-B137; A4-B138; A4-B139; A4-B 40; A4-B141; A4-B142; A4-B143; A4-B144; A4-B145; A4-B146; A4-B147; A4-B148; A4-B149; A4-B150; A4-B151; A4-B152; A4-B153; A4-B154; A4-B155; A4-B156; A4-B157; A4-B158; A4-B159; A4-B160; A4-B161; A4-B162; A4-B163; A4-B164; A4-B165; A4-B166; A4-B167; A4-B168; A4-B169; A5-B1; A5-B2; A5-B3; A5-B4; A5-B5; A5-B6; A5-B7; A5-B8; A5-B9; A5-B10; A5-B11; A5-B12; A5-B13; A5-B14; A5-B15; A5-B16; A5-B17; A5-B18; A5-B19; A5-B20; A5-B21; A5-B22; A5-B23; A5-B24; A5-B25; A5-B26; A5-B27; A5-B28; A5-B29; A5-B30; A5-B31; A5-B32; A5-B33; A5-B34; A5-B35; A5-B36; A5-B37; A5-B38; A5-B39; A5-B40; A5-B41; A5-B42; A5-B43; A5-B44; A5-B45; A5-B46; A5-B47; A5-B48; A5-B49; A5-B50; A5-B51; A5-B52; A5-B53; A5-B54; A5-B55; A5-B56; A5-B57; A5-B58; A5-B59; A5-B60; A5-B61; A5-B62; A5-B63; A5-B64; A5-B65; A5-B66; A5-B67; A5-B68; A5-B69; A5-B70; A5-B71; A5-B72; A5-B73; A5-B74; A5-B75; A5-B76; A5-B77; A5-B78; A5-B79; A5-B80; A5-B81; A5-B82; A5-B83; A5-B84; A5-B85; A5-B86; A5-B87; A5-B88; A5-B89; A5-B90; A5-B91; A5-B92; A5-B93; A5-B94; A5-B95; A5-B96; A5-B97; A5-B98; A5-B99; A5-B100; A5-B101; A5-B102; A5-B103; A5-B104; A5-B105; A5-B106; A5-B107; A5-B108; A5-B109; A5-B110; A5-B1 11; A5-B112; A5-B113; A5-B114; A5-B115; A5-B1 16; A5-B1 17; A5-B118; A5-B119; A5-B120; A5-B121; A5-B122; A5-B123; A5-B124; A5-B125; A5-B126; A5-B127; A5-B128; A5-B129; A5-B130; A5-B131; A5-B132; A5-B133; A5-B134; A5-B135; A5-B136; A5-B137; A5-B138; A5-B139; A5-B140; A5-B141; A5-B142; A5-B143; A5-B144; A5-B145; A5-B146; A5-B147; A5-B148; A5-B149; A5-B150; A5-B151; A5-B152; A5-B153; A5-B154; A5-B155; A5-B156; A5-B157; A5-B158; A5-B159; A5-B160; A5-B161; A5-B162; A5-B163; A5-B164; A5-B165; A5-B166; A5-B167; A5-B168; A5-B169; A6-B1; A6-B2; A6-B3; A6-B4; A6-B5; A6-B6; A6-B7; A6-B8; A6-B9; A6-B10; A6-B11; A6-B 2; A6-B13; A6-B14; A6-B15; A6-B16; A6-B17; A6-B18; A6-B19; A6-B20; A6-B21; A6-B22; A6-B23; A6-B24; A6-B25; - A6-B26; A6-B27; A6-B28; A6-B29; A6-B30; A6-B31; A6-B32; A6-B33; A6-B34; A6-B35; A6-B36; A6-B37; A6-B38; A6-B39; A6-B40; A6-B41; A6-B42; A6-B43; A6-B44; A6-B45; A6-B46; A6-B47; A6-B48; A6-B49; A6-B50; A6-B51; A6-B52; A6-B53; A6-B54; A6-B55; A6-B56; A6-B57; A6-B58; A6-B59; A6-B60; A6-B61; A6-B62; A6-B63; A6-B64; A6-B65; A6-B66; A6-B67; A6-B68; A6-B69; A6-B70; A6-B71; A6-B72; A6-B73; A6-B74; A6-B75; A6-B76; A6-B77; A6-B78; A6-B79; A6-B80; A6-B81; A6-B82; A6-B83; A6-B84; A6-B85; A6-B86; A6-B87; A6-B88; A6-B89; A6-B90; A6-B91; A6-B92; A6-B93; A6-B94; A6-B95; A6-B96; A6-B97; A6-B98; A6-B99; A6-B10Q; A6-B101; A6-B 02; A6-B103; A6-B104; A6-B105; A6-B106; A6-B107; A6-B108; A6-B109; A6-B110; A6-B111; A6-B112; A6-B113; A6-B114; A6-B115; A6-B116; A6-B117; A6-B118; A6-B119; A6-B120; A6-B121; A6-B122; A6-B123; A6-B124; A6-B125; A6-B126; A6-B127; A6-B128; A6-B129; A6-B130; A6-B131; A6-B132; A6-B133; A6-B134; A6-B135; A6-B136; A6-B137; A6-B138; A6-B139; A6-B140; A6-B141; A6-B142; A6-B143; A6-B144; A6-B145; A6-B146; A6-B147; A6-B148; A6-B149; A6-B150; A6-B151; A6-B152; A6-B153; A6-B154; A6-B155; A6-B156; A6-B157; A6-B158; A6-B159; A6-B160; A6-B161; A6-B162; A6-B163; A6-B164; A6-B165; A6-B166; A6-B167; . A6-B168; A6-B169; A7-B1; A7-B2; A7-B3; A7-B4; A7-B5; A7-B6; A7-B7; A7-B8; A7-B9; A7-B10; A7-B11; A7-B12; A7-B13; A7-B14; A7-B15; A7-B16; A7-B17; A7-B18; A7-B19; A7-B20; A7-B21; A7-B22; A7-B23; A7-B24; A7-B25; A7-B26; A7-B27; A7-B28; A7-B29; A7-B30; A7-B31; A7-B32; A7-B33; A7-B34; A7-B35; A7-B36; A7-B37; A7-B38; A7-B39; A7-B40; A7-B41; A7-B42; A7-B43; A7-B44; A7-B45; A7-B46; A7-B47; A7-B48; A7-B49; A7-B50; A7-B51; A7-B52; A7-B53; A7-B54; A7-B55; A7-B56; A7-B57; A7-B58; A7-B59; A7-B60; A7-B61; A7-B62; A7-B63; A7-B64; A7-B65; A7-B66; A7-B67; A7-B68; A7-B69; A7-B70; A7-B71; A7-B72; A7-B73; A7-B74; A7-B75"; A7-B76; A7-B77; A7-B78; A7-B79; A7-B80; A7-B81; A7-B82; A7-B83; A7-B84; A7-B85; A7-B86; A7-B87; A7-B88; A7-B89; A7-B90; A7-B91; A7-B92; A7-B93; A7-B94; A7-B95; A7-B96; A7-B97; A7-B98; A7-B99; A7-B100; A7-B101; A7-B102; A7-B103; A7-B104; A7-B105; A7-B106; A7-B107; A7-B108; A7-B109; A7-B110; A7-B111; A7-B112; A7-B113; A7-B114; A7-B115; A7-B116; A7-B117; A7-B118; A7-B119; A7-B120; A7-B121; A7-B122; A7-B123; A7-B124; A7-B125; A7-B126; A7-B127; A7-B128; A7-B129; A7-B130; A7-B131; A7-B132; A7-B133; A7-B134; A7-B135; A7-B136; A7-B137; A7-B138; A7-B139; A7-B140; A7-B141; A7-B142; A7-B143; A7-B144; A7-B145; A7-B146; A7-B147; A7-B148; A7-B149; A7-B150; A7-B15 I; A7-B152; A7-B153; A7-B154; A7-B155; A7-B156; A7-B157; A7-B158; A7-B159; A7-B160; A7-B161; A7-B162; A7-B163; A7-B164; A7-B165; A7-B166; A7-B167; A7-B168; A7-B169; A8-B1; A8-B2; A8-B3; A8-B4; A8-B5; A8-B6; A8-B7; A8-B8; A8-B9; A8-B10; A8-B1 1; A8-B12; A8-B13; A8-B1; A8-B15; A8-B16; A8-B17; A8-B18; A8-B19; A8-B20; A8-B21; A8-B22; A8-B23; A8-B24; A8-B25; A8-B26; A8-B27; A8-B28; A8-B29; A8-B30; A8-B31; A8-B32; A8-B33; A8-B34; A8-B35; A8-B36; A8-B37; A8-B38; A8-B39; A8-B40; A8-B41; A8-B42; A8-B43; A8-B44; A8-B45; A8-B46; A8-B47; A8-B48; A8-B49; A8-B50; A8-B51; A8-B52; A8-B53; A8-B54; A8-B55; A8-B56; A8-B57; A8-B58; A8-B59; A8-B60; A8-B61; A8-B62; A8-B63; A8-B64; A8-B65; A8-B66; A8-B67; A8-B68; A8-B69; A8-B70; A8-B71; A8-B72; A8-B73; A8-B74; A8-B75; A8-B76; A8-B77; A8-B78; A8-B79; A8-B80; A8-B81; A8-B82; A8-B83; A8-B84; A8-B85; A8-B86; A8-B87; A8-B88; A8-B89; A8-B90; A8-B91; A8-B92; A8-B93; A8-B94; A8-B95; A8-B96; A8-B97; A8-B98; A8-B99; A8-B100; A8-B101; A8-B102; A8-B103; A8-B104; A8-B105; A8-B106; A8-B107; A8-B108; A8-B109; A8-B110; A8-B111; A8-B112; A8-B113; A8-B114; A8-B115; A8-B116; A8-B117; A8-B118; A8-B119; A8-B120; A8-B121; A8-B122; A8-B123; A8-B124; A8-B125; A8-B126; A8-B127; A8-B128; A8-B129; A8-B130; A8-B131; A8-B132; A8-B133; A8-B134; A8-B135; A8-B136; A8-B137; A8-B138; A8-B139; A8-B140; A8-B141; A8-B142; A8-B143; A8-B144; A8-B145; A8-B146; A8-B147; A8-B148; A8-B149; A8-B150; A8-B151; A8vB152; A8-B153; A8-B154; A8-B155; A8-B156; A8-B157; A8-B158; A8-B159; A8-B160; A8-B161; A8-B162; A8-B163; A8-B164; A8-B165; A8-B166; A8-B167; A8-B168; A8-B169; A9-B1; A9-B2; A9-B3; A9-B4; A9-B5; A9-B6; A9-B7; A9-B8; A9-B9; A9-B10; A9-B1 1; A9-B12; A9-B13; A9-B14; A9-B15; A9-B16; A9-B17; A9-B18; A9-B19; A9-B20; A9-B21; A9-B22; A9-B23; A9-B24; A9-B25; A9-B26; A9-B27; A9-B28; A9-B29; A9-B30; A9-B31; A9-B32; A9-B33; A9-B34; A9-B35; A9-B36; A9-B37; A9-B38; A9-B39; A9-B40; A9-B41; A9-B42; A9-B43; A9-B44; A9-B45; A9-B46; A9-B47; A9-B48; A9-B49; A9-B50; A9-B51; A9-B52; A9-B53; A9-B54; A9-B55; A9-B56; A9-B57; A9-B58; A9-B59; A9-B60; A9-B61; A9-B62; A9-B63; A9-B64; A9-B65; A9-B66; A9-B67; A9-B68; A9-B69; A9-B70; A9-B71; A9-B72; A9-B73; A9-B74; A9-B75; A9-B76; A9-B77; A9-B78; A9-B79; A9-B80; A9-B81; A9-B82; A9-B83; A9-B84; A9-B85; A9-B86; A9-B87; A9-B88; A9-B89; A9-B90; A9-B91; A9-B92; A9-B93; A9-B94; A9-B95; A9-B96; A9-B97; A9-B98; A9-B99; > A9-B100; A9-B101; A9-B102; A9-B103; A9-B104; A9-B105; A9-B106; A9-B107; A9-B108; A9-B109; · A9-B110; A9-B111; A9-B112; A9-B1 13; A9-B1 14; A9-B115; A9-B1 16; A9-B117; A9-B118; A9-B119; A9-B120; A9-B121; A9-B122; A9-B123; A9-B124; A9-B125; A9-B126; A9-B127; A9-B128; A9-B129; A9-B130; A9-B131-, A9-B132; A9-B133; A9-B134; A9-B135; A9-B136; A9-B137; A9-B138; A9-B139; A9-B140; A9-B141; A9-B142; A9-B143; A9-B144; A9-B145; A9-B146; A9-B147; A9-B148; A9-B149; A9-B150; A9-B151; A9-B152; A9-B153; A9-B154; A9-B155; A9-B156; A9-B157; A9-B158; A9-B159; A9-B160; A9-B161; A9-B162; A9-B163; A9-B164; A9-B165; A9-B166; A9-B167; A9-B168; A9-B169; A10-B1; A10-B2; A10-B3; A10-B4; A10-B5; A10-B6; A10-B7; A10-B8; A10-B9; A10-B10; A10-B11; A10-B12; A10-B13; A10-B14; A10-B15; A10-B16; A10-B17; A10-B18; A10-B19; A10-B20; A10-B21; A10-B22; A10-B23; A10-B24; A10-B25; A10-B26; A10-B27; A10-B28; A10-B29; A10-B30; A10-B31; A10-B32; A10-B33; A10-B34; A10-B35; A10-B36; A10-B37; A10-B38; A10-B39; A10-B40; A10-B41; A10-B42; A10-B43; A10-B44; A10-B45; A10-B46; A10-B47; A10-B48; A10-B49; A10-B50; A10-B51; A10-B52; A10-B53; A10-B54; A10-B55; A10-B56; A10-B57; A10-B58; A10-B59; A10-B60; A10-B61; A10-B62; A10-B63; A10-B64; A10-B65; A10-B66; A10-B67; A10-B68; A10-B69; A10-B70; A10-B71; A10-B72; A10-B73; A10-B74; A10-B75; A10-B76; A10-B77; A10-B78; A10-B79; A10-B80; A10-B81; A10-B82; A10-B83; A10-B84; A10-B85; A10-B86; A10-B87; A10-B88; A10-B89; A10-B90; A10-B91; A10-B92; A10-B93; A10-B94; A10-B95; A10-B96; A10-B97; A10-B98; A10-B99; A10-B100; A10-B101; A10-B102; A10-B103; A10-B104; A10-B105; A10-B106; A10-B107; A10-B108; A10-B109; A10-B110; A10-B111; A10-B112; A10-B113; A10-B114; A10-B115; A10-B116; A10-B117; A10-B118; A10-B119; A10-B120; A10-B121; A10-B122; A10-B123; A10-B124; A10-B125; A10-B126; A10-B 27; A10-B128; A10-B129; A10-B130; A10-B131; 10 - ?? 32; A10-B133; A10-B134; A10-B135; A10-B136; A10-B137; A10-B138; A10-B139; A10-B140; A10-B141; A10-B142; A10-B143; A10-B144; · A10-B145; A10-B146; A10-B147; A10-B148; A10-B149; A10-B150; A10-B151; A10-B152; A10-B153; A10-B154; A10-B155; A10-B156; A10-B157; A10-B158; A10-B159; A10-B160; A10-B161; A10-B162; A10-B163; A10-B164; A10-B165; A10-B166; A10-B167; A10-B168; A10-B169; A11-B1; A11-B2; A11-B3; A11-B4; A11-B5; A11-B6; A11-B7; A11-B8; A11-B9; A11-B10; A11-B1 1; A11-B12; A1 1-B13; A11-B14; A11 -B15; A11-B16; A1 1-B17; A11-B18; A11-B19; A11-B20; A11-B21; A11-B22; A11-B23; A11-B24; A11-B25; A11-B26; A11-B27; A11-B28; A11-B29; A11-B30; A11-B31; A11-B32; A11-B33; A11-B34; A11-B35; A11-B36; A11-B37; A11-B38; A11-B39; A11-B40; A11-B41; A11-B42; A11-B43; A11-B44; A11-B45; A11-B46; A11-B47; A11-B48; A11-B49; A11-B50; A11-B51; A11-B52; A11-B53; A11-B54; A11-B55; A11-B56; A11-B57; A11-B58; A11-B59; A11-B60; A1 1-B61; A11-B62; A11-B63; A11-B64; A1 1-B65; A11-B66; A1 1-B67; A11-B68; A11-B69; A1 1-B70; A11-B71; A11-B72; A11-B73; A11-B74; A11-B75; A11-B76; A11-B77; A11-B78; A11-B79; A11-B80; A11-B81; A11-B82; A11-B83; A11-B84; A11-B85; A11-B86; A11-B87; A11-B88; A11-B89; A11-B90; A11-B91; A11-B92; A11-B93; A11-B94; A11-B95; A11-B96; A11-B97; A11-B98; A11-B99; A11-B100; A11-B101; A11-B102; A11-B103; A11-B104; A11-B105; A11-B106; A11-B107; A11-B108; A11-B109; A11-B110; A11-B111; A11-B112; A11-B113; A11-B114; A11-B115; A11-B116; A11-B117; A11-B118; A11-B119; A11-B120; A11-B121; A11-B122; A11-B123; A11-B124; A11-B125; A11-B126; A11-B127; A11-B128; A11-B129; A11-B130; A11-B131; A11-B132; A11-B133; A11-B134; A11-B135; A11-B136; A11-B137; A11-B138; A11-B139; A11-B140; A11-B141; A11-B142; A11-B143; A11-B144; A11-B145; A11-B146; A11-B147; A11-B148; A11-B149; A11-B150; A11-B151; A11-B152; A11-B153; A11-B154; A11-B155; A11-B156; A11-B157; A11-B158; A11-B159; A11-B160; A11-B161; A11-B162; A11-B163; A11-B164; A11-B165; A11-B166; A11-B167; A11-B168; A11-B169; A12-B1; A12-B2; A12-B3; A12-B4; A12-B5; A12-B6; A12-B7; A12-B8; A12-B9; A12-B10; A12-B11; A12-B12; A12-B13; A12-B14; A12-B15; A12-B16; A12-B17; A12-B18; A12-B19; A12-B20; A12-B21; A12-B22; A12-B23; A12-B24; A12-B25; A12-B26; A12-B27; A12-B28; A12-B29; A12-B30; A12-B31; A12-B32; A12-B33; A12-B34; A12-B35; A12-B36; A12-B37; A12-B38; A12-B39; A12-B40; A12-B41; A12-B42; A12-B43; A12-B44; A12-B45; A12-B46; 'A12-B47; A12-B48; A12-B49; A12-B50; A12-B51; A12-B52; A12-B53; A12-B54; A12-B55; A12-B56; A12-B57; A12-B58; A12-B59; A12-B60; A12-B61; A12-B62; A12-B63; A12-B64; A12-B65; - A12-B66; A12-B67; A12-B68; A12-B69; A12-B70; A12-B71; A12-B72; A12-B73; A12-B74; A12-B75; A12-B76; A12-B77; A12-B78; A12-B79; A12-B80; A12-B81; A12-B82; A12-B83; A12-B84; A12-B85; A12-B86; A12-B87; A12-B88; A12-B89; A12-B90; A12-B91; A12-B92; A12-B93; A12-B94; A12-B95; A12-B96; A 2-B97; A12-B98; A12-B99; A12-B100; A12-B101; A12-B102; A12-B103; A12-B104; A12-B105; A12-B106; 'A12-B107; A12-B108; A12-B109; A12-B110; A12-B111; A12-B112; A12-B 13; A12-B114; A12-B115; A12-B116; A12-B117; A12-B118; A12-B119; A12-B120; A12-B121; A12-B122; A12-B123; A12-B124; A12-B125; A12-B126; A12-B127; A12-B128; A12-B129; A12-B130; A12-B131; A12-B132; A12-B133; A12-B134; A12-B135; A12-B136; A12-B137; A12-B138; A12-B139; A12-B140; A12-B141; A12-B142; A12-B143; A12-B144; A12-B145; A12-B146; A12-B147; A12-B148; A12-B149; A12-B150; A12-B151; A12-B152; A12-B153; A12-B154; A12-B155; A12-B156; A12-B157; A12-B158; A12-B159; A12-B160; A12-B161; A12-B162; A12-B163; A12-B164; A12-B165; A12-B166; A12-B167; A12-B168; A12-B169; A13-B1; A13-B2; A13-B3; A13-B4; A13-B5; A13-B6; A13-B7; A13-B8; A13-B9; A13-B10; A13-B11; A13-B12; A13-B13; A13-B14; A13-B15; A13-B16; A13.-B17; A13-B18; A13-B19; A13-B20; A13-B21; A13-B22; A13-B23; A13-B24; A13-B25; A13-B26; A13-B27; A13-B28; A13-B29; A13-B30; A13-B31; A13-B32; A13-B33; A13-B34; A13-B35; A13-B36; A13-B37; A13-B38; A13-B39; A13-B40; A13-B41; A13-B42; A13-B43; A13-B44; A13-B45; A13-B46; A13-B47; A13-B48; A13-B49; A13-B50; A13-B51; A13-B52; A13-B53; A13-B54; A13-B55; A13-B56; A13-B57; A13-B58; A13-B59; A13-B60; A13-B61; A13-B62; A13-B63; A13-B64; A13-B65; A13-B66; A13-B67; A13-B68; A13-B69; A13-B70; A13-B71; A13-B72; A13-B73; A13-B74; A13-B75; A13-B76; A13-B77; A13-B78; A13-B79; A13-B80; A13-B81; A13-B82; A13-B83; A13-B84; A13-B85; A13-B86; A13-B87; A13-B88; A13-B89; A13-B90; A13-B91; A13-B92; A13-B93; A13-B94; A13-B95; A13-B96; A13-B97; A13-B98; A13-B99; A13-B100; A13-B101; A13-B102; A13-B103; A13-B104; A13-B105; A13-B106; A13-B107; A13-B108; A13-B109; A13-B1 10; A13-B1 1 1; A13-B1 12; . A13-B1 13; A13-B1 14; A13-B1 15; A13-B1 16; A13-B1 17; A13-B1 18; A13-B1 19; A13-B120; A13-B121; A13-B122; A13-B123; A13-B124; A13-B125; A13-B126; A13-B127; A13-B128; A13-B129; A13-B130; A13-B131; A13-B132; A13-B133; A13-B134; A13-B135; A13-B136; A13-B137; A13-B138; A13-B139; A13-B140; A13-B141; A13-B142; A13-B143; A13-B144; A13-B145; A13-B146; A13-B147; A13-B148; A13-B149; A13-B150; A13-B151; A13-B152; A13-B153; A13-B154; A13-B155; A13-B156; A13-B157; A13-B158; A13-B159; A13-B160; A13-B161; A13-B162; A13-B163; A13-B164; A13-B165; A13-B166; A13-B167; A13-B168; A13-B169; A14-B1; A14-B2; A14-B3; A14-B4; A14-B5; A14-B6; A14-B7; A14-B8; A14-B9; A14-B10; 'A14-B11; A14-B12; A14-B13; A14-B14; A14-B15; A14-B16; A14-B17; A14-B18; A14-B19; A14-B20; A14-B21; A14-B22; A14-B23; A14-B24; A14-B25; A14-B26; A14-B27; A14-B28; A14-B29; A14-B30; A14-B31; A14-B32; A14-B33; A14-B34; A14-B35; A14-B36; A14-B37; A14-B38; A14-B39; A14-B40; A14-B41; A14-B42; A14-B43; A14-B44; A14-B45; A14-B46; A14-B47; A14-B48; A14-B49; A14-B50; A14-B51; A14-B52; A14-B53; A14-B54; A14-B55; A14-B56; A14-B57; A14-B58; A14-B59; A14-B60; A14-B61; A14-B62; A14-B63; A14-B64; A14-B65; A14-B66; A14-B67; A14-B68; . A14-B69; A14-B70; A14-B71; A14-B72; A14-B73; A14-B74; A14-B75; A14-B76; A14-B77; A14-B78; A14-B79; A14-B80; A14-B81; A14-B82; A14-B83; A14-B84; A14-B85; A14-B86; A14-B87; A14-B88; A14-B89; A14-B90; A14-B91; A14-B92; A14-B93; A14-B94; A14-B95; A14-B96; A14-B97; A14-B98; A14-B99; A14-B100; A14-B101; A14-B102; A14-B103; A14-B104; A14-B105; A14-B106; A14-B107; A14-B108; A14-B109; A14-B110; A14-B111; A14-B112; A14-B113; A14-B114; A14-B115; A14-B116; A14-B117; A14-B118; A14-B119; A14-B120; A14-B121; A14-B122; A14-B123; A14-B124; A14-B125; A14-B126; A14-B127; A14-B128; A14-B129; A14-B130; A14-B131; A14-B132; A14-B133; A14-B134; A14-B135; A14-B136; A14-B137; A14-B138; A14-B139; A14-B140; A14-B141; A14-B142; A14-B143; A14-B144; A14-B145; A14-B146; A14-B147; A14-B148; A14-B149; A14-B150; A14-B151; A14-B152; A14-B153; A14-B154; A14-B155; A14-B156; A14-B157; A14-B158; A14-B159; A14-B160; A14-B161; A14-B162; A14-B163; A14-B164; A14-B165; A14-B166; A14-B167; A14-B168; A14-B169; A15-B1; A15-B2; A15-B3; A15-B4; A15-B5; A15-B6; A15-B7; A15-B8; A15-B9; A15-B10; A15-B11; A15-B12; A15-B13; A15-B14; A15-B15; A15-B16; A15-B17; A15-B18; A15-B19; A15-B20; A15-B21; A15-B22; A15-B23; A15-B24; A15-B25; A15-B26; A15-B27; A15-B28; A15-B29; A15-B30; A15-B31; A15-B32; A15-B33; A15-B34; A15-B35; A15-B36; A15-B37; A15-B38; A15-B39; A15-B40; A15-B41; A15-B42; A15-B43; A15-B44; A15-B45; A15-B46; A15-B47; A15-B48; A15-B49; A15-B50; A15-B51; A15-B52; A15-B53; A15-B54; A15-B55; A15-B56; A15-B57; A15-B58; A15-B59; A15-B60; A15-B61; A15-B62; A15-B63; A15-B64; A15-B65; A15-B66; A15-B67; A15-B68; A15-B69; A15-B70; A15-B71; A15-B72; A15-B73; A15-B74; A15-B75; A15-B76; A15-B77; A15-B78; A15-B79; A15-B80; A15-B81; A15-B82; A15-B83; A15-B84; A15-B85; A15-B86; A15-B87; A15-B88; A15-B89; A15-B90; A15-B91; A15-B92; A15-B93; A15-B94; A15-B95; A15-B96; A15-B97; A15-B98; A15-B99; A15-B100; A15-B101; A15-B102; A15-B103; A15-B104; A15-B105; A15-B106; A15-B107; A15-B108; A15-B109; A15-B110; A15-B111; A15-B112; A15-B113; A15-B114; A15-B115; A15-B116; A15-B117; A15-B118; A15-B119; A15-B120; A15-B121; A15-B122; A15-B123; A15-B124; A15-B125; A15-B126; A15-B127; A15-B128; A15-B129; A15-B130; A15-B131; A15-B132; A15-B133; A15-B134; A15-B135; A15-B136; A15-B137; A15-B138; A15-B139; A15-B140; A15-B141; A15-B142; A15-B143; A15-B144; A15-B145; A15-B146; A15-B147; A15-B148; A15-B149; A15-B150; A15-B151; A15-B152; A15-B153; A15-B154; A15-B155; A15-B156; A15-B157; A15-B158; A15-B159; A15-B160; A15-B161; A15-B162; A15-B163; A15-B164; A15-B165; A15-B166; A15-B167; A15-B168; A15-B169; A16-B1; A16-B2; A16-B3; A16-B4; A16-B5; A16-B6; A16-B7; A16-B8; A16-B9; A16-B10; A16-B11; A16-B12; A16-B13; A16-B14; A16-B15; A16-B16; A16-B17; A16-B18; A16-B19; A16-B20; A16-B21; A16-B22; A16-B23; A16-B24; A16-B25; A16-B26; A16-B27; A16-B28; A16-B29; A16-B30; A16-B31; A16-B32; A16-B33; A16-B34; A16-B35; A16-B36; A16-B37; A16-B38; A16-B39; A16-B40; A16-B41; -A16-B42; A16-B43; A16-B44; A 6-B45; A16-B46; A16-B47; A16-B48; A16-B49; A16-B50; A16-B51; A16-B52; A16-B53; A16-B54; A16-B55; A16-B56; A16-B57; A16-B58; A16-B59; A16-B60; A16-B61; A16-B62; A16-B63; A16-B64; A16-B65; A16-B66; A16-B67; A16-B68; A16-B69; A16-B70; A16-B71; A16-B72; A16-B73; A16-B74; A16-B75; A16-B76; A16-B77; A16-B78; A16-B79; A16-B80; A16-B81; A16-B82; A16-B83; A16-B84; A16-B85; A16-B86; A16-B87; A16-B88; A16-B89; A16-B90; A16-B91; A16-B92; A16-B93; A16-B94; A16-B95; A16-B96; A16-B97; A16-B98; A16-B99; A16-B100; A16-B101; A16-B102; A16-B103; A16-B104; A16-B105; A16-B106; A16-B107; A16-B108; A16-B1.09; A16-B110; A16-B111; A16-B112; A16-B113; A16-B114; A16-B115; A16-B116; A16-B117; A16-B118; A16-B119; A16-B120; A16-B121; A16-B122; A16-B123; A16-B124; A16-B125; A16-B126; A16-B127; A16-B128; A16-B129; A16-B130; A16-B131; A16-B132; A16-B133; A16-B134; A16-B135; A16-B136; A16-B137; A16-B138; A16-B139; A16-B140; A16-B141; A16-B142; A16-B143; A16-B144; A16-B145; A16-B146; A16-B147; A16-B148; A16-B149; A16-B150; A16-B151; A16-B152; A16-B153; A16-B154; A16-B155; A16-B156; A16-B157; A16-B158; A16-B159; A16-B160; A16-B161; A16-B162; A16-B163; A16-B164; A16-B165; A16-B166; A16-B167; A16-B168; A16-B169; A17-B1; A17-B2; A17-B3; A17-B4; A17-B5; A17-B6; A17-B7; A17-B8; A17-B9; A17-B10; A17-B11; A17-B12; A17-B13; A17-B14; A17-B15; A17-B16; A17-B17; A17-B18; A17-B19; A17-B20; A17-B21; A1-B22; A17-B23; A17-B24; A17-B25; A17-B26; A17-B27; A17-B28; A17-B29; A17-B30; A17-B31; A17-B32; A17-B33; A17-B34; A17-B35; A17-B36; A17-B37; A17-B38; A17-B39; A17-B40; A17-B41; A17-B42; A17-B43; A17-B44; A17-B45; A17-B46; A17-B47; A17-B48; A17-B49; A17-B50; A17-B51; A17-B52; A17-B53; A17-B54; A17-B55; A17-B56; A17-B57; A17-B58; A17-B59; A17-B60; A17-B61; A17-B62; A17-B63; A17-B64; A17-B65; A17-B66; A17-B67; A17-B68; A17-B69; A17-B70; A17-B71; A17-B72; A17-B73; A17-B74; A17-B75; A17-B76; A17-B77; A17-B78; A17-B79; A17-B80; A17-B81; A17-B82; A17-B83; A17-B84; A17-B85; A17-B86; A17-B87; A17-B88; A17-B89; A17-B90; A17-B91; A17-B92; A17-B93; A17-B94; A17-B95; A17-B96; A17-B97; A17-B98; A17-B99; A17-B100; A17-B101; A17-B102; A17-B103; A17-B104; A17-B105; A17-B106; A17-B107; A17-B108; A17-B109; A17-B110; A17-B111; A17-B112; A17-B1 13; A17-B1 14; A17-B115; A17-B116; A17-B1 17; A17-B118; A17-B1 19; A17-B120; A17-B121; A17-B122; A17-B123; A17-B124; A17-B125; A17-B126; A17-B127; A17-B128; A17-B129; A17-B130; A17-B131; A17-B132; A17-B133; A17-B134; A17-B135; A17-B136; A17-B137; A17-B138; A17-B139; A17-B140; A17-B141; A17-B142; A17-B143; A17-B144; A17-B145; A17-B146; A17-B147; A17-B148; A17-B149; A17-B150; A17-B151; . A17-B152; A17-B153; A17-B154; A17-B155; A17-B156; A17-B157; A17-B158; A17-B159; A17-B160; A17-B161; A17-B162; A17-B163; A17-B164; A17-B165; A17-B166; A17-B167; A17-B168; A17-B169; A18-B1; A18-B2; A18-B3; ? 18-? 4; · A18-B5; A18-B6; A18-B7; A18-B8; A18-B9; A18-B10; A18-B11; ? 18-? 12; - · "A18-B13; A18-B14; A18-B15; A18-B16; A18-B17; A18-B18; A18-B19; A18-B20; A18-B21; A18-B22; A18-B23; A18-B24; A18-B25; A18-B26; A18-B27; A18-B28; A18-B29; A18-B30; A18-B31; A18-B32; A18-B33; A18-B34; A18-B35; A18-B36; A18-B37; A18-B38; A18-B39; A18-B40; A18-B41; A18-B42; A18-B43; A18-B44; A18-B45; A18-B46; A18-B47; A18-B48; A18-B49; A18-B50; A18-B51; A18-B52; A18-B53; A18-B54; A18-B55; A18-B56; A18-B57; A18-B58; A18-B59; A18-B60; A18-B61; A18-B62; A18-B63; A18-B64; A18-B65; A18-B66; A18-B67; A18-B68; A18-B69; A18-B70; A18-B71; A18-B72; A18-B73; A18-B74; A18-B75; A18-B76; A18-B77; A18-B78; A18-B79; A18-B80; A18-B81; A18-B82; A18-B83; A18-B84; A18-B85; A18-B86; A18-B87; A18-B88; A18-B89; A18-B90; A18-B91; A18-B92; A18-B93; A18-B94; A18-B95; A18-B96; A18-B97; A18-B98; A18-B99; A18-B100; A18-B101; A18-B102; A18-B103; A18-B104; A18-B105; A18-B106; A18-B107; A18-B108; A18-B109; A18-B110; A18-B11 1; A18-B112; A18-B113; A18-B114; A18-B115; A18-B116; A18-B117; A18-B118; A18-B119; A18-B120; A18-B121; A18-B122; A18-B123; A18-B124; A18-B125; A18-B126; A18-B127; A18-B128; A18-B129; A18-B1.30; A18-B131; A18-B132; A18-B133; A18-B134; A18-B135; A18-B136; A18-B137; A18-B138; A18-B139; A18-B140; A18-B141; A18-B1 2; A18-B143; A18-B144; A18-B145; A18-B146; A18-B147; A18-B148; A18-B149; A18-B150; A18-B151; A18-B152; A18-B153; A18-B154; A18-B155; A18-B156; A18-B157; A18-B158; A18-B159; A18-B160; A18-B161; A18-B162; A18-B163; A18-B164; A18-B165; A18-B166; A18-B167; A18-B168; A18-B169; A19-B1; A19-B2; A19-B3; A19-B4; A19-B5; A19-B6; A19-B7; A19-B8; A19-B9; A19-B10; A19-B11; A19-B12; A19-B13; A19-B14; A19-B15; A19-B16; A19-B17; A19-B18; A19-B19; A19-B20; A19-B21; A19-B22; A19-B23; A19-B24; A19-B25; A19-B26; A19-B27; A19-B28; A19-B29; A19-B30; A19-B31; A19-B32; A19-B33; A19-B34; A19-B35; A19-B36; A19-B37; A19-B38; A19-B39; A19-B40; A19-B41; A19-B42; A19-B43; A19-B44; A19-B45; · A19-B46; A19-B47; A19-B48; A19-B49; A19-B50; A19-B51; A19-B52; A19-B53; A19-B54; A19-B55; A19-B56; A19-B57; A19-B58; A19-B59; A19-B60; A19-B61; A19-B62; A19-B63; A19-B64; A19-B65; A19-B66; A19-B67; A19-B68; A19-B69; A19-B70; A19-B71; A19-B72; A19-B73; A19-B74; A19-B75; A19-B76; A19-B77; A19-B78; A19-B79; A19-B80; A19-B81; A19-B82; A19-B83; A19-B84; A19-B85; A19-B86; A19-B87; A19-B88; A19-B89; A19-B90; A19-B91; A19-B92; A19-B93; A19-B94; A19-B95; A19-B96; A19-B97; A19-B98; A19-B99; A19-B100; A19-B101; A19-B102; A19-B103; A19-B104; A19-B105; A19-B 06; A19-B107; A19-B108; A19-B109; A19-B110; A19-B111; A19-B112; A19-B113; A19-B114; A19-B1 15; A19-B116; A19-B117; A19-B118; A19-B119; A19-B120; A19-B121; A19-B122; A19-B123; A19-B124; A19-B125; A19-B126; A19-B127; A19-B128; A19-B129; A19-B130; A19-B131; A19-B132; A19-B133; A19-B134; A19-B135; A19-B136; A19-B137; A19-B138; A19-B139; A19-B140; A19-B141; A19-B142; A19-B143; A19-B144; A19-B145; A19-B146; A19-B147; A19-B148; A19-B149; A19-B150; A19-B151; A19-B152; A19-B153; A19-B154; A19-B155; A19-B156; A19-B157; A19-B158; A19-B159; A19-B160; A19-B161; A19-B162; A19-B163; A19-B164; A19-B165; A19-B166; A19-B167; A19-B168; A19-B169; A20-B1; A20-B2; A20-B3; A20-B4; A20-B5; A20-B6; A20-B7; A20-B8; A20-B9; A20-B10; A20-B11; A20-B12; A20-B13; A20-B14; A20-B15; A20-B16; A20-B17; A20-B18; A20-B19; A20-B20; A20-B21; A20-B22; A20-B23; A20-B24; A20-B25; A20-B26; A20-B27; A20-B28; A20-B29; A20-B30; A20-B31; A20-B32; A20-B33; A20-B34; A20-B35; A20-B36; A20-B37; A20-B38; A20-B39; A20-B40; A20-B41; A20-B42; A20-B43; A20-B44; A20-B45; A20-B46; A20-B47; A20-B48; A20-B49; A20-B50; A20-B51; A20-B52; A20-B53; A20-B54; A20-B55; A20-B56; A20-B57; A20-B58; A20-B59; A20-B60; A20-B61; A20-B62; A20-B63; A20-B64; A20-B65; A20-B66; A20-B67; A20-B68; A20-B69; A20-B70; A20-B71; A20-B72; A20-B73; A20-B74; A20-B75; A20-B76; A20-B77; A20-B78; A20-B79; A20-B80; A20-B81; A20-B82; A20-B83; A20-B84; A20-B85; A20-B86; A20-B87; A20-B88; A20-B89; A20-B90; A20-B91; A20-B92; A20-B93; A20-B94; A20-B95; A20-B96; A20-B97; A20-B98; A20-B99; A20-B100; A20-B101; A20-B102; A20-B103; A20-B104; A20-B105; A20-B106; A20-B107; A20-B108; A20-B109; A20-B110; A20-B111; A20-B112; A20-B113; A20-B114; A20-B115; A20-B116; A20-B117; A20-B118; A20-B119; A20-B120; A20-B121; A20-B122; A20-B123; A20-B124; A20-B125; A20-B126; A20-B127; A20-B128; A20-B129; A20-B130; A20-B131; A20-B132; A20-B133; A20-B134; A20-B135; A20-B136; A20-B137; A20-B138; A20-B139; A20-B140; A20-B141; A20-B142; A20-B143; A20-B144; A20-B145; A20-B146; A20-B147; A20-B148; A20-B149; A20-B150; A20-B151; A20-B152; A20-B153; A20-B154; A20-B155; A20-B156; A20-B157; A20-B158; A20-B159; A20-B160; A20-B161; A20-B162; A20-B163; A20-B164; A20-B165; A20-B166; A20-B167; A20-B168; A20-B169; A21-B1; A21-B2; A21-B3; A21-B4; A21-B5; A21-B6; A21-B7; A21-B8; A21-B9; A21-B10; A21-B11; A21-B12; A21-B13; A21-B14; A21-B15; A21-B16; A21-B17; A21-B18; A21-B19; A21-B20; A21-B21; A21-B22; A21-B23; A21-B24; A21-B25; A21-B26; A21-B27; A21-B28; A21-B29; A21-B30; A21-B31; A21-B32; A21-B33; A21-B34; A21-B35; A21-B36; A21-B37; A21-B38; A21-B39; A21-B40; A21-B41; A21-B42; A21-B43; A21-B44; A21-B45; A21-B46; A21-B47; A21-B48; A21-B49; A21-B50; A21-B51; A21-B52; A21-B53; A21-B54; A21-B55; A21-B56; A21-B57; A21-B58; A21-B59; A21-B60; A21-B61; A21-B62; A21-B63; A21-B64; A21-B65; A21-B66; A21-B67; A21-B68; A21-B69; A21-B70; A21-B71; A21-B72; A21-B73; A21-B74; A21-B75; A21-B76; A21-B77; A21-B78; A21-B79; A21-B80; A21-B81; A21-B82; A21-B83; A21-B84; A21-B85; A21-B86; A21-B87; A21-B88; A21-B89; A21-B90; A21-B91; A21-B92; A21-B93; A21-B94; A21-B95; A21-B96; A21-B97; A21-B98; A21-B99; A21-B100; A21-B101; A21-B102; A21-B103; A21-B104; A21-B105; A21-B106; A21-B107; A21-B108; A21-B109; A21-B1 10; A21-B111; A21-B112; A21-B113; A21-B114; A21-B115; A21-B116; A21-B117; A21-B118; A21-B119; A21-B120; A21-B121; A21-B122; A21-B123; A21-B124; A21-B125; A21-B126; A21-B127; A21-B128; A21-B129; A21-B130; A21-B131; A21-B132; 21 - ?? 33; A21-B134; A21-B135; A21-B136; A21-B137; A21-B138; A21-B139; A21-B140; A21-B141; A21-B142; A21-B143; A21-B144; A21-B145; A21-B146; A21-B147; A21-B148; A21-B149; A21-B150; A21-B151; A21-B152; A21-B153; A21-B154; A21-B155; A21-B156; A21-B157; A21-B158; A21-B159; A21-B160; A21-B161; A21-B162; A21-B163; A21-B164; A21-B165; A21-B166; A21-B167; A21-B168; A21-B169; A22-B1; A22-B2; A22-B3; A22-B4; A22-B5; A22-B6; A22-B7; A22-B8; A22-B9; A22-B10; A22-B11; A22-B12; A22-B13; A22-B14; A22-B15; A22-B16; A22-B17; A22-B18; A22-B19; A22-B20; A22-B21; A22-B22; A22-B23; A22-B24; A22-B25; A22-B26; A22-B27; A22-B28; A22-B29; A22-B30; A22-B31; A22-B32; A22-B33; A22-B34; A22-B35; A22-B36; A22-B37; A22-B38; A22-B39; A22-B40; A22-B41; A22-B42; A22-B43; A22-B44; A22-B45; A22-B46; A22-B47; A22-B48; A22-B49; A22-B50; A22-B51; A22-B52; A22-B53; A22-B54; A22-B55; A22-B56; A22-B57; A22-B58; A22-B59; A22-B60; A22-B61; A22-B62; A22-B63; A22-B64; A22-B65; A22-B66; A22-B67; A22-B68; A22-B69; A22-B70; A22-B71; A22-B72; A22-B73; A22-B74; A22-B75; A22-B76; A22-B77; A22-B78; A22-B79; A22-B80; A22-B81 A22-B82; A22-B83; A22-B84; A22-B85; A22-B86; A22-B87; A22-B88; A22-B89; A22-B90; A22-B91; A22-B92; A22-B93; A22-B94; A22-B95; A22-B96; A22-B97; A22-B98; A22-B99; A22-B100; A22-B101; A22-B102; A22-B103; A22-B104; A22-B105; A22-B106; A22-B107; A22-B108; A22-B109; A22-B110; A22-B111; A22-B112; A22-B113; A22-B114; A22-B115; A22-B116; A22-B117; A22-B118; A22-B119; A22-B120; A22-B121; A22-B122; A22-B123; A22-B124; A22-B125; A22-B126; A22-B127; A22-B128; A22-B129; A22-B130; A22-B131; A22-B132; A22-B133; A22-B134; A22-B135; A22-B136; A22-B137; A22-B138; A22-B139; A22-B140; A22-B141; A22-B142; A22-B143; A22-B144; A22-B145; A22-B146; A22-B147; A22-B1 8; A22-B149; A22-B150; A22-B151; A22-B152; A22-B153; A22-B154; A22-B155; A22-B156; A22-B157; A22-B158; A22-B159; A22-B160; A22-B161; A22-B162; . A22-B163; A22-B164; A22-B165; A22-B166; A22-B167; A22-B168; . A22-B169; A23-B1; A23-B2; A23-B3; A23-B4; A23-B5; A23-B6; A23-B7; A23-B8; A23-B9; A23-B10; A23-B11; A23-B12; A23-B13; A23-B14; A23-B15; A23-B16; A23-B17; A23-B18; A23-B19; A23-B20; A23-B21; A23-B22; A23-B23; A23-B24; A23-B25; A23-B26; A23-B27; A23-B28; A23-B29; A23-B30; A23-B31; A23-B32; A23-B33; A23-B34; A23-B35; A23-B36; A23-B37; A23-B38; A23-B39; A23-B40; A23-B41; A23-B42; A23-B43; A23-B44; A23-B45; A23-B46; A23-B47; A23-B48; A23-B49; A23-B50; A23-B51; A23-B52; A23-B53; A23-B54; A23-B55; A23-B56; A23-B57; A23-B58; A23-B59; A23-B60; A23-B61; A23-B62; A23-B63; A23-B64; A23-B65; A23-B66; A23-B67; A23-B68; A23-B69; A23-B70; A23-B71; A23-B72; A23-B73; A23-B74; A23-B75; A23-B76; A23-B77; A23-B78; A23-B79; A23-B80; A23-B81; A23-B82; A23-B83; A23-B84; A23-B85; A23-B86; A23-B87; A23-B88; A23-B89; A23-B90; A23-B91; A23-B92; A23-B93; A23-B94; A23-B95; A23-B96; A23-B97; A23-B98; A23-B99; A23-B100; A23-B101; A23-B102; A23-B103; A23-B104; A23-B105; A23-B106; A23-B107; A23-B108; A23-B109; A23-B110; A23-B111; A23-B112; A23-B113; A23-B114; A23-B1 15; A23-B116; A23-B117; A23-B118; A23-B119; A23-B120; A23-B121; A23-B122; A23-B123; A23-B124; .A23-B125; A23-B126; A23-B127; A23-B128; A23-B129; A23-B130; A23-B131; A23-B132; A23-B133; A23-B134; A23-B135; A23-B136; A23-B137; A23-B138; A23-B1-39; A23-B140; A23-B141; A23-B142; A23-B143; A23-B144; A23-B145; A23-B146; A23-B147; A23-B148; A23-B149; A23-B150; A23-B151; A23-B152; A23-B153; A23-B154; A23-B155; A23-B156; A23-B157; A23-B158; A23-B159; A23-B160; A23-B161; A23-B162; A23-B163; A23-B164; A23-B165; A23-B166; A23-B167; A23-B168; A23-B169; A24-B1; A24-B2; A24-B3; A24-B4; A24-B5; A24-B6; 'A24-B7; A24-B8; A24-B9; A24-B10; .. A24-B11; A24-B12; A24-B13; A24-B14; A24-B15; A24-B16; A24-B17; A24-B18; A24-B19; A24-B20; A24-B21; A24-B22; A24-B23; A24-B24; A24-B25; A24-B26; A24-B27; A24-B28; A24-B29; A24-B30; A24-B31; A24-B32; A24-B33; A24-B34; A24-B35; A24-B36; A24-B37; A24-B38; A24-B39; A24-B40; A24-B41; A24-B42; A24-B43; A24-B44; A24-B45; A24-B46; A24-B47; A24-B48; A24-B49; A24-B50; A24-B51; A24-B52; A24-B53; A24-B54; A24-B55; A24-B56; A24-B57; A24-B58; A24-B59; A24 ^ B60; A24-B61; A24-B62; A24-B63; A24-B64; A24-B65; A24-B66; A24-B67; A24-B68; A24-B69; A24-B70; A24-B71; A24-B72; A24-B73; A24-B74; A24-B75; A24-B76; A24-B77; A24-B78; A24-B79; A24-B80; A24-B81; A24-B82; A24-B83; A24-B84; A24-B85; A24-B86; A24-B87; A24-B88; A24-B89; A24-B90; A24-B91; A24-B92; A24-B93; A24-B94; A24-B95; A24-B96; A24-B97; A24-B98; A24-B99; A24-B100; A24-B101; A24-B102; A24-B103; A24-B104; A24-B105; A24-B106; A24-B107; A24-B108; A24-B109; A24-B1 10; A24-B111; A24-B112; A24-B113; A24-B114; A24-B115; A24-B1 6; A24-B117; A24-B118; A24-B119; A24-B120; A24-B 21; A24-B122; A24-B123; A24-B124; A24-B125; A24-B126; A24-B127; A24-B128; A24-B129; A24-B130; A24-B131; A24-B132; A24-B133; A24-B134; A24-B135; A24-B136; A24-B137; A24-B138; A24-B139; A24-B140; A24-B141; A24-B142; A24-B143; A24-B144; A24-B145; A24-B146; A24-B147; A24-B148; A24-B149; A24-B150; A24-B151; A24-B152; A24-B153; A24-B154; A24-B155; A24-B156; A24-B157; A24-B158; A24-B159; A24-B160; A24-B161; A24-B162; A24-B163; A24-B164; A24-B165; A24-B166; A24-B167; A24-B168; A24-B169; A25-B1; A25-B2; A25-B3; A25-B4; A25-B5; A25-B6; A25-B7; A25-B8; A25-B9; A25-B10; A25-B11; A25-B12; A25-B13; A25-B14; A25-B15; A25-B16; A25-B17; A25-B18; A25-B19; A25-B20; . A25-B21; A25-B22; A25-B23; A25-B24; A25-B25; A25-B26; A25-B27; A25-B28; A25-B29; A25-B30; A25-B31; A25-B32; A25-B33; A25-B34; A25-B35; A25-B36; A25-B37; A25-B38; 'A25-B39; A25-B40; A25-B41; A25-B42; A25-B43; A25-B44; A25-B45; A25-B46; A25-B47; A25-B48; A25-B49; A25-B50; A25-B51; A25-B52; A25-B53; A25-B54; A25-B55; A25-B56; A25-B57; A25-B58; A25-B59; A25-B60; A25-B61; A25-B62; A25-B63; A25-B64; A25-B65; A25-B66; A25-B67; A25-B68; A25-B69; A25-B70; A25-B71; A25-B72; A25-B73; A25-B74; A25-B75; A25-B76; A25-B77; A25-B78; A25-B79; A25-B80; A25-B81; A25-B82; A25-B83; A25-B84; A25-B85; ? 25-? 86; · A25-B87; A25-B88; A25-B89; A25-B90; ? 25-? 9; A25-B92; A25-B93; A25-B94; A25-B95; A25-B96; A25-B97; A25-B98; A25-B99; A25-B100; A25-B101; A25-B102; A25-B103; A25-B104; A25-B105; A25-B106; A25-B107; A25-B108; A25-B109; A25-B110; A25-B11 1; A25-B112; A25-B113; A25-B114; A25-B115; A25-B116; ? 25-? 117; A25-B118; A25-B119; A25-B120; A25-B121; A25-B122; A25-B123; A25-B124; A25-B125; A25-B126; A25-B127; A25-B128; A25-B129; A25-B130; A25-B131; A25-B132; A25-B133; A25-B134; A25-B135; A25-B136; A25-B137; A25-B138; A25-B139; A25-B140; A25-B141; A25-B142; A25-B143; A25-B144; A25-B145; A25-B146; A25-B147; A25-B148; A25-B149; A25-B150; A25-B151; A25-B152; A25-B153; A25-B154; A25-B155; A25-B156; A25-B157; A25-B158; A25-B159; A25-B160; A25-B161; A25-B162; A25-B163; A25-B164; A25-B165; A25-B166; A25-B167; A25-B168; A25-B169; A26-B1; A26-B2; A26-B3; A26-B4; A26-B5; A26-B6; A26-B7; A26-B8; A26-B9; A26-B10; A26-B11; A26-B12; A26-B13; A26-B14; A26-B15; A26-B16; A26-B17; A26-B18; A26-B19; A26-B20; A26-B21; A26-B22; A26-B23; A26-B24; A26-B25; A26-B26; A26-B27; A26-B28; A26-B29; A26-B30; A26-B31; A26-B32; A26-B33; A26-B34; A26-B35; A26-B36; A26-B37; A26-B38; A26-B39; A26-B40; A26-B41; A26-B42; A26-B43; A26-B44; A26-B45; A26-B46; A26-B47; A26-B48; A26-B49; A26-B50; A26-B51; A26-B52; A26-B53; A26-B54; A26-B55; A26-B56; A26-B57; A26-B58; A26-B59; A26-B60; A26-B61; A26-B62; A26-B63; A26-B64; A26-B65; A26-B66; A26-B67; A26-B68; A26-B69; A26-B70; A26-B71; A26-B72; A26-B73; A26-B74; A26-B75; A26-B76; A26-B77; A26-B78-, A26-B79; A26-B80; A26-B81; A26-B82; A26-B83; A26-B84; A26-B85; A26-B86; A26-B87; A26-B88; A26-B89; A26-B90; A26-B91; A26-B92; A26-B93; A26-B94; A26-B95; A26-B96; A26-B97; A26-B98; A26-B99; A26-B100; A26-B101; A26-B102; A26-B103; A26-B104; A26-B105; A26-B106; A26-B107; A26-B108; A26-B109; A26-B110; A26-B111; A26-B112; A26-B113; A26-B114; A26-B115; A26-B116; A26-B117; A26-B118; A26-B119; A26-B120; A26-B121; A26-B122; A26-B123; A26-B124; A26-B125; A26-B126; A26-B127; A26-B128; A26-B129; A26-B130; A26-B131; A26-B132; A26-B133; A26-B134; A26-B135; A26-B136; A26-B137; A26-B138; A26-B139; A26-B140; A26-B141; A26-B142; A26-B143; A26-B144; A26-B145; A26-B146; A26-B147; A26-B148; A26-B149; A26-B 50; A26-B151; A26-B152; A26-B153; A26-B154; A26-B155; A26-B156; A26-B157; A26-B158; A26-B159; A26-B160; A26-B161; A26-B162; A26-B163; A26-B164; A26-B165; A26-B166; A26-B167; A26-B168; A26-B169; A27-B1; A27-B2; A27-B3; A27-B4; A27-B5; A27-B6; A27-B7; A27-B8; A27-B9; A27-B10; A27-B11; A27-B12; A27-B13; A27-B14; A27-B15; A27-B16; A27-B17; A27-B18; A27-B19; A27-B20; A27-B21; A27-B22; A27-B23; A27-B24; A27-B25; A27-B26; A27-B27: A27-B28; A27-B29; A27-B30; A27-B31; A27-B32; A27-B33; A27-B34; A27-B35; A27-B36; A27TB37; A27-B38; A27-B39; A27-B40; A27-B41; A27-B42; A27-B43; A27-B44; A27-B45; A27-B46; A27-B47; A27-B48; A27-B49; A27-B50; A27-B51; A27-B52; A27-B53; A27-B54; A27-B55; A27-B56; A27-B57; A27-B58; A27-B59; A27-B60; A27-B61; A27-B62; A27-B63; A27-B64; A27-B65; A27-B66; A27-B67; A27-B68; A27-B69; A27-B70; A27-B71; A27-B72; A27-B73; A27-B74; A27-B75; A27-B76; A27-B77; A27-B78; A27-B79; A27-B80; A27-B81; A27-B82; A27-B83; A27-B84; A27-B85; A27-B86; A27-B87; A27-B88; A27-B89; A27-B90; A27-B91; A27-B92; A27-B93; A27-B94; A27-B95; A27-B96; A27-B97; A27-B98; A27-B99; A27-B100; A27-B101; A27-B102; A27-B103; A27-B104; A27-B105; A27-B106; A27-B107; A27-B108; A27-B109; A27-B110; A27-B111; A27-B112; A27-B113; A27-B114; A27-B115; A27-B116; A27-B117; A27-B118; A27-B119; A27-B120; A27-B121; A27-B122; A27-B123; A27-B124; A27-B125; A27-B126; A27-B127; A27-B128; A27-B129; A27-B130; A27-B131; A27-B132; A27-B133; A27-B134; A27-B135; A27-B136; A27-B137; A27-B138; A27-B139; A27-B140; A27-B141; A27-B142; A27-B143; A27-B144; A27-B145; A27-B146; A27-B147; A27-B148; A27-B149; A27-B150; A27-B151; A27-B152; A27-B153; A27-B154; A27-B155; A27-B156; A27-B157; A27-B158; A27-B159; A27-B160; A27-B161; A27-B162; A27-B163; A27-B164; A27-B165; A27-B166; A27-B167; A27-B168; A27-B169; A28-B1; A28-B2; A28-B3; A28-B4; A28-B5; A28-B6; A28-B7; A28-B8; A28-B9; A28-B10; A28-B11; A28-B12; A28-B13; A28-B14; A28-B15; A28-B16; A28-B17; A28-B18; A28-B19; A28-B20; A28-B21; A28-B22; A28-B23; A28-B24; A28-B25; A28-B26; A28-B27; A28-B28; A28-B29; A28-B30; A28-B31; A28-B32; A28-B33; A28-B34; A28-B35; A28-B36; A28-B37; A28-B38; A28-B39; A28-B40; A28-B41; A28-B42; A28-B43; A28-B44; A28-B45; A28-B46; A28-B47; A28-B48; A28-B49; A28-B50; A28-B51; A28-B52; A28-B53; A28-B54; A28-B55; A28-B56; A28-B57; A28-B58; A28-B59; A28-B60; A28-B61; . A28-B62; A28-B63; A28-B64; A28-B65; A28-B66; A28-B67; A28-B68; A28-B69; A28-B70; A28-B71; A28-B72; A28-B73; A28-B74; A28-B75; A28-B76; A28-B77; A28-B78; A28-B79; A28-B80; A28-B81; A28-B82; A28-B83; A28-B84; A28-B85; A28-B86; A28-B87; A28-B88; A28-B89; A28-B90; A28-B91; A28-B92; A28-B93; A28-B94; A28-B95; A28-B96; A28-B97; A28-B98; A28-B99; A28-B100; A28-B101; A28-B102; A28-B103; A28-B104; A28-B105; A28-B106; A28-B107; A28-B108; A28-B109; A28-B1 10; A28-B11 1; A28-B112; A28-B113; A28-B114; A28-B115; A28-B116; A28-B1 7; A28-B118; A28-B1 19; A28-B120; A28-B121; A28-B122; A28-B123; A28-B124; A28-B125; A28-B126; A28-B127; A28-B128; A28-B129; A28-B130; A28-B131; A28-B132; A28-B133; A28-B134; A28-B135; A28-B136; A28-B137; A28-B138; A28-B139; A28-B140; A28-B141; A28-B142; A28-B143; A28-B144; A28-B145; A28-B146; A28-B147; A28-B148; A28-B149; A28-B150; A28-B151; A28-B152; A28-B153; A28-B154; A28-B155; A28-B156; A28-B157; A28-B158; A28-B159; A28-B160; A28-B161; A28-B162; A28-B163; A28-B164; A28-B165; A28-B166; A28-B167; A28-B168; A28-B169; A29-B1; A29-B2; A29-B3; A29-B4; A29-B5; A29-B6; A29-B7; A29-B8; A29-B9; A29-B10; A29-B11; A29-B12; A29-B13; A29-B14; A29-B15; A29-B16; . A29-B17; A29-B18; A29-B19; A29-B20; A29-B21; A29-B22; A29-B23; A29-B24; A29-B25; A29-B26; A29-B27; A29-B28; A29-B29; A29-B30; A29-B31; A29-B32; A29-B33; A29-B34; A29-B35; A29-B36; A29-B37; A29-B38; A29-B39; A29-B40; A29-B41; A29-B42; A29-B43; A29-B44; A29-B45; A29-B46; A29-B47; A29-B48; A29-B49; A29-B50; A29-B51; A29-B52; A29-B53; A29-B54; A29-B55; A29-B56; A29-B57; A29-B58; A29-B59; A29-B60; A29-B61; A29-B62; A29-B63; A29-B64; A29-B65; A29-B66; A29-B67; A29-B68; A29-B69; A29-B70; A29-B71; A29-B72; A29-B73; A29-B74; A29-B75; A29-B76; A29-B77; A29-B78; A29-B79; A29-B80; A29-B81; A29-B82; A29-B83; A29-B84; A29-B85; A29-B86; A29-B87; A29-B88; A29-B89; A29-B90; A29-B91; A29-B92; A29-B93; A29-B94; A29-B95; A29-B96; A29-B97; A29-B98; A29-B99; A29-B100; A29-B101; A29-B102; A29-B103; A29-B104; A29-B105; A29-B106; A29-B107; A29-B108; A29-B109; A29-B110; A29-B111; A29-B112; A29-B113; A29-B114; A29-B115; A29-B116; A29-B1 17; A29-B118; A29-B119; A29-B120; A29-B121; A29-B122; A29-B123; A29-B124; A29-B125; A29-B126; A29-B127; A29-B128; A29-B129; A29-B130; A29-B131; A29-B132; A29-B133; A29-B134; A29-B135; A29-B136; A29-B137; A29-B138; A29-B139; A29-B140; A29-B141; A29-B142; A29-B143; A29-B144; A29-B145; A29-B146; A29-B147; A29-B148; A29-B149; A29-B150; A29-B151; A29-B152; A29-B153; A29-B154; A29-B155; A29-B156; A29-B157; A29-B158; A29-B159; A29-B160; A29-B61; A29-B162; A29-B163; A29-B164; A29-B165; A29-B166; A29-B167; A29-B168; A29-B169; A30-B1; A30-B2; A30-B3; A30-B4; A30-B5; A30-B6; A30-B7; A30-B8; A30-B9; A30-B10; A30-B11; A30-B12; A30-B13; A30-B14; A30-B15; A30-B16; A30-B17; A30-B18; A30-B19; A30-B20; A30-B21; A30-B22; A30-B23; A30-B24; A30-B25; A30-B26; A30-B27; A30-B28; A30-B29; A30-B30; A30-B31; A30-B32; A30-B33; · A30-B34; A30-B35; A30-B36; A30-B37; A30-B38; A30-B39; 30-? 40G A30-B41; A30-B42; A30-B43; A30-B44; A30-B45; A30-B46; A30-B47; A30-B48; A30-B49; A30-B50; A30-B51; A30-B52; A30-B53; A30-B54; A30-B55; A30-B56; A30-B57; A30-B58; A30-B59; A30-B60; A30-B61; A30-B62; A30-B63; A30-B64; A30-B65; A30-B66; A30-B67; A30-B68; A30-B69; A30-B70; A30-B71; A30-B72; A30-B73; A30-B74; A30-B75; A30-B76; A30-B77; A30-B78; A30-B79; A30-B80; A30-B81; A30-B82; A30-B83; A30-B84; A30-B85; A30-B86; A30-B87; A30-B88; A30-B89; A30-B90; A30-B91; A30-B92; A30-B93; A30-B94; A30-B95; A30-B96; A30-B97; A30-B98; A30-B99; A30-B100; A30-B101; A30-B102; A30-B103; A30-B104; A30-B105; A30-B106; A30-B107; A30-B108; A30-B109; A30-B110; A30-B111; A30-B112; A30-B113; A30-B114; A30-B115; A30-B116; A30-B117; A30-B118; A30-B119; A30-B120; A30-B121; A30-B122; A30-B123; A30-B124; A30-B125; A30-B126; A30-B127; A30-B128; A30-B129; A30-B130; A30-B131; A30-B132; A30-B133; A30-B134; A30-B135; A30-B136; A30-B137; A30-B138; A30-B139; A30-B140; A30-B141; A30-B142; A30-B143; A30-B144; A30-B145; A30-B146; A30-B147; A30-B148; A30-B149; A30-B150; A30-B151; A30-B 52; A30-B153; A30-B154; 30-? 155; A30-B156; A30-B157; A30-B158; A30-B159; A30-B 60; A30-B161; A30-B 62; A30-B 63; A30-B164; A30-B165; A30-B166; A30-B167; A30-B168; A30-B169; A31-B1; A31-B2; A31-B3; A31-B4; A31-B5; A31-B6; A31-B7; A31-B8; A31-B9; A31-B10; A31-B11; A31-B12; A31-B13; A31-B14; A31-B15; A31-B16; A31-B17; A31-B18; A31-B19; A31-B20; A31-B21; A31-B22; A31-B23; A31-B24; A31-B25; A31-B26; A31-B27; A31-B28; A31-B29; A31-B30; A31-B31; A31-B32; A31-B33; A31-B34; A31-B35; A31-B36; A31-B37; A31-B38; A31-B39; A31-B40; A31-B41; A31-B42; A31-B43; A31-B44; A31-B45; A31-B46; A31-B47; A31-B48; A31-B49; A31-B50; A31-B51; A31-B52; A31-B53; A31-B54; A31-B55; A31-B56; A31-B57; A31-B58; A31-B59; A31-B60; A31-B61; A31-B62; A31-B63; A31-B64; A31-B65; A31-B66; A31-B67; A31-B68; A31-B69; A31-B70; A31-B71; A31-B72; A31 -B73; A31-B74; A31-B75; A31-B76; A31-B77; A31-B78; A31-B79; A31-B80; A31-B81; A31-B82; A31-B83; A31-B84; A31-B85; A31-B86; A31-B87; A31-B88; A31-B89; A31-B90; A31-B91; A31-B92; A31-B93; A31-B94; A31-B95; A31-B96; A31-B97; A31-B98; A31-B99; A31-B100; A31-B101; A31-B102; A31-B103; A31-B104; A31-B105; A31-B106; A31-B107; A31-B108; A31-B109; A31-B110; A31-B111; A31-B112; A31-B113; A31-B114; A31-B115; A31-B116; A31-B117; A31-B118; A31-B119; A31-B120; A31-B121; A31-B122; A31-B123; A31-B124; A31-B125; A31-B126; A31-B127; A31 -B128; A31-B129; A31-B130; A31-B131; A31-B132; A31-B133; A31-B134; A31-B135; A31-B136; A31-B137; A31-B138; A31-B139; A31-B140; A31-B141; A31-B142; A31-B143; A31-B144; A31-B145; A31-B146; A31-B147; A31-B148; A31-B149; A31 -B150; A31-B151; A31-B152; A31-B153; A31-B154; A31-B155; A31-B156; A31-B157; A31-B158; A31-B159; A31-B160; A31-B161; A31-B162; A31-B163; A31-B164; A31-B165; A31-B166; A31-B167; A31-B168; A31-B169; A32-B1; A32-B2; A32-B3; A32-B4; A32-B5; A32-B6; A32-B7; A32-B8; A32-B9; A32-B10; A32-B11; A32-B12; A32-B13; A32-B14; A32-B15; A32-B16; A32-B17; A32-B18; A32-B19; A32-B20; A32-B21; A32-B22; A32-B23; A32-B24; A32-B25; A32-B26; A32-B27; A32-B28; A32-B29; A32-B30; A32-B31; A32-B32; A32-B33; A32-B34; A32-B35; A32-B36; A32-B37; A32-B38; A32-B39; A32-B40; A32-B41; A32-B42; A32-B43; A32-B44; A32-B45; A32-B46; A32-B47; A32-B48; A32-B49; A32-B50; A32-B51; A32-B52; A32-B53; A32-B54; A32-B55; A32-B56; A32-B57; A32-B58; A32-B59; A32-B60; A32-B61; A32-B62; A32-B63; A32-B64; A32-B65; A32-B66; A32-B67; A32-B68; A32-B69; A32-B70; A32-B71; A32-B72; A32-B73; A32-B74; A32-B75; A32-B76; A32-B77; A32-B78; A32-B79; A32-B80; A32-B81; A32-B82; A32-B83; A32-B84; A32-B85; A32-B86; A32-B87; A32-B88; A32-B89; A32-B90; A32-B91; A32-B92; A32-B93; A32-B94; A32-B95; A32-B96; A32-B97; A32-B98; A32-B99; A32-B100; A32-B101; A32-B102; A32-B103; A32-B104; A32-B105; A32-B106; A32-B107; A32-B108; A32-B109; A32-B110; A32-B11 1; A32-B112; A32-B113; A32-B114; A32-B115; A32-B116; A32-B117; A32-B118; A32-B119; A32-B120; A32-B121; A32-B122; A32-B123; A32-B124; A32-B125; A32-B126; A32-B127; A32-B128; A32-B129; A32-B130; A32-B131; A32-B132; A32-B133; A32-B134; A32-B135; A32-B136; A32-B137; A32-B138; A32-B139; A32-B140; A32-B141; A32-B142; A32-B143; A32-B144; A32-B145; A32-B146; A32-B147; A32-B148; A32-B149; A32-B150; A32-B151; A32-B152; A32-B153; A32-B154; A32-B155; A32-B156; A32-B157; A32-B158; A32-B159; A32-B160; A32-B161; A32-B162; A32-B163; A32-B164; A32-B165; A32-B166; A32-B167; A32-B168; A32-B169; A33-BÍ; A33-B2; A33-B3; A33-B4; A33-B5; A33-B6; A33-B7; A33-B8; A33-B9; A33-B10; A33-B1 1; A33-B12; A33-B13; A33-B14; A33-B15; A33-B16; A33-B17; A33-B18; A33-B19; A33-B20; A33-B21; A33-B22; A33-B23; A33-B24; A33-B25; A33-B26; A33-B27; A33-B28; A33-B29; A33-B30; A33-B31; A33-B32; A33-B33; A33-B34; A33-B35; A33-B36; A33-B37; A33-B38; A33-B39; A33-B40; A33-B41; A33-B42; A33-B43; A33-B44; A33-B45; A33-B46; A33-B47; A33-B48; A33-B49; A33-B50; A33-B51; A33-B52; A33-B53; A33-B54; A33-B55; A33-B56; A33-B57; A33-B58; A33-B59; A33-B60; A33-B61; A33-B62; A33-B63; . A33-B64; A33-B65; A33-B66; A33-B67; A33-B68; A33-B69; A33-B70; A33-B71; A33-B72; A33-B73; A33-B74; A33-B75; A33-B76; A33-B77; A33-B78; A33-B79; A33-B80; A33-B81; A33-B82; ? 33-? 83 · A33-B84; A33-B85; A33-B86; A33-B87; A33-B88; A33-B89; A33-B90; A33-B91; A33-B92; A33-B93; A33-B94; A33-B95; A33-B96; A33-B97; A33-B98; A33-B99; A33-B100; A33-B101; A33-B102; A33-B103; A33-B104; A33-B105; A33-B106; A33-B107; A33-B108; A33-B109; A33-B110; A33-B11 1; A33-B112; A33-B113; A33-B114; A33-B115; A33-B116; A33-B117; A33-B118; A33-B119; A33-B120; A33-B121; A33-B122; A33-B123; A33-B124; A33-B125; A33-B126; A33-B127; A33-B128; A33-B129; A33-B130; A33-B131; A33-B132; A33-B133; A33-B134; A33-B135; A33-B136; A33-B137; A33-B138; A33-B139; A33-B140; A33-B141; A33-B142; A33-B143; A33-B144; A33-B145; A33-B146; A33-B147; A33-B148; A33-B149; A33-B150; A33-B151; A33-B152; A33-B153; A33-B 54; A33-B155; A33-B156; A33-B157; A33-B158; A33-B159; A33-B160; A33-B161; A33-B162; A33-B163; A33-B164; A33-B165; A33-B166; A33-B167; A33-B168; A33-B169; A34-B1; A34-B2; A34-B3; A34-B4; A34-B5; A34-B6; A34-B7; A34-B8; A34-B9; A34-B10; A34-B11; A34-B12; A34-B13; A34-B14; A34-B15; A34-B16; A34-B17; A34-B18; A34-B19; A34-B20; A34-B21; A34-B22; A34-B23; A34-B24; A34-B25; A34-B26; A34-B27; A34-B28; A34-B29; A34-B30; A34-B31; A34-B32; A34-B33; A34-B34; A34-B35; A34-B36; A34-B37; A34-B38; A34-B39; A34-B40; A34-B41; A34-B42; A34-B43; A34-B44; A34-B45; A34-B46; A34-B47; A34-B48; A34-B49; A34-B50; A34-B51; A34-B52; A34-B53; A34-B54; A34-B55; A34-B56; A34-B57; A34-B58; A34-B59; A34-B60; A34-B61; A34-B62; A34-B63; A34-B64; A34-B65; A34-B66; A34-B67; A34-B68; A34-B69; A34-B70; A34-B71; A34-B72; A34-B73; A34-B74; A34-B75; A34-B76; A34-B77; A34-B78; A34-B79; A34-B80; A34-B81; A34-B82; A34-B83; A34-B84; A34-B85; A34-B86; A34-B87; A34-B88; A34-B89; A34-B90; A34-B91; A34-B92; A34-B93; A34-B94; A34-B95; A34-B96; A34-B97; A34-B98; A34-B99; A34-B100; A34-B101; A34-B102; A34-B103; A34-B104; A34-B105; A34-B106; A34-B107; A34-B108; A34-B109; A34-B110; A34-B111; A34-B112; A34-B113; A34-B1 14; A34-B1 15; A34-B1 16; A34-B117; A34-B118; A34-B119; A34-B120; A34-B121; A34-B122; A34-B123; A34-B124; A34-B125; A34-B126; A34-B127; A34-B128; A34-B129; A34-B130; A34-B131; A34-B132; A34-B133; A34-B134; A34-B135; A34-B136; A34-B137; A34-B138; A34-B139; A34-B140; A34-B141; A34-B142; A34-B 43; A34-B144; A34-B145; A34-B146; A34-B147; A34-B148; A34-B149; A34-B150; A34-B151; A34-B152; A34-B153; A34-B154; A34-B155; A34-B156; A34-B157; A34-B158; A34-B159; A34-B160; A34-B161; A34-B162; A34-B163; A34-B164; A34-B165; A34-B166; A34-B167; A34-B168; A34-B169; A35-B1; A35-B2; A35-B3; A35-B4; A35-B5; A35-B6; A35-B7; A35-B8; A35-B9; A35-B10; A35-B11; A35-B12; A35-B13; A35-B14; A35-B15; A35-B16; A35-B17; A35-B18; A35-B19; A35-B20; A35-B21; A35-B22; A35-B23; A35-B24; A35-B25; A35-B26; A35-B27; A35-B28; A35-B29; A35-B30; A35-B31; A35-B32; A35-B33; A35-B34; A35-B35; A35-B36; A35-B37; A35-B38; A35-B39; A35-B40; A35-B41; A35-B42; A35-B43; A35-B44; A35-B45; A35-B46; A35-B47; A35-B48; A35-B49; A35-B50; A35-B51; A35-B52; A35-B53; A35-B54; A35-B55; A35-B56; A35-B57; A35-B58; A35-B59; A35-B60; A35-B61; A35-B62; A35-B63; A35-B64; A35-B65; A35-B66; A35-B67; A35-B68; A35-B69; A35-B70; A35-B71; A35-B72; A35-B73; A35-B74; A35-B75; A35-B76; A35-B77; A35-B78; A35-B79; A35-B80; A35-B81; A35-B82; A35-BS3; A35-B84; A35-B85; A35-B86; A35-B87; A35-B88; A35-B89; A35-B90; A35-B91; A35-B92; A35-B93; A35-B94; A35-B95; A35-B96; A35-B97; A35-B98; A35-B99; A35-B100; A35-B101; A35-B102; A35-B103; A35-B104; A35-B105; A35-B106; A35-B107; A35-B108; A35-B109; A35-B1 10; A35-B111; A35-B1 12; A35-B113; A35-B114; A35-B115; A35-B116; A35-B1 17; A35-B1 18; A35-B119; A35-B120; A35-B121; A35-B122; A35-B123; A35-B124; A35-B125; A35-B126; A35-B127; A35-B128; A35-B129; A35-B130; A35-B131; A35-B132; A35-B133; A35-B134; A35-B135; A35-B136; A35-B137; A35-B138; A35-B139; A35-B140; A35-B141; A35-B142; A35-B143; A35-B144; A35-B145; A35-B146; A35-B147; A35-B148; A35-B149; A35-B150; A35-B151; A35-B152; A35-B153; A35-B154; A35-B155; A35-B156; A35-B157; A35-B158; A35-B159; A35-B160; A35-B161; A35-B162; A35-B163; A35-B164; A35-B165; A35-B166; A35-B167; A35-B168; A35-B169; A36-B1; A36-B2; A36-B3; A36-B4; A36-B5; A36-B6; A36-B7; A36-B8; A36-B9; A36-B10; A36-B11; A36-B12; A36-B13; A36-B14; A36-B15; A36-B16; A36-B17; A36-B18; A36-B19; A36-B20; A36-B21; A36-B22; A36-B23; A36-B24; A36-B25; A36-B26; A36-B27; ? 36-? 28; · A36-B29; A36-B30; A36-B31; A36-B32; A36-B33; A36-B34; A36-B35; A36-B36; A36-B37; A36-B38; A36-B39; A36-B40; A36-B41; A36-B42; A36-B43; A36-B44; A36-B45; A36-B46; A36-B47; A36-B48; A36-B49; A36-B50; A36-B51; A36-B52; A36-B53; A36-B54; A36-B55; A36-B56; A36-B57; A36-B58; A36-B59; A36-B60; A36-B61; A36-B62; A36-B63; A36-B64; A36-B65; A36-B66; A36-B67; A36-B68; A36-B69; A36-B70; A36-B71; A36-B72; A36-B73; A36-B74; A36-B75; A36-B76; A36-B77; A36-B78; A36-B79; ? 36-? 80 ·, A36-B81; A36-B82; A36-B83; A36-B84; A36-B85; A36-B86; A36-B87; A36-B88; A36-B89; A36-B90; A36-B91; A36-B92; A36-B93; A36-B94; A36-B95; A36-B96; A36-B97; A36-B98; A36-B99; A36-B100; A36-B101; A36-B102; A36-B103; A36-B104; A36-B105; A36-B106; A36-B107; A36-B108; A36-B109; A36-B1 10; A36-B111; A36-B112; A36-B113; A36-B114; A36-B115; A36-B116; A36-B117; A36-B118; A36-B119; A36-B120; A36-B121; A36-B122; A36-B123; A36-B124; A36-B125; A36-B126; A36-B127; A36-B128; A36-B129; A36-B130; A36-B131; A36-B132; A36-B133; A36-B134; A36-B135; A36-B136; A36-B137; A36-B138; A36-B139; A36-B140; A36-B141; A36-B142; A36-B143; A36-B144; A36-B145; A36-B146; A36-B147; A36-B148; A36-B149; A36-B150; A36-B151; A36-B152; A36-B153; A36-B154; A36-B155; A36-B156; A36-B157; A36-B158; A36-B159; A36-B160; A36-B161; A36-B162; A36-B163; A36-B164; A36-B165; A36-B166; A36-B167; A36-B168; A36-B169; A37-B1; A37-B2; A37-B3; A37-B4; A37-B5; A37-B6; A37-B7; A37-B8; A37-B9; A37-B10; A37-B11; A37-B12; A37-B13; A37-B14; A37-B15; A37-B16; A37-B17; A37-B18; A37-B19; A37-B20; A37-B21; A37-B22; A37-B23; A37-B24; A37-B25; A37-B26; A37-B27; A37-B28; A37-B29; A37-B30; A37-B31; A37-B32; A37-B33; A37-B34; A37-B35; A37-B36; A37-B37; A37-B38; A37-B39; A37-B40; A37-B41; A37-B42; A37-B43; A37-B44; A37-B45; A37-B46; A37-B47; A37-B48; A37-B49; A37-B50; A37-B51; A37-B52; A37-B53; A37-B54; A37-B55; A37-B56; A37-B57; A37-B58; A37-B59; A37-B60; A37-B61; A37-B62; A37-B63; A37-B64; A37-B65; A37-B66; A37-B67; A37-B68; . A37-B69; A37-B70; A37-B71; A37-B72; A37-B73; A37-B74; A37-B75; A37-B76; A37-B77; A37-B78; A37-B79; A37-B80; A37-B81; A37-B82; A37-B83; A37-B84; A37-B85; A37-B86; A37-B87; A37-B88; A37-B89; A37-B90; A37-B91; A37-B92; A37-B93, A37-B94; A37-B95; A37-B96; A37-B97; A37-B98; A37-B99; A37-B100; A37-B101; A37-B102; A37-B103; A37-B104; A37-B105; A37-B106; A37-B107; A37-B108; A37-B109; A37-B110; A37-B111; A37-B112; A37-B113; A37-B114; A37-B115; A37-B116; A37-B117; A37-B118; A37-B119; A37-B120; A37-B121; A37-B122; A37-B123; A37-B124; A37-B125; A37-B126; A37-B127; A37-B128; A37-B129; A37-B130; A37-B131; A37-B132; A37-B133; A37-B134; A37-B135; A37-B136; A37-B137; A37-B138; A37-B139; A37-B140; A37-B141; A37-B142; A37-B143; A37-B144; A37-B145; A37-B146; A37-B147; A37-B148; A37-B149; A37-B150; A37-B151; A37-B152; A37-B153; A37-B154; A37-B155; A37-B156; A37-B157; A37-B158; A37-B159; A37-B160; A37-B161; A37-B162; A37-B163; A37-B164; A37-B165; A37-B166; A37-B167; A37-B168; A37-B169; A38-B1; A38-B2; A38-B3; A38-B4; A38-B5; A38-B6; A38-B7; A38-B8; A38-B9; A38-B10; A38-B11; A38-B12; A38-B13; A38-B14; A38-B15; A38-B16; A38-B17; A38-B18; A38-B19; A38-B20; A38-B21; A38-B22; A38-B23; A38-B24; A38-B25; A38-B26; A38-B27; A38-B28; A38-B29; A38-B30; A38-B31; A38-B32; A38-B33; A38-B34; A38-B35; A38-B36; A38-B37; A38-B38; A38-B39; A38-B40; A38-B41; A38-B42; A38-B43; A38-B44; A38-B45; A38-B46; A38-B47; A38-B48; A38-B49; A38-B50; A38-B51; A38-B52; A38-B53; A38-B54; A38-B55; A38-B56; A38-B57; A38-B58; A38-B59; A38-B60; A38-B61; A38-B62; A38-B63; A38-B64; A38-B65; A38-B66; A38-B67; A38-B68; A38-B69; A38-B70; A38-B71; A38-B72; A38-B73; A38-B74; A38-B75; A38-B76; A38-B77; A38-B78; A38-B79; A38-B80; A38-B81; A38-B82; A38-B83; A38-B84; A38-B85; A38-B86; A38-B87; A38-B88; A38-B89; A38-B90; A38-B91; A38-B92; A38-B93; A38-B94; A38-B95; A38-B96; A38-B97; A38-B98; A38-B99; A38-B100; A38-B101; A38-B102; A38-B103; A38-B104; A38-B105; A38-B106; A38-B107; A38-B108; A38-B109; A38-B110; A38-B111; A38-B112; A38-B113; A38-B114; A38-B115; A38-B116; A38-B117; A38-B118; A38-B119; A38-B120; A38-B I 21; A38-B122; A38-B123; A38-B124; A38-B125; A38-B126; A38-B127; A38-B128; A38-B129; A38-B130; A38-B131; A38-B132; A38-B133; A38-B134; A38-B135; A38-B136; A38-B137; A38-B138; A38-3139; A38-B140; A38-B141; A38-B142; A38-B143; A38-B144; A38-B145; A38-B146; A38-B147; A38-B1 8; A38-B149; A38-B150; A38-B151; A38-B152; A38-B153; 'A38-B154; A38-B155; A38-B156; A38-B157; A38-B158; A38-B159; A38-B160; A38-B161; A38-B162; A38-B163; A38-B164; A38-B165; A38-B166; A38-B167; A38-B168; A38-B169; A39-B1; A39-B2; A39-B3; A39-B4; A39-B5; A39-B6; A39-B7; A39-B8; A39-B9; A39-B10; A39-B11; A39-B12; A39-B13; A39-B14; A39-B15; A39-B16; A39-B17; A39-B18; A39-B19; A39-B20; A39-B21; A39-B22; A39-B23; A39-B24; A39-B25; A39-B26; A39-B27; A39-B28; A39-B29; A39-B30; A39-B31; A39-B32; A39-B33; A39-B34; A39-B35; A39-B36; A39-B37; A39-B38; A39-B39; A39-B40; A39-B41; A39-B42; A39-B43; A39-B44; A39-B45; A39-B46; A39-B47; A39-B48; A39-B49; A39-B50; A39-B51; A39-B52; A39-B53; A39-B54; A39-B55; A39-B56; A39-B57; A39-B58; A39-B59; A39-B60; A39-B61; A39-B62; A39-B63; A39-B64; A39-B65; A39-B66; A39-B67; A39-B68; A39-B69; A39-B70; A39-B71; A39-B72; A39-B73; A39-B74; A39-B75; A39-B76; A39-B77; A39-B78; A39-B79; A39-B80; A39-B81; A39-B82; A39-B83; A39-B84; A39-B85; A39-B86; A39-B87; A39-B88; A39-B89; A39-B90; A39-B91; A39-B92; A39-B93; A39-B94; A39-B95; A39-B96; A39-B97; A39-B98; A39-B99; A39-B100; A39-B101; A39-B102; A39-B103; A39-B104; A39-B105; A39-B106; A39-B107; A39-B108; A39-B109; A39-B110; A39-B111; A39-B112; A39-B113; A39-B114; A39-B115; A39-B116; A39-B117; A39-B118; A39-B1 19; A39-B120; A39-B121; A39-B122; A39-B123; A39-B124; A39-B125; A39-B126; A39-B127; A39-B128; A39-B129; A39-B130; A39-B131; A39-B132; "A39-B133; A39-B134; A39-B135; A39-B136; A39-B137; A39-B138; A39-B139; A39-B140; A39-B141; A39-B142; A39-B143; A39-B144; A39-B145; A39-B146; A39-B147; A39-B148; A39-B149; A39-B150; A39-B151; A39-B152; A39-B153; A39-B154; A39-B155; A39-B156; A39-B157; A39-B158; A39-B159; A39-B160; A39-B161; A39-B162; A39-B163; A39-B164; A39-B165; A39-B166; A39-B167; A39-B168; A39-B169; A40-B1; A40-B2; A40-B3; A40-B4; A40-B5; A40-B6; A40-B7; A40-B8; A40-B9; A40-B10; A40-B11; A40-B12; A40-B13; A40-B14; A40-B15; A40-B16; A40-B17; A40-B18; A40-B19; A40-B20; A40-B21; A40-B22; A40-B23; A40-B24; A40-B25; A40-B26; A40-B27; A40-B28; A40-B29; A40-B30; A40-B31; A40-B32; A40-B33; A40-B34; A40-B35; A40-B36; A40-B37; A40-B38; A40-B39; A40-B40; A40-B41; A40-B42; A40-B43; A40-B44; A40-B45; A40-B46; A40-B47; A40-B48; A40-B49; A40-B50; A40-B51; A40-B52; A40-B53; A40-B54; A40-B55; A40-B56; A40-B57; A40-B58; A40-B59; A40-B60; A40-B61; A40-B62; A40-B63; A40-B64; A40-B65; A40-B66; A40-B67; A40-B68; A40-B69; A40-B70; A40-B71; A40-B72; A40-B73; A40-B74; A40-B75; A40-B76; A40-B77; A40-B78; A40-B79; A40-B80; A40-B81; A40-B82; A40-B83; A40-B84; A40-B85; A40-B86; A40-B87; A40-B88; A40-B89; A40-B90; A40-B91; A40-B92; A40-B93; A40-B94; A40-B95; A40-B96; A40-B97; A40-B98; A40-B99; A40-B100; A40-B101; A40-B102; A40-B103; A40-B104; A40-B105; A40-B106; A40-B107; A40-B108; A40-B109; A40-B110; A40-B111; A40-B112; A40-B113; A40-B114; A40-B115; A40-B116; A40-B117; A40-B118; A40-B119; A40-B120; A40-B121; A40-B122; A40-B123; A40-B124; ? 40-? 125; ? 40-? 126; ? 40-? 127; ? 40-? 128; ? 40-? 129; A40-B130; ? 40-? 131; ? 40-? 132; ? 40-? 133; ? 40-? 134; ? 40-? 135; A40-B136; ? 40-? 137; ? 40-? 138; ? 40-? 139; 40-? 140; ? 40-? 141; A40-B142; ? 40-? 143; ? 40-? 144; ? 40-? 145; ? 40-? 146; ? 40-? 147; A40-B148; ? 40-? 149; ? 40-? 150; ? 40-? 151; ? 40-? 152; ? 40-? 153; A40-B154; ? 40-? 155; 40- 156; ? 40-? 157; ? 40-? 158; ? 40-? 159; A40-B160; ? 40-? 161; ? 40-? 162; ? 40-? 163; 40-? 164; ? 40-? 165; A40-B166; ? 40-? 167; ? 40-? 168; ? 40-? 169; 41-? 1; 41-? 2; A41-B3; 41-? 4; 41-? 5; 41-? 6; 41-? 7; 41-? 8; A41-B9; 41-? 10; 41-? 11; ? 41-? 12; 41-? 13; 41-? 14; A41-B15; 41-? 16; 41-? 17; 41-? 18; ? 41-? 19; 41-? 20; A41-B21; 41-? 22; 41-? 23; 41-? 24; 41-? 25; 41-? 26; A41-B27; 41-? 28; 41-? 29; 41-? 30; 41-31; 41-32; A41-B33; 41-? 34; 41-? 35; 41 -? 36; ? 41-? 37; 41-? 38; A41-B39; 41-40; 41-41; 41-42; 41-? 43; 41-? 44; A41-B45; ? 41 -? 46; 41-? 47; '? 41-? 48; 41-? 49; 41-? 50; A41-B51; 41-? 52; 41-? 53; 41-? 54; 41-? 55; 41-? 56; A41-B57; 41-? 58; 41-? 59; . 41-60; 41-61; 41-? 62; A41-B63; 41-64; 41-65; 41-66; 41-67; 41-? 68; A41-B69; 41-? 70; 41-? 71; 41-? 72; ? 41 ÷? 73; 41-74; A41-B75; 41 - 76; 41-? 77; 41-? 78; 41-? 79; ? 41-? 80; A41-B81; 41-82; 41-? 83; 41-? 84; 41-? 85; 41-86; A41-B87; ,? 41-? 88; 41-? 89; 41-? 90; 41-? 91; 41-? 92; ? 41-? 93; 41-? 94; 41-? 95; ? 41-? 96; 41-? 97; 41-? 98; 41-? 99; ? 41-? 100; 41-? 101; 41-? 102; 41-? 103; 41-? 104; A41-B105; A41-B106; A41-B107; A41-B108; A41 -B 09; A41-B110; A41-B1 11; A41-B112; A41-B113; · A41-B114; A41-B115; A41-B116; A41-B117; A41-B1 18; A41-B119; A41-B120; A41-B121; A41-B122; A41-B123; A41-B124; A41-B125; A41-B126; A41-B127; A41-B128; A41-B129; A41-B130; A41-B131; A41-B132; A41-B133, A41-B134; A41-B135; A41-B136; A41-B137; A41-B138; A41-B139; A41-B140; A41-B141; A41-B142; A41-B143; A41-B144; A41-B145; A41-B146; A41-B147; A41-B148; A41-B149; A41-B150; A41-B151; A41-B152; A41-B153; A41-B154; A41-B155; A41-B156; A41-B157; A41-B158; A41-B159; A41-B160; A41-B161; A41-B162; A41-B163; A41-B164; A41-B165; A41-B166; A41-B167; A41-B168; A41-B169; A42-B1; A42-B2; A42-B3; A42-B4; A42-B5; A42-B6; A42-B7; A42-B8; A42-B9; A42-B10; A42-B11; A42-B12; A42-B13; A42-B14; A42-B15; A42-B16; A42-B17; A42-B18; A42-B19; A42-B20; A42-B21; A42-B22; A42-B23; A42-B24; A42-B25; A42-B26; A42-B27; A42-B28; A42-B29; A42-B30; A42-B31; A42-B32; A42-B33; A42-B34; A42-B35; A42-B36; A42-B37; A42-B38; A42-B39; A42-B40; A42-B41; A42-B42; A42-B43; A42-B44; A42-B45; A42-B46; A42-B47; A42-B48; A42-B49; ' A42-B50; A42-B51; A42-B52; A42-B53; A42-B54; A42-B55; A42-B56; A42-B57; A42-B58; A42-B59; A42-B60; A42-B61; A42-B62; . A42-B63; A42-B64; A42-B65; A42-B66; A42-B67; A42-B68; A42-B69; A42-B70; A42-B71; A42-B72; A42-B73; A42-B74; A42-B75; A42-B76; A42-B77; A42-B78; A42-B79; A42-B80; A42-B81; A42-B82; A42-B83; A42-B84; A42-B85; A42-B86; A42-B87; A42-B88; A42-B89; A42-B90; A42-B91; A42-B92; A42-B93; A42-B94; A42-B95; A42-B96; A42-B97; A42-B98; A42-B99; A42-B100; A42-B101; A42-B102; A42-B103; A42-B104; A42-B105; A42-B106; A42-B107; A42-B108; A42-B109; A42-B110; A42-B1 11; A42-B112; A42-B113; A42-B114; A42-B115; A42-B116; A42-B117; A42-B118; A42-B119; A42-B120; A42-B121; A42-B122; A42-B123; A42-B124; A42-B125; A42-B126; A42-B127; A42-B128; A42-B129; A42-B130; A42-B131; A42-B132; A42-B133; A42-B134; A42-B135; A42-B136; A42-B137; A42-B138; A42-B139; A42-B140; A42-B141; A42-B142; A42-B143; A42-B144; A42-B145; A42-B146; A42-B147; A42-B148; A42-B149; A42-B150; A42-B151; A42-B152; A42-B153; A42-B154; A42-B155; A42-B156; A42-B157; A42-B158; A42-B159; A42-B160; A42-B161; A42-B162; A42-B163; A42-B164; A42-B165; A42-B166; A42-B167; A42-B168; A42-B169; A43-B1; A43-B2; A43-B3; A43-B4; A43-B5; A43-B6; A43-B7; A43-B8; A43-B9; A43-B10; A43-B11; A43-B12; A43-B13; A43-B14; A43-B 5; A43-B16; A43-B17; A43-B18; A43-B19; A43-B20; A43-B21; A43-B22; A43-B23; A43-B24; A43-B25; A43-B26; A43-B27; A43-B28; A43-B29; A43-B30; A43-B31; A43-B32; A43-B33; A43-B34; A43-B35; A43-B36; A43-B37; A43-B38; A43-B39; A43-B40; A43-B41; A43-B42; A43-B43; A43-B44; A43-B45; A43-B46; A43-B47; A43-B48; A43-B49; A43-B50; A43-B51; A43-B52; A43-B53; A43-B54; A43-B55; A43-B56; A43-B57; A43-B58; A43-B59; A43-B60; A43-B61; A43-B62; A43-B63; A43-B64; A43-B65; A43-B66; A43-B67; A43-B68; A43-B69; A43-B70; A43-B71; A43-B72; A43-B73; A43-B74; A43-B75; A43-B76; A43-B77; A43-B78; A43-B79; A43-B80; A43-B81; A43-B82; A43-B83; A43-B84; A43-B85; A43-B86; A43-B87; A43-B88; A43-B89; A43-B90; A43-B91; A43-B92; A43-B93; A43-B94; A43-B95; A43-B96; A43-B97; A43-B98; A43-B99; A43-B100; A43-B101; A43-B102; A43-B103; A43-B104; A43-B105; A43-B106; A43-B107; A43-B108; A43-B109; A43-B1 10; A43-B1 1; A43-B112; A43-B113; A43-B114; A43-B115; A43-B116; A43-B117; A43-B118; A43-B119; A43-B120; A43-B121; A43-B122; A43-B123; A43-B124; A43-B125; A43-B126; A43-B127; A43-B128; A43-B129; A43-B130; A43-B131; A43-B132; A43-B133; A43-B134; A43-B135; A43-B136; A43-B137; A43-B138; A43-B139; A43-B140; A43-B141; A43-B142; A43-B143; A43-B1 4; A43-B145; A43-B146; A43-B147; A43-B148; A43-B149; A43-B150; A43-B151; A43-B152; A43-B153; A43-B154; A43-B155; A43-B156; A43-B157; A43-B158; A43-B159; A43-B160; A43-B161; A43-B162; A43-B163; A43-B164; A43-B165; A43-B166; A43-B167; A43-B168; A43-B169; A44-B1; A44-B2; A44-B3; A44-B4; A44-B5; A44-B6; A44-B7; A44-B8; A44-B9; A44-B10; A44-B11; A44-B12; A44-B13; A44-B14; A44-B15; A44-B16; A44-B17; A44-B18; A44-B19; A44-B20; A44-B21; A44-B22; A44-B23; A44-B24; A44-B25; A44-B26; A44-B27; A44-B28; A44-B29; A44-B30; A44-B31; A44-B32; A44-B33; A44-B34; A44-B35; A44-B36; A44-B37; A44-B38; A44-B39; A44-B40; A44-B41; A44-B42; A44-B43; A44-B44; A44-B45; A44-B46; A44-B47; A44-B48; A44-B49; A44-B50; A44-B51; A44-B52; A44-B53; A44-B54; A44-B55; A44-B56; A44-B57; A44-B58; A44-B59; A44-B60; A44-B61; A44-B62; A44-B63; A44-B64; A44-B65; A44-B66; A44-B67; A44-B68; A44-B69; A44-B70; A44-B71; A44-B72; A44-B73; A44-B74; A44-B75; A44-B76; A44-B77; A44-B78; A44-B79; A44-B80; A44-B81; A44-B82; A44-B83; A44-B84; A44-B85; A44-B86; A44-B87; A44-B88; A44-B89; A44-B90; A44-B91; A44-B92; A44-B93; A44-B94; A44-B95; A44-B96; A44-B97; A44-B98; A44-B99; A44-B100; A44-B101; A44-B102; A44-B103; A44-B104; A44-B105; A44-B106; A44-B107; A44-B108; A44-B109; A44-B110; A44-B111; A44-B112; A44-B113; A44-B114; A44-B115; A44-B116; A44-B117; A44-B118; A44-B119; A44-B120; A44-B121; A44-B122; A44-B123; A44-B124; A44-B125; A44-B126; A44-B127; A44-B128; A44-B129; A44-B130; A44-B131; A44-B132; A44-B133; A44-B134; A44-B135; A44-B136; A44-B137; A44-B138; A44-B139; A44-B140; A44-B141; A44-B142; A44-B143; A44-B144; A44-B145; A44-B146; A44-B147; A44-B148; A44-B149; A44-B150; A44-B151; A44-B152; A44-B153; A44-B154; A44-B155; A44-B156; A44-B157; A44-B158; A44-B159; 44- ?? 60; A44-B161; A44-B162; A44-B163; A44-B164; A44-B165; A44-B166; A44-B167; A44-B168; A44-B169; A45-B1; . A45-B2; A45-B3; A45-B4; A45-B5; A45-B6; A45-B7; A45-B8; A45-B9; A45-B10; A45-B11; A45-B12; A45-B13; A45-B14; A45-B15; A45-B16; A45-B17; A45-B18; A45-B19; A45: B20; A45-B21; A45-B22; A45-B23; A45-B24; A45-B25; A45-B26; A45-B27; A45-B28; A45-B29; A45-B30; A45-B31; A45-B32; A45-B33; A45-B34; A45-B35; A45-B36; A45-B37; A45-B38; A45-B39; A45-B40; A45-B41; A45-B42; A45-B43; A45-B44; A45-B45; A45-B46; A45-B47; A45-B48; A45-B49; A45-B50; A45-B51; A45-B52; A45-B53; A45-B54; A45-B55; A45-B56; A45-B57; A45-B58; A45-B59; A45-B60; A45-B61; A45-B62; A45-B63; A45-B64; A45-B65; A45-B66; A45-B67; A45-B68; A45-B69; A45-B70; A45-B71; A45-B72; A45-B73; A45-B74; A45-B75; A45-B76; A45-B77; A45-B78; A45-B79; A45-B80; A45-B81; A45-B82; A45-B83; A45-B84; A45-B85; A45-B86; A45-B87; A45-B88; A45-B89; A45-B90; A45-B91; A45-B92; A45-B93; A45-B94; A45-B95; A45-B96; A45-B97; · A45-B98; A45-B99; A45-B100; A45-B101; A45-B102; A45-B103; A45-B104; A45-B105; A45-B106; A45-B107; A45-B108; A45-B109; A45-B110; A45-B111; A45-B112; A45-B113; A45-B114; A45-B115; A45-B116; A45-B117; A45-B118; A45-B119; A45-B120; A45-B121; A45-B122; A45-B123; A45-B124; A45-B125; A45-B126; A45-B127; A45-B128; A45-B129; A45-B130; A45-B131; A45-B132; A45-B133; A45-B134; A45-B135; A45-B136; A45-B137; A45-B138; A45-B139; A45-B140; A45-B141; A45-B142; A45-B143; A45-B144; A45-B145; A45-B146; A45-B147; A45-B148; A45-B149; A45-B150; A45-B151; A45-B152; A45-B153; A45-B154; A45-B155; A45-B156; A45-B157; A45-B158; A45-B159; A45-B160; A45-B161; A45-B162; A45-B163; A45-B164; A45-B165; A45-B166; A45-B167; A45-B168; A45-B169; A46-B1; A46-B2; A46-B3; A46-B4; A46-B5; A46-B6; A46-B7; A46-B8; A46-B9; A46-B10; A46-B11; A46-B12; A46-B13; A46-B14; A46-B15; A46-B16; A46-B17; A46-B18; A46-B19; A46-B20; A46-B21; A46-B22; A46-B23; A46-B24; A46-B25; A46-B26; A46-B27; A46-B28; A46-B29; A46-B30; A46-B31; A46-B32; A46-B33; A46-B34; A46-B35; A46-B36; A46-B37; A46-B38; A46-B39; A46-B40; A46-B41; A46-B42; A46-B43; A46-B44; A46-B45; A46-B46; A46-B47; A46-B48; A46-B49; A46-B50; A46-B51; A46-B52; A46-B53; A46-B54; A46-B55; A46-B56; A46-B57; A46-B58; A46-B59; A46-B60; A46-B61; A46-B62; A46-B63; A46-B64; A46-B65; A46-B66; A46-B67; A46-B68; A46-B69; A46-B70; A46-B71; A46-B72; A46-B73; A46-B74; A46-B75; A46-B76; A46-B77; A46-B78; A46-B79; A46-B80; A46-B81; A46-B82; A46-B83; A46-B84; A46-B85; A46-B86; A46-B87; A46-B88; A46-B89; A46-B90; A46-B91; A46-B92; A46-B93; A46-B94; A46-B95; A46-B96; A46-B97; A46-B98; A46-B99; A46-B100; A46-B101; A46-B102; A46-B103; A46-B104; A46-B105; A46-B106; A46-B107; A46-B108; A46-B109; A46-B110; A46-B111; A46-B112; A46-B113; A46-B114; A46-B115; A46-B116; A46-B117; A46-B118; A46-B119; A46-B120; A46-B121; A46-B122; A46-B123; A46-B124; A46-B125; A46-B126; A46-B127; A46-B128; A46-B129; A46-B130; A46-B131; A46-B132; A46-B133; A46-B134; A46-B135; A46-B136; A46-B137; A46-B138; A46-B139; A46-B140; A46-B141; A46-B142; A46-B143; A46-B144; 'A46-B145; A46-B146; A46-B147; A46-B14S; A46-B149; A46-B150; A46-B151; A46-B152; A46-B153; A46-B154; A46-B155; A46-B156; A46-B157; A46-B158; A46-B159; A46-B160; A46-B161; A46-B162; A46-B163; A46-B164; A46-B165; A46-B166; A46-B167; A46-B168; A46-B 69; A47-B1; A47-B2; A47-B3; A47-B4; A47-B5; A47-B6; A47-B7; A47-B8; A47-B9; A47-B10; A47-B11; A47-B12; A47-B13; A47-B14; A47-B15; A47-B16; A47-B17; · A47-B18; A47-B19; A47-B20; A47-B21; A47-B22; A47-B23; A47-B24; A47-B25; A47-B26; A47-B27; A47-B28; A47-B29; A47-B30; A47-B31; A47-B32; A47-B33; A47-B34; A47-B35; · A47-B36; A47-B37; A47-B38; A47-B39; A47-B40; A47-B41; A47-B42; A47-B43; A47-B44; A47-B45; A47-B46; A47-B47; A47-B48; A47-B49; A47-B50; A47-B51; A47-B52; A47-B53; A47-B54; A47-B55; A47-B56; A47-B57; A47-B58; A47-B59; A47-B60; A47-B61; A47-B62; A47-B63; A47-B64; A47-B65; A47-B66; A47-B67; A47-B68; A47-B69; A47-B70; A47-B71; A47-B72; A47-B73; A47-B74; A47-B75; A47-B76; A47-B77; A47-B78; A47-B79; A47-B80; A47-B81; A47-B82; A47-B83; A47-B84; A47-B85; A47-B86; A47-B87; A47-B88; A47-B89; A47-B90; A47-B91; A47-B92; A47-B93; A47-B94; A47-B95; A47-B96; A47-B97; A47-B98; A47-B99; A47-B100; A47-B101; A47-B102; A47-B103; A47-B104; A47-B105; A47-B106; A47-B107; A47-B108; A47-B109; A47-B110; A47-B111; A47-B112; A47-B113; A47-B114; A47-B115; A47-B116; A47-B117; A47-B1 8; A47-B119; A47-B120; A47-B121; A47-B122; A47-B123; A47-B124; A47-B 25; A47-B126; A47-B127; A47-B128; A47-B129; A47-B130; A47-B131; A47-B132; A47-B133; A47-B134; A47-B135; A47-B136; A47-B137; A47-B138; A47-B139; A47-B140; A47-B141; A47-B142; A47-B143; A47-B144; A47-B145; A47-B146; A47-B147; A47-B148; A47-B149; A47-B150; A47-B151; A47-B152; A47-B153; A47-B154; A47-B155; A47-B156; A47-B157; A47-B158; A47-B159; A47-B160; A47-B161; A47-B162; A47-B163; A47-B164; A47-B165; A47-B166; A47-B167; A47-B168; A47-B169; A48-B1; A48-B2; A48-B3; A48-B4; A48-B5; A48-B6; A48-B7; A48-B8; A48-B9; A48-B10; A48-B11; A48-B12; A48-B13; A48-B14; A48-B15; A48-B16; A48-B17; A48-B18; A48-B19; A48-B20; A48-B21; A48-B22; · A48-B23; A48-B24; A48-B25; A48-B26; A48-B27; A48-B28; A48-B29; A48-B30; A48-B31; A48-B32; A48-B33; A48-B34; A48-B35; A48-B36; A48-B37; A48-B38; A48-B39; A48-B40; A48-B41; A48-B42; A48-B43; A48-B44; A48-B45; A48-B46; A48-B47; A48-B48; A48-B49; A48-B50; A48-B51; A48-B52; A48-B53; A48-B54; A48-B55; A48-B56; A48-B57; A48-B58; A48-B59; A48-B60; A48-B61; A48-B62; A48-B63; A48-B64; A48-B65; A48-B66; A48-B67; A48-B68; A48-B69; . A48-B70; A48-B71; A48-B72; A48-B73; A48-B74; A48-B75; A48-B76; A48-B77; A48-B78; A48-B79; A48-B80; A48-B81; A48-B82; A48-B83; A48-B84; A48-B85; A48-B86; A48-B87; A48-B88; A48-B89; A48-B90; A48-B91; A48-B92; A48-B93; A48-B94; A48-B95; A48-B96; A48-B97; A48-B98; A48-B99; A48-B100; A48-B101; A48-B102; A48-B103; A48-B104; A48-B105; A48-B106; A48-B107; A48-B108; A48-B109; A48-B110; A48-B111; A48-B112; A48-B113; A48-B114; A48-B115; A48-B116; A48-B117; A48-B118; A48-B119; A48-B120; A48-B121; A48-B122; A48-B123; A48-B124; A48-B125; A48-B126; A48-B127; A48-B128; A48-B129; A48-B130; A48-B131; A48-B132; A48-B133; A48-B134; A48-B135; A48-B136; A48-B137; A48-B138; A48-B139; A48-B1 0; A48-B141; A48-B142; A48-B143; A48-B144; A48-B145; A48-B146; A48-B147; A48-B148; A48-B149; A48-B150; A48-B151; A48-B152; A48-B153; A48-B154; | A48-B155; A48-B156; A48-B157; A48-B158; A48-B159; A48-B160; A48-B161; A48-B162; A48-B163; A48-B164; A48-B165; A48-B166; A48-B167; A48-B168; A48-B169; A49-B1; A49-B2; A49-B3; A49-B4; A49-B5; A49-B6; A49-B7; A49-B8; A49-B9; A49-B10; A49-B11; A49-B12; A49-B13; A49-B14; A49-B15; A49-B16; A49-B17; A49-B18; A49-B19; A49-B20; A49-B21; A49-B22; A49-B23; A49-B24; A49-B25; A49-B26; A49-B27; A49-B28; A49-B29; A49-B30; A49-B31; A49-B32; A49-B33; A49-B34; A49-B35; A49-B36; A49-B37; A49-B38; A49-B39; A49-B40; A49-B41; A49-B42; A49-B43; A49-B44; A49-B45; A49-B46; A49-B47; A49-B48; A49-B49; A49-B50; A49-B51; A49-B52; A49-B53; A49-B54; A49-B55; A49-B56; A49-B57; A49-B58; A49-B59; A49-B60; A49-B61; A49-B62; A49-B63; A49-B64; A49-B65; A49-B66; A49-B67; A49-B68; A49-B69; A49-B70; A49-B71; A49-B72; A49-B73; A49-B74; A49-B75; A49-B76; A49-B77; A49-B78; A49-B79; A49-B80; A49-B81; A49-B82; A49-B83; A49-B84; A49-B85; A49-B86; A49-B87; A49-B88; A49-B89; A49-B90; A49-B91; A49-B92; 'A49-B93; A49-B94; A49-B95; A49-B96; A49-B97; A49-B98; A49-B99; · A49-B100; A49-B101; A49-B102; A49-B103; A49-B104; A49-B105; A49-B106; A49-B107; A49-B108; A49-B109; A49-B110; A49-B1 11; A49-B112; A49-B113; A49-B114; A49-B1 5; A49-B116; A49-B117; A49-B118; A49-B1 9; A49-B120; A49-B121; A49-B122; A49-B123; A49-B124; A49-B125; A49-B126; A49-B127; A49-B128; A49-B129; A49-B130; A49-B131; A49-B132; A49-B133; A49-B134; A49-B135; A49-B136; A49-B137; A49-B138; A49-B139; A49-B140; A49-B141; A49-B142; A49-B143; A49-B144; A49-B145; A49-B146; A49-B147; A49-B148; A49-B149; A49-B150; A49-B151; A49-B152; A49-B153; A49-B154; A49-B155; A49-B156; A49-B157; A49-B158; A49-B159; A49-B160; A49-B161; A49-B162; A49-B163; A49-B164; A49-B165; A49-B166; A49-B167; A49-B168; A49-B169; A50-B1; A50-B2; A50-B3; A50-B4; A50-B5; A50-B6; A50-B7; A50-B8; A50-B9; A50-B10; A50-B11; A50-B12; A50-B13; A50-B14; A50-B15; A50-B16; A50-B17; A50-B18; A50-B19; A50-B20; A50-B21; A50-B22; A50-B23; A50-B24; A50-B25; A50-B26; A50-B27; A50-B28; A50-B29; A50-B30; A50-B31; A50-B32; A50-B33; A50-B34; A50-B35; A50-B36; A50-B37; A50-B38; . A50-B39; A50-B40; A50-B41; A50-B42; A50-B43; A50-B44; A50-B45; A50-B46; A50-B47; A50-B48; A50-B49; A50-B50; A50-B51; A50-B52; A50-B53; A50-B54; A50-B55; A50-B56; A50-B57; A50-B58; A50-B59; A50-B60; A50-B61; A50-B62; A50-B63; A50-B64; A50-B65; A50-B66; A50-B67; A50-B68; A50-B69; A50-B70; A50-B71; A50-B72; A50-B73; A50-B74; A50-B75; A50-B76; A50-B77; A50-B78; A50-B79; A50-B80; A50-B81; A50-B82; A50-B83; A50-B84; A50-B85; A50-B86; A50-B87; A50-B88; A50-B89; A50-B90; A50-B91; A50-B92; A50-B93; A50-B94; A50-B95; A50-B96; A50-B97; A50-B98; A50-B99; A50-B100; A50-B101; A50-B102; A50-B103; A50-B104; A50-B105; A50-B106; A50-B107; A50-B108; A50-B109; A50-B110; A50-B111; A50-B1 2; A50-B113; A50-B114; A50-B115; A50-B116; A50-B117; A50-B118; A50-B119; A50-B120; A50-B121; A50-B122; A50-B123; A50-B124; A50-B125; A50-B126; A50-B127; A50-B128; A50-B129; A50-B130; A50-B131; A50-B132; A50-B133; A50-B134; A50-B135; A50-B136; A50-B137; A50-B138; A50-B139; A50-B140; A50-B141; A50-B142; A50-B143; A50-B144; A50-B145; A50-B146; A50-B147; A50-B148; A50-B149; A50-B150; A50-B151; A50-B152; A50-B153; A50-B154; A50-B155; A50-B156; A50-B157; A50-B158; A50-B159; A50-B160; A50-B161; A50-B162; A50-B163; A50-B164; · A50-B165; A50-B166; A50-B167; A50-B168; A50-B169; A51-B1; A51-B2; A51-B3; A51-B4; A51-B5; A51-B6; A51-B7; A51-B8; A51-B9; A51-B10; A51-B11; A51-B12; A51-B13; A51-B14; A51-B15; A51-B16; A51-B17; A51-B18; A51-B19; A51-B20; A51-B21; A51-B22; A51-B23; A51-B24; A51-B25; | A51-B26; A51-B27; A51-B28; A51-B29; A51-B30; A51-B31; A51-B32; A51-B33; A51-B34; A51-B35; A51-B36; A51-B37; A51-B38; A51-B39; A51-B40; A51-B41; A51-B42; A51-B43; A51-B44; A51-B45; A51-B46; A51-B47; A51-B48; A51-B49; A51-B50; A51-B51; A51-B52; A51-B53; A51-B54; A51-B55; A51-B56; A51-B57; A51-B58; A51-B59; A51-B60; A51-B61; A51-B62; A51-B63; A51-B64; A51-B65; A51-B66; A51-B67; A51-B68; A51-B69; A51-B70; A51-B71; A51-B72; A51-B73; A51-B74; A51-B75; A51-B76; A51-B77; A51-B78; A51-B79; A51-B80; A51-B81; A51-B82; A51-B83; A51-B84; A51-B85; A51-B86; A51-B87; A51-B88; A51-B89; A51-B90; A51-B91; A51-B92; A51-B93; A51-B94; A51-B95; A51-B96; A51-B97; A51-B98; A51-B99; A51-B100; A51-B101; A51-B102; A51-B103; A51-B104; A51-B105; A51-B106; A51-B107; A51-B108; A51-B109; A51-B110; A51-B111; A51-B112; A51-B113; A51-B114; A51-B115; A51-B116; A51-B117; A51-B118; A51-B119; A51-B120; A51-B121; A51-B122; A51-B123; A51-B124; A51-B125; A51-B126; A51-B127; A51-B128; A51-B129; A51-B130; A51-B131; A51-B132; A51-B133; A51-B134; A51-B135; A51-B136; A51-B137; A51-B138; A51-B139; A51-B140; A51-B141; A51-B142; A51-B143; A51-B144; A51-B145; A51-B146; A51-B147; A51-B148; A51-B149; A51-B150; A51-B151; A51-B152; A51-B153; A51-B154; A51-B155; A51-B156; A51-B157; A51-B158; A51-B159; A51-B160; A51-B161; A51-B162; A51-B163; A51-B164; A51-B165; A51-B166; A51-B167; A51-B168; A51-B169; A52-B1; A52-B2; A52-B3; A52-B4; A52-B5; A52-B6; A52-B7; A52-B8; A52-B9; A52-B10; A52-B11; A52-B12; A52-B13; A52-B14; A52-B15; A52-B16; A52-B17; A52-B18; A52-B19; A52-B20; A52-B21; A52-B22; A52-B23; A52-B24; A52-B25; A52-B26; A52-B27; A52-B28; A52-B29; A52-B30; A52-B31; A52-B32; A52-B33; A52-B34; A52-B35; A52-B36; A52-B37; A52-B38; A52-B39; A52-B40; A52-B41; A52-B42; A52-B43; A52-B44; A52-B45; A52-B46; A52-B47; A52-B48; A52-B49; A52-B50; A52-B51; A52-B52; A52-B53; A52-B54; A52-B55; A52-B56; A52-B57; A52-B58; A52-B59; A52-B60; A52-B61; A52-B62; A52-B63; A52-B64; A52-B65; A52-B66; A52-B67; A52-B68; A52-B69; A52-B70; A52-B71; A52-B72; A52-B73; A52-B74; A52-B75; A52-B76; A52-B77; A52-B78; · A52-B79; A52-B80; A52-B81; A52-B82; A52-B83; A52-B84; A52-B85; A52-B86; A52-B87; A52-B88; A52-B89; A52-B90; A52-B91; A52-B92; A52-B93; A52-B94; A52-B95; A52-B96; A52-B97; A52-B98; A52-B99; A52-B100; A52-B101; A52-B102; A52-B103; A52-B104; A52-B105; A52-B106; A52-B107; A52-B108; A52-B109; A52-B110; A52-B111; A52-B112; A52-B113; A52-B114; A52-B115; A52-B116; A52-B117; A52-B118; A52-B119; A52-B120; A52-B121; A52-B122; A52-B123; A52-B124; A52-B125; A52-B126; A52-B127; A52-B128; A52-B129; A52-B130; A52-B131; A52-B132; A52-B133; A52-B134; A52-B135; A52-B136; A52-B137; A52-B138; A52-B139; A52-B140; A52-B141; A52-B142; A52-B143; A52-B144; A52-B145; A52-B146; A52-B147; A52-B148; A52-B149; A52-B150; A52-B151; A52-B152; A52-B153; A52-B154; A52-B155; A52-B156; A52-B157; A52-B158; A52-B159; A52-B 60; A52-B161; A52-B162; A52-B163; A52-B164; A52-B165; A52-B166; A52-B167; A52-B168; A52-B169; A53-B1; A53-B2; A53-B3; A53-B4; A53-B5; A53-B6; A53-B7; A53-B8; A53-B9; A53-B10; A53-B11; A53-B12; A53-B13; A53-B14; A53-B15; | A53-B16; A53-B17; A53-B18; A53-B19; A53-B20; A53-B21; A53-B22; A53-B23; A53-B24; A53-B25; A53-B26; A53-B27; A53-B28; A53-B29; A53-B30; A53-B31; A53-B32; A53-B33; A53-B34; A53-B35; A53-B36; A53-B37; A53-B38; A53-B39; A53-B40; A53-B41; A53-B42; A53-B43; A53-B44; A53-B45; A53-B46; A53-B47; A53-B48; A53-B49; A53-B50; A53-B51; A53-B52; A53-B53; A53-B54; A53-B55; A53-B56; A53-B57; A53-B58; A53-B59; A53-B60; A53-B61; A53-B62; A53-B63; A53-B64; A53-B65; A53-B66; A53-B67; A53-B68; A53-B69; A53-B70; A53-B71; A53-B72; A53-B73; A53-B74; A53-B75; A53-B76; A53-B77; A53-B78; A53-B79; A53-B80; A53-B81; A53-B82; A53-B83; A53-B84; A53-B85; A53-B86; A53-B87; A53-B88; A53-B89; . A53-B90; A53-B91; A53-B92; A53-B93; A53-B94; A53-B95; A53-B96; A53-B97; A53-B98; A53-B99; A53-B100; A53-B101; A53-B102; A53-B103; A53-B104; A53-B105; A53-B106; A53-B107; A53-B108; A53-B109; A53-B110; A53-B111; A53-B112; A53-B113; A53-B114; A53-B115; A53-B116; A53-B117; A53-B118; A53-B119; A53-B120; A53-B121; A53-B122; A53-B123; A53-B124; A53-B125; A53-B126; A53-B127; A53-B128; A53-B129; A53-B130; A53-B131; A53-B132; A53-B133; A53-B134; A53-B135; A53-B136; A53-B137; A53-B138; A53-B139; A53-B140; A53-B141; A53-B142; A53-B143; A53-B144; A53-B145; A53-B146; A53-B147; A53-B148; A53-B149; A53-B150; A53-B151; A53-B152; A53-B153; A53-B154; A53-B155; A53-B156; A53-B157; A53-B158; A53-B159; A53-B160; A53-B161; A53-B162; A53-B163; A53-B164; A53-B165; A53-B166; A53-B167; A53-B168; A53-B169; A54-B1; A54-B2; A54-B3; . A54-B4; A54-B5; A54-B6; A54-B7; A54-B8; A54-B9; A54-B10; A54-B11; A54-B12; A54-B13; A54-B14; A54-B15; A54-B16; A54-B17; A54-B18; A54-B19; A54-B20; A54-B21; A54-B22; A54-B23; A54-B24; A54-B25; A54-B26; A54-B27; A54-B28; A54-B29; A54-B30; A54-B31; A54-B32; A54-B33; A54-B34; A54-B35; A54-B36; A54-B37; A54-B38; A54-B39; A54-B40; A54-B41; A54-B42; A54-B43; A54-B44; A54-B45; A54-B46; A54-B47; A54-B48; A54-B49; A54-B50; A54-B51; A54-B52; A54-B53; A54-B54; A54-B55; A54-B56; A54-B57; A54-B58; A54-B59; A54-B60; A54-B61; A54-B62; A54-B63; A54-B64; A54-B65; A54-B66; A54-B67; A54-B68; A54-B69; A54-B70; A54-B71; A54-B72; A54-B73; A54-B74; A54-B75; A54 ÷ B76; A54-B77; A54-B78; A54-B79; A54-B80; A54-B81; A54-B82; A54-B83; A54-B84; A54-B85; A54-B86; A54-B87; A54-B88; A54-B89; A54-B90; A54-B91; A54-B92; A54-B93; A54-B94; A54-B95; A54-B96; A54-B97; A54-B98; A54-B99; A54-B100; A54-B101; A54-B102; A54-B103; A54-B104; A54-B105; A54-B106; A54-B107; A54-B108; A54-B109; A54-B110; A54-B111; A54-B112; A54-B113; A54-B114; A54-B115; A54-B116; A54-B117; A54-B1 18; A54-B119; A54-B120; A54-B121; A54-B122; A54-B123; A54-B124; A54-B125; A54-B126; A54-B127; A54-B128; A54-B129; A54-B130; A54-B131; A54-B132; A54-B133; A54-B134; A54-B135; A54-B136; A54-B137; A54-B138; A54-B139; A54-B140; A54-B141; A54-B142; A54-B143; A54-B144; A54-B1 5; A54-B146; A54-B147; A54-B148; A54-B149; A54-B150; A54-B151; A54-B152; A54-B153; A54-B154; A54-B155; A54-B156; A54-B157; A54-B158; A54-B159; A54-B160; A54-B161; A54-B162; A54-B163; A54-B164; A54-B165; A54-B166; A54-B167; A54-B168; A54-B169; A55-B1; A55-B2; A55-B3; A55-B4; A55-B5; A55-B6; A55-B7; A55-B8; A55-B9; A55-B10; A55-B1 1; A55-B12; A55-B13; A55-B14; A55-B15; A55-B16; A55-B17; A55-B18; A55-B19; A55-B20; A55-B21; A55-B22; A55-B23; A55-B24; A55-B25; A55-B26; A55-B27; A55-B28; A55-B29; A55-B30; A55-B31; A55-B32; A55-B33; A55-B34; A55-B35; A55-B36; A55-B37; A55-B38; A55-B39; A55-B40; A55-B41; A55-B42; A55-B43; A55-B44; A55-B45; A55-B46; A55-B47; A55-B48; A55-B49; A55-B50; A55-B51; A55-B52; A55-B53; A55-B54; A55-B55; A55-B56; A55-B57; A55-B58; A55-B59; A55-B60; A55-B61; A55-B62; A55-B63; A55-B64; A55-B65; A55-B66; A55-B67; A55-B68; A55-B69; A55-B70; A55-B71; A55-B72; A55-B73; A55-B74; A55-B75; A55-B76; A55-B77; A55-B78; A55-B79; A55-B80; A55-B81; A55-B82; A55-B83; A55-B84; A55-B85; A55-B86; A55-B87; A55-B88; A55-B89; A55-B90; A55-B91; A55-B92; A55-B93; A55-B94; A55-B95; A55-B96; A55-B97; A55-B98; A55-B99; · A55-B100; A55-B101; A55-B102; A55-B103; A55-B104; A55-B105; A55-B106; A55-B107; A55-B108; A55-B109; A55-B110; A55-B111; A55-B112; A55-B113; A55-B114; A55-B115; A55-B1 16; A55-B1 17; A55-B118; A55-B119; A55-B120; A55-B121; A55-B122; A55-B123; A55-B124; A55-B125; A55-B126; A55-B127; ' A55-B128; A55-B129; A55-B130; A55-B131; A55-B132; A55-B133; A55-B134; A55-B135; A55-B136; A55-B137; A55-B138; A55-B139; A55-B140; A55-B141; A55-B142; A55-B143; A55-B144; A55-B145; A55-B146; • A55-B147; A55-B148; A55-B149; A55-B150; A55-B151; A55-B152; A55-B153; A55-B154; A55-B155; A55-B156; A55-B157; A55-B158; A55-B159; A55-B160; A55-B161; A55-B162; A55-B163; A55-B164; A55-B165; A55-B166; A55-B167; A55-B168; A55-B169; A56-B1; A56-B2; A56-B3; A56-B4; A56-B5; A56-B6; A56-B7; A56-B8; A56-B9; A56-B10; A56-B11; A56-B12; A56-B13; A56-B14; A56-B15; A56-B16; A56-B17; A56-B18; A56-B19; A56-B20; A56-B21; A56-B22; A56-B23; A56-B24; A56-B25; A56-B26; A56-B27; A56-B28; A56-B29; A56-B30; A56-B31; A56-B32; A56-B33; A56-B34; A56-B35; A56-B36; A56-B37; A56-B38; A56-B39; A56-B40; A56-B41; A56-B42; A56-B43; A56-B44; A56-B45; A56-B46; A56-B47; A56-B48; A56-B49; A56-B50; A56-B51; A56-B52; A56-B53; A56-B54; A56-B55; A56-B56; A56-B57; A56-B58; A56-B59; A56-B60; A56-B61; A56-B62; A56-B63; A56-B64; A56-B65; A56-B66; A56-B67; A56-B68; · A56-B69; A56-B70; A56-B71; A56-B72; A56-B73; A56-B74; A56-B75; A56-B76; A56-B77; A56-B78; A56-B79; A56-B80; A56-B81; A56-B82; A56-B83; A56-B84; A56-B85; A56-B86; A56-B87; A56-B88; A56-B89; A56-B90; A56-B91; A56-B92; A56-B93; A56-B94; A56-B95; A56-B96; A56-B97; A56-B98; A56-B99; A56-B100; A56-B101; A56-B102; A56-B103; A56-B104; A56-B105; A56-B106; A56-B107; A56-B108; A56-B109; A56-B110; A56-B1 11; A56-B112; A56-B113; A56-B114; A56-B115; A56-B116; A56-B117; A56-B1 18; A56-B119; A56-B120; A56-B121; A56-B122; A56-B123; A56-B124; A56-B125; A56-B126; A56-B127; A56-B128; A56-B129; A56-B130; A56-B131; A56-B132; A56-B133; A56-B134; A56-B135; A56-B136; A56-B137; A56-B138; A56-B139; A56-B140; A56-B141; A56-B142; A56-B143; A56-B144; A56-B145; A56-B146; A56-B147; A56-B148; A56-B149; A56-B150; A56-B151; A56-B152; A56-B153; A56-B154; A56-B155; A56-B156; A56-B157; A56-B158; A56-B159; A56-B160; A56-B161; A56-B162; A56-B163; A56-B164; A56-B165; A56-B166; A56-B167; A56-B168; A56-B169; A57-B1; A57-B2; A57-B3; A57-B4; A57-B5; A57-B6; A57-B7; A57-B8; A57-B9; A57-B10; A57-B11; A57-B12; A57-B13; A57-B14; A57-B15; A57-B16; A57-B17; ? 57-? 18; A57-B19; A57-B20; A57-B21; A57-B22; A57-B23; A57-B24; A57-B25; A57-B26; A57-B27; A57-B28; A57-B29; A57-B30; A57-B31; A57-B32; A57-B33; A57-B34; A57-B35; A57-B36; A57-B37; A57-B38; A57-B39; A57-B40; A57-B41; A57-B42; A57-B43; A57-B44; A57-B45; A57-B46; A57-B47; A57-B48; A57-B49; A57-B50; A57-B51; A57-B52; A57-B53; A57-B54; A57-B55; A57-B56; A57-B57; A57-B58; A57-B59; A57-B60; A57-B61; A57-B62; A57-B63; A57-B64; A57-B65; A57-B66; A57-B67; A57-B68; A57-B69; A57-B70; A57-B71; A57-B72; A57-B73; A57-B74; A57-B75; A57-B7S; A57-B77; A57-B78; A57-B79; A57-B80; A57-B81; A57-B82; A57-B83; A57-B84; A57-B85; A57-B86; A57-B87; A57-B88; A57-B89; A57-B90; A57-B91; A57-B92; A57-B93; A57-B94; A57-B95; A57-B96; A57-B97; A57-B98; A57-B99; A57-B100; A57-B101; A57-B102; A57-B103; A57-B104; A57-B105; A57-B106; A57-B107; A57-B108; A57-B109; A57-B110; A57-B111; A57-B1 12; A57-B113; A57-B114; A57-B1-15; A57-B1 16; A57-B117; A57-B118; A57-B119; A57-B120; A57-B121; A57-B122; A57-B123; A57-B124; A57-B125; A57-B126; A57-B127; A57-B128; A57-B129; A57-B130; A57-B131; A57-B132; A57-B1-33; A57-B134; A57-B135; A57-B136; A57-B137; A57-B138; A57-B139; A57-B140; A57-B141; A57-B142; A57-B143; A57-B144; A57-B145; A57-B146; A57-B147; A57-B148; A57-B149; A57-B150; A57-B151; A57-B152; A57-B153; A57-B154; A57-B155; A57-B156; A57-B157; A57-B158; A57-B159; A57-B160; A57-B161; A57-B162; A57-B163; A57-B164; A57-B165; A57-B166; A57-B167; A57-B168; A57-B169; A58-B1; A58-B2; A58-B3; A58-B4; A58-B5; A58-B6; A58-B7; A58-B8; A58-B9; A58-B10; A58-B11; A58-B12; A58-B13; A58-B14; A58-B15; A58-B16; A58-B17; A58-B18; A58-B19; A58-B20; A58-B21; A58-B22; A58-B23; A58-B24; A58-B25; A58-B26; A58-B27; A58-B28; A58-B29; A58-B30; A58-B31; A58-B32; A58-B33; A58-B34; A58-B35; A58-B36; A58-B37; A58-B38; A58-B39; A58-B40; A58-B41; A58-B42; A58-B43; A58-B44; A58-B45; A58-B46; A58-B47; A58-B48; A58-B49; A58-B50; A58-B51; A58-B52; A58-B53; A58-B54; A58-B55; A58-B56; A58-B57; A58-B58; A58-B59; A58-B60; A58-B61; A58-B62; A58-B63; A58-B64; A58-B65; A58-B66; A58-B67; A58-B68; A58-B69; A58-B70; A58-B71; A58-B72; A58-B73; A58-B74; A58-B75; A58-B76; A58-B77; A58-B78; A58-B79; A58-B80; A58-B81; A58-B82; A58-B83; A58-B84; A58-B85; A58-B86; A58-B87; A58-B88; A58-B89; A58-B90; A58-B91; A58-B92; A58-B93; A58-B94; A58-B95; A58-B96; A58-B97; A58-B98; A58-B99; A58-B100; A58-B101; A58-B102; A58-B103; A58-B104; A58-B105; A58-B106; A58-B107; A58-B108; A58-B109; A58-B110; A58-B111; A58-B112; A58-B113; A58-B114; A58-B115; A58-B116; A58-B117; A58-B118; A58-B119; A58-B120; A58-B121; A58-B122; A58-B123; A58-B124; A58-B125; A58-B126; A58-B127; A58-B128; A58-B129; A58-B130; A58-B131; A58-B132; A58-B133; A58-B 34; A58-B135; A58-B136; A58-B137; A58-B138; A58-B139; A58-B140; A58-B141; A58-B 42; A58-B143; A58-B144; A58-B145; A58-B146; A58-B147; A58-B148; A58-B149; A58-B150; A58-B151; A58-B152; A58-B153; A58-B154; A58-B155; A58-B156; A58-B157; A58-B158; A58-B159; A58-B160; A58-B161; A58-B162; A58-B163; A58-B164; A58-B165; A58-B166; A58-B167; A58-B168; A58-B169; A59-B1; A59.-B2; A59-B3; A59-B4; A59-B5; A59-B6; A59-B7; A59-B8; A59-B9; A59-B10; A59-B11; A59-B12; A59-B13; A59-B14; A59-B15; A59-B16; A59-B17; A59-B18; A59-B19; A59-B20; A59-B21; A59-B22; A59-B23; A59-B24; A59-B25; A59-B26; A59-B27; A59-B28; A59-B29; A59-B30; A59-B31; A59-B32; A59-B33; A59-B34; A59-B35; A59-B36; A59-B37; A59-B38; A59-B39; A59-B40; A59-B41; A59-B42; A59-B43; A59-B44; A59-B45; A59-B46; A59-B47; A59-B48; A59-B49; A59-B50; A59-B51; A59-B52; A59-B53; A59-B54; A59-B55; A59-B56; A59-B57; A59-B58; A59-B59; A59-B60; A59-B61; A59-B62; A59-B63; A59-B64; A59-B65; A59-B66; A59-B67; A59-B68; A59-B69; A59-B70; A59-B71; A59-B72; A59-B73; A59-B74; A59-B75; A59-B76; A59-B77; A59-B78; A59-B79; A59-B80; A59-B81; A59-B82; A59-B83; A59-B84; A59-B85; A59-B86; A59-B87; A59-B88; A59-B89; A59-B90; A59-B91; A59-B92; A59-B93; A59-B94; A59-B95; A59-B96; A59-B97; A59-B98; A59-B99; A59-B100; A59-B101; A59-B102; A59-B103; A59-B104; A59-B105; A59-B106; A59-B107; A59-B108; A59-B109; A59-B110; A59-B111; A59-B112; A59-B1 Í.3; A59-B114; A59-B115; A59-B116; A59-B1 17; A59-B118; A59-B119; A59-B120; A59-B121; A59-B122; A59-B123; A59-B124; A59-B125; A59-B126; A59-B127; A59-B128; A59-B129; A59-B130; A59-B131; A59-B132; A59-B133; A59-B134; A59-B135; A59-B136; A59-B137; A59-B138; A59-B139; A59-B140; A59-B141; A59-B142; A59-B143; A59-B144; A59-B145; A59-B146; A59-B147; A59-B148; A59-B149; A59-B150; A59-B151; A59-B152; A59-B153; A59-B154; A59-B155; A59-B156; A59-B157; A59-B158; A59-B159; A59-B160; A59-B161; A59-B162; A59-B163; A59-B164; A59-B165; A59-B166; A59-B167; A59-B168; A59-B169; A60-B1; A60-B2; A60-B3; A60-B4; A60-B5; A60-B6; A60-B7; A60-B8; A60-B9; A60-B1.0; A60-B11; A60-B12; A60-B13; A60-B14; A60-B15; A60-B16; A60-B17; A60-B18; A60-B19; A60-B20; A60-B21; A60-B22; A60-B23; A60-B24; A60-B25; A60-B26; A60-B27; A60-B28; A60-B29; A60-B30; A60-B31; A60-B32; A60-B33; A60-B34; A60-B35; A60-B36; A60-B37; A60-B38; A60-B39; A60-B40; A60-B41; A60-B42; A60-B43; A60-B44; A60-B45; A60-B46; A60-B47; A60-B48; A60-B49; A60-B50; A60-B51; A60-B52; A60-B53; A60-B54; A60-B55; A60-B56; A60-B57; A60-B58; A60-B59; A60-B60; A60-B61; A60-B62; A60-B63; A60-B64; A60-B65; A60-B66; A60-B67; A60-B68; A60-B69; A60-B70; A60-B71; A60-B72; A60-B73; A60-B74; A60-B75; A60-B76; A60-B77; A60-B78; A60-B79; A60-B80; A60-B81; A60-B82; A60-B83; A60-B84; A60-B85; A60-B86; A60-B87; A60-B88; A60-B89; A60-B90; A60-B91; A60-B92; A60-B93; A60-B94; A60-B95; A60-B96; A60-B97; A60-B98; A60-B99; A60-B100; A60-B101; A60-B102; A60-B103; A60-B104; A60-B105; A60-B106; A60-B107; A60-B108; A60-B109; A60-B110; A60-B111; A60-B112; A60-B113; A60-B114; A60-B115; A60-B116; A60-B117; A60-B118; A60-B119; A60-B120; A60-B121; A60-B122; A60-B123; A60-B124; A60-B125; A60-B126; A60-B127; A60-B128; A60-B129; A60-B130; A60-B131; A60-B132; A60-B133; A60-B134; A60-B135; A60-B136; A60-B137; A60-B138; A60-B139; A60-B140; A60-B141; A60-B142; A60-B143; A60-B144; A60-B145; A60-B146-, A60-B1 7; A60-B1 8; A60-B149; A60-B150; A60-B151; A60-B152; A60-B153; A60-B154; A60-B155; A60-B156; A60-B157; A60-B158; A60-B159; A60-B160; A60-B161; A60-B162; A60-B163; A60-B164; A60-B165; A60-B166; A60-B167; A60-B168; A60-B169; A61-B1; A61-B2; A61-B3; A61-B4; A61-B5; A61-B6; A61-B7; A61-B8; A61-B9; A61-B10; A61-B11; A61-B12; A61-B13; A61-B14; A61-B15; A61-B16; A61-B17; A61-B18; A61-B19; A61-B20; A61-B21; A61-B22; A61-B23; A61-B24; A62-B6; A62-B7; A62-B8; A62-B9; A62-B10; A62-B11; A62-B12; A62-B13; A62-B14; A62-B15; A62-B16; A62-B17; A62-B18; A62-B19; A62-B2.0; A62-B21; A62-B22; A62-B23; A62-B24; A62-B25; A62-B26; A62-B27; A62-B28; A62-B29; A62-B30; A62-B31; A62-B32; A62-B33; A62-B34; A62-B35; A62-B36; A62-B37; A62-B38; A62-B39; A62-B40; A62-B41; A62-B42; A62-B43; A62-B44; A62-B45; A62-B46; A62-B47; A62-B48; A62-B49; A62-B50; A62-B51; A62-B52; A62-B53; A62-B54; A62-B55; A62-B56; A62-B57; A62-B58; A62-B59; A62-B60; A62-B61; A62-B62; A62-B63; A62-B64; A62-B65; A62-B66; A62-B67; A62-B68; A62-B69; A62-B70; A62-B71; A62-B72; A62-B73; A62-B74; A62-B75; A62-B76; A62-B77; A62-B78; A62-B79; A62-B80; A62-B81; A62-B82; A62-B83; A62-B84; A62-B85; A62-B86; A62-B87; A62-B88; A62-B89; A62-B90; A62-B91; A62-B92; A62-B93; A62-B94; A62-B95; A62-B96; A62-B97; A62-B98; A62-B99; A62-B100; A62-B101; A62-B102; A62-B103; A62-B104; A62-B105; A62-B106; A62-B107; A62-B108; A62-B109; A62-B110; A62-B1 11; A62-B1 12; A62-B113; A62-B114; A62-B115; A62-B116; A62-B1 17; A62-B1 18; A62-B119; A62-B120; A62-B121; A62-B122; A62-B123; A62-B124; A62-B125; A62-B126; A62-B127; A62-B128; A62-B129; A62-B130; A62-B131; A62-B132; A62-B133; A62-B134; A62-B135; A62-B136; A62-B137; A62-B138; A62-B139; A62-B140; · A62-B141; A62-B142; A62-B143; A62-B144; A62-B 4545; A62-B146; A62-B147; A62-B148; A62-B149; A62-B150; A62-B151; A62-B152; A62-B153; A62-B154; A62-B155; A62-B156; A62-B157; A62-B158; A62-B159; A62-B160; A62-B161; A62-B162; A62-B163; A62-B164; A62-B165; A62-B166; A62-B167; A62-B168; A62-B169; A63-B1; A63-B2; A63-B3; A63-B4; A63-B5; A63-B6; A63-B7; A63-B8; A63-B9; A63-B10; A63-B11; A63-B12; A63-B13; A63-B14; A63-B15; A63-B16; A63-B17; A63-B18; A63-B19; A63-B20; A63-B21; A63-B22; A63-B23; A63-B24; A63-B25; A63-B26; A63-B27; A63-B28; A63-B29; A63-B30; A63-B31; A63-B32; A63-B33; A63-B34; A63-B35; A63-B36; A63-B37; A63-B38; A63-B39; A63-B40; A63-B41; A63-B42; A63-B43; A63-B44; A63-B45; A63-B46; A63-B47; A63-B48; A63-B49; A63-B50; A63-B51; A63-B52; A63-B53; A63-B54; A63-B55; A63-B56; A63-B57; A63-B58; A63-B59; A63-B60; A63-B61; A63-B62; A63-B63; A63-B64; A63-B65; A63-B66; A63-B67; A63-B68; A63-B69; A63-B70; A63-B71; A63-B72; A63-B73; A63-B74; A63-B75; A63-B76; A63-B77; A63-B78; A63-B79; A63-B80; A63-B81; A63-B82; A63-B83; A63-B84; A63-B85; A63-B86; A63-B87; A63-B88; A63-B89; A63-B90; A63-B91; A63-B92; A63-B93; A63-B94; A63-B95; A63-B96; A63-B97; A63-B98; A63-B99; A63-B100; A63-B101; A63-B102; A63-B103; A63-B104; A63-B105; A63-B106; A63-B107; A63-B108; A63-B109; A63-B110; A63-B111; A63-B112; A63-B113; A63-B114; A63-B115; A63-B1 16; A63-B117; A63-B118; A63-B119; A63-B120; A63-B121; A63-B122; A63-B123; A63-B124; A63-B125; A63-B126; A63-B127; A63-B128; A63-B129; A63-B130; A63-B131; A63-B132; A63-B133; A63-B134; A63-B135; A63-B136; A63-B137; A63-B138; A63-B139; A63-B140; A63-B141; A63-B142; A63-B143; A63-B144; A63-B145; A63-B146; A63-B147; A63-B148; A63-B149; A63-B150; A63-B151; A63-B152; A63-B153; A63-B154; A63-B155; A63-B156; A63-B157; A63-B158; A63-B159; A63-B160; A63-B161; A63-B162; A63-B163; A63-B164; A63-B165; A63-B166; A63-B167; A63-B168; A63-B169; A64-B1; A64-B2; A64-B3; A64-B4; A64-B5; A64-B6; A64-B7; A64-B8; A64-B9; A64-B10; A64-B11; A64-B12; A64-B13; A64-B14; A64-B15; A64-B16; A64-B17; A64-B18; A64-B19; A64-B20; A64-B21; A64-B22; A64-B23; A64-B24; A64-B25; A64-B26; A64-B27; A64-B28; A64-B29; A64-B30; A64-B31; A64-B32; A64-B33; A64-B34; A64-B35; A64-B3B; A64-B37; A64-B38; A64-B39; A64-B40; A64-B41; A64-B42; A64-B43; A64-B44; A64-B45; A64-B46; A64-B47; A64-B48; A64-B49; A64-B50; A64-B51; A64-B52; A64-B53; A64-B54; A64-B55; A64-B56; A64-B57; A64-B58; A64-B59; A64-B60; A64-B61; A64-B62; A64-B63; A64-B64; A64-B65; A64-B66; A64-B67; A64-B68; A64-B69; A64-B70; A64-B71; A64-B72; A64-B73; A64-B74; A64-B75; A64-B76; A64-B77; A64-B78; A64-B79; A64-B80; A64-B81; A64-B82; A64-B83; A64-B84; A64-B85; A64-B86; A64-B87; A64-B88; A64-B89; A64-B90; A64-B91; A64-B92; 'A64-B93; A64-B94; A64-B95; A64-B96; A64-B97; A64-B98; A64-B99; A64-B100; A64-B101; A64-B102; A64-B103; A64-B104; A64-B105; A64-B106; A64-B107; A64-B108; A64-B109; A64-B110; A64-B1 11; A64-B1 12; A64-B1 13; A64-B114; A64-B115; A64-B116; A64-B117; A64-B118; A64-B1 19; A64-B120; A64-B121; A64-B122; A64-B123; A64-B124; A64-B125; A64-B126; A64-B127; A64-B128; A64-B129; A64-B130; A64-B131; A64-B132; A64-B133; A64-B134; A64-B135; A64-B136; A64-B137; A64-B138; "A64-B139; A64-B140; A64-B141; A64-B142; A64-B143; A64-B144; A64-B145; A64-B146; A64-B147; A64-B148; A64-B149; A64-B150; A64-B151; A64-B152; A64-B153; A64-B154; A64-B155; A64-B156; A64-B157; A64-B158; A64-B159; A64-B160; A64-B161; A64-B162; A64-B163; A64-B164; A64-B165; A64-B166; A64-B167; A64-B168; A64-B169; A65-B1; A65-B2; A65-B3; A65-B4; A65-B5; A65-B6; A65-B7; A65-B8; A65-B9; A65-B10; A65-B11; A65-B12; A65-B13; A65-B14; A65-B15; A65-B16; A65-B17; A65-B18; A65-B19; A65-B20; A65-B21; A65-B22; A65-B23; A65-B24; A65-B25; A65-B26; A65-B27; A65-B28; A65-B29; A65-B30; A65-B31; A65-B32; A65-B33; A65-B34; A65-B35; A65-B36; A65-B37; A65-B38; A65-B39; A65-B40; A65-B41; A65-B42; A65-B43; A65-B44; A65-B45; A65-B46; A65-B47; A65-B48; A65-B49; A65-B50; A65-B51; A65-B52; A65-B53; A65-B54; A65-B55; A65-B56; A65-B57; A65-B58; A65-B59; A65-B60; A65-B61; A65-B62; A65-B63; A65-B64; A65-B65; A65-B66; A65-B67; A65-B68; A65-B69; A65-B70; A65-B71; A65-B72; A65-B73; A65-B74; A65-B75; A65-B76; A65-B77; A65-B78; A65-B79; A65-B80; A65-B81; A65-B82; A65-B83; A65-B84; A65-B85; A65-B86; A65-B87; A65-B88; A65-B89; A65-B90; A65-B91; A65-B92; A65-B93; A65-B94; A65-B95; A65-B96; A65-B97; A65-B98; A65-B99; A65-B100; A65-B101; A65-B102; A65-B103; A65-B104; A65-B105; A65-B106; A65-B107; A65-B10S; A65-B109; A65-B110; A65-B111; A65-B112; A65-B113; A65-B1 14; A65-B115; A65-B116; A65-B117; A65-B1 18; A65-B119; A65-B120; A65-B121; A65-B122; A65-B123; A65-B124; A65-B125; A65-B126; A65-B127; A65-B128; A65-B129; A65-B130; A65-B131; A65-B132; A65-B133; A65-B134; A65-B135; A65-B136; A65-B137; A65-B138; A65-B139; A65-B140; A65-B141; A65-B142; A65-B143; A65-B144; A65-B145; A65-B146; A65-B147; A65-B148; A65-B149; A65-B150; A65-B151; A65-B152; A65-B153; A65-B154; A65-B155; A65-B156; A65-B157; A65-B158; A65-B159; A65-B160; A65-B161; A65-B162; A65-B163; A65-B164; A65-B165; A65-B166; A65-B167; A65-B168; A65-B169; A66-B1; A66-B2; A66-B3; A66-B4; A66-B5; A66-B6; A66-B7; A66-B8; A66-B9; A66-B10; A66-B11; A66-B12; A66-B13; A66-B14; A66-B15; A66-B16; A66-B17; A66-B18; A66-B19; A66-B20; A66-B21; A66-B22; A66-B23; A66-B24; A66-B25; A66-B26; A66-B27; A66-B28; A66-B29; A66-B30; A66-B31; A66-B32; A66-B33; A66-B34; A66-B35; A66-B36; A66-B37; A66-B38; A66-B39; A66-B40; A66-B41; A66-B42; A66-B43; A66-B44; A66-B45; A66-B46; A66-B47; A66-B48; A66-B49; A66-B50; A66-B51; A66-B52; A66-B53; A66-B54; A66-B55; A66-B56; A66-B57; A66-B58; A66-B59; A66-B60; A66-B61; A66-B62; A66-B63; A66-B64; A66-B65; A66-B66; A66-B67; A66-B68; * A66-B69; A66-B70; A66-B71; A66-B72; A66-B73; A66-B74; A66-B75; A66-B76; ? 66-? 77; · A66-B78; A66-B79; A66-B80; A66-B81; A66-B82; A66-B83; A66-B84; A66-B85; A66-B86; A66-B87; A66-B88; A66-B89; A66-B90; A66-B91; A66-B92; A66-B93; A66-B94; · A66-B95; A66-B96; A66-B97; A66-B98; A66-B99; A66-B100; A66-B101; A66-B102; A66-B103; A66-B104; A66-B105; A66-B106; A66-B107; A66-B108; A66-B109; A66-B110; A66-B111; A66-B112; A66-B113; A66-B114; A66-B115; A66-B116; A66-B117; A66-B118; A66-B119; A66-B120; A66-B121; A66-B122; A66-B123; A66-B124; A66-B125; A66-B126; A66-B127; A66-B128; A66-B129; A66-B130; A66-B131; A66-B132; A66-B133; A66-B134; A66-B135; A66-B136; A66-B137; A66-B138; A66-B139; A66-B140; A66-B141; A66-B142; A66-B143; A66-B144; A66-B145; A66-B146; A66-B147; A66-B148; A66-B149; A66-B150; A66-B151; A66-B152; A66-B153; A66-B154; . A66-B155; A66-B156; A66-B157; A66-B158; A66-B159; A66-B160; A66-B161; A66-B162; A66-B163; A66-B164; A66-B165; A66-B166; A66-B167; A66-B168; A66-B169; A67-B1; A67-B2; A67-B3; A67-B4; A67-B5; A67-B6; A67-B7; A67-B8; A67-B9; A67-B10; A67-B11; A67-B12; A67-B13; A67-B1; A67-B15; ? 67 - ?? 6; A67-B17; A67-B18; A67-B19; A67-B20; A67-B21; A67-B22; A67-B23; A67-B24; A67-B25; A67-B26; A67-B27; A67-B28; A67-B29; A67-B30; A67-B31; A67-B32; A67-B33; A67-B34; A67-B35; A67-B36; A67-B37; A67-B38; A67-B39; A67-B40; A67-B41; A67-B42; A67-B43; A67-B44; A67-B45; . A67-B46; A67-B47; A67-B48; A67-B49; A67-B50; A67-B51; A67-B52; A67-B53; A67-B54; A67-B55; A67-B56; A67-B57; A67-B58; A67-B59; A67-B60; A67-B61; A67-B62; A67-B63; A67-B64; A67-B65; A67-B66; A67-B67; A67-B68; A67-B69; A67-B70; A67-B71; A67-B72; A67-B73; A67-B74; A67-B75; A67-B76; A67-B77; A67-B78; A67-B79; A67-B80; A67-B81; A67-B82; A67-B83; A67-B84; A67-B85; A67-B86; A67-B87; A67-B88; A67-B89; A67-B90; A67-B91; A67-B92; A67-B93; A67-B94; A67-B95; A67-B96; A67-B97; A67-B98; A67-B99; A67-B100; A67-B101; A67-B102; A67-B103; A67-B104; ? 67-? 1? 5; A67-B106; A67-B107; A67-B108; A67-B109; A67-B110; A67-B111; A67-B112; A67-B113; A67-B114; A67-B1 15; A67-B116; A67-B117; A67-B118; A67-B119; A67-B120; A67-B121; A67-B122; A67-B123; A67-B124; A67-B125; A67-B126; A67-B127; A67-B128; A67-B129; A67-B130; A67-B131; A67-B132; A67-B133; A67-B134; A67-B135; A67-B136; A67-B137; A67-B138; A67-B139; A67-B140; A67-B141; A67-B142; A67-B143; A67-B144; A67-B145; A67-B146; A67-B147; A67-B148; A67-B149; A67-B150; A67-B151; A67-B152; A67-B153; A67-B154; A67-B155; A67-B156; A67-B157; A67-B158; A67-B159; A67-B160; A67-B161; A67-B162; A67-B163; A67-B164; A67-B165; A67-B166; A67-B167; A67-B168; A67-B169; A68-B1; A68-B2; A68-B3; A68-B4; A68-B5; A68-B6; A68-B7; A68-B8; A68-B9; A68-B10; A68-B11; A68-B12; A68-B13; A68-B14; A68-B15; A68-B16; A68-B17; A68-B18; A68-B19; A68-B20; A68-B21; A68-B22; A68-B23; A68-B24; A68-B25; A68-B26; A68-B27; A68-B28; A68-B29; A68-B30; A68-B31; A68-B32; A68-B33; A68-B34; A68-B35; A68-B36; A68-B37; A68-B38; A68-B39; A68-B40; A68-B41; A68-B42; A68-B43; A68-B44; A68-B45; A68-B46; A68-B47; A68-B48; A68-B49; A68-B50; A68-B51; A68-B52; A68-B53; A68-B54; A68-B55; A68-B56; A68-B57; A68-B58; A68-B59; A68-B60; A68-B61; A68-B62; A68-B63; A68-B64; A68-B65; A68-B66; A68-B67; A68-B68; A68-B69; A68-B70; A68-B71; A68-B72; A68-B73; A68-B74; A68-B75; A68-B76; A68-B77; A68-B78; A68-B79; A68-B80; A68-B81; A68-B82; A68-B83; A68-B84; A68-B85; A68-B86; A68-B87; A68-B88; A68-B89; A68-B90; A68-B91; A68-B92; A68-B93; A68-B94; A68-B95; A68-B96; A68-B97; A68-B98; A68-B99; A68-B100; A68-B101; A68-B102; A68-B103; A68-B104; A68-B105; A68-B106; A68-B107; A68-B108; A68-B109; A68-B1-10; A68-B1 11; A68-B112; A68-B113; A68-B114; A68-B115; A68-B1 16; A68-B1 17; A68-B118; A68-B119; A68-B120; A68-B121; A68-B122; A68-B123; A68-B124; A68-B125; A68-B126; A68-B127; A68-B128; A68-B129; A68-B130; A68-B131; A68-B132; A68-B133; A68-B134; · A68-B135; A68-B136; A68-B137; A68-B138; A68-B139; A68-B140; A68-B141; A68-B142; A68-B143; A68-B144; A68-B145; A68-B146; A68-B147; A68-B148; A68-B149; A68-B150; A68-B151; A68-B152; A68-B153; A68-B154; A68-B155; A68-B156; A68-B157; A68-B158; A68-B159; A68-B160; A68-B161; A68-B162; A68-B163; A68-B164; A68-B165; A68-B166; A68-B167; A68-B168; A68-B169; A69-B1; A69: B2; A69-B3; A69-B4; A69-B5; A69-B6; A69-B7; A69-B8; A69-B9; A69-B10; A69-B11; A69-B12; A69-B13; A69-B14; A69-B15; A69-B16; A69-B17; A69-B18; A69-B19; A69-B20; A69-B21; A69-B22; A70-B4; A70-B5; A70-B6; A70-B7; A70-B8; A70-B9; A70-B10; A70-B11; A70-B12; A70-B13; A70-B14; A70-B15; A70-B16; A70-B17; A70-B18; A70-B19; A70-B20; A70-B21; A70-B22; A70-B23; A70-B24; A70-B25; A70-B26; A70-B27; A70-B28; A70-B29; A70-B30; A70-B31; A70-B32; A70-B33; A70-B34; A70-B35; A70-B36; A70-B37; A70-B38; A70-B39; A70-B40; A70-B41; A70-B42; A70-B43; A70-B44; A70-B45; A70-B46; A70-B47; A70-B48; A70-B49; A70-B50; A70-B51; A70-B52; A70-B53; A70-B54; A70-B55; A70-B56; A70-B57; A70-B58; A70-B59; A70-B60; - A70-B61; A70-B62; A70-B63; A70-B64; A70-B65; A70-B66; A70-B67; A70-B68; A70-B69; A70-B70; A70-B71; A70-B72; A70-B73; A70-B74; A70-B75; A70-B76; A70-B77; A70-B78; · A70-B79; A70-B80; A70-B81; A70-B82; A70-B83; A70-B84; A70-B85; A70-B86; A70-B87; A70-B88; A70-B89; A70-B90; A70-B91; A70-B92; A70-B93; A70-B94; A70-B95; A70-B96; A70-B97; A70-B98; A70-B99; A70-B100; A70-B101; A70-B102; A70-B103; A70-B104; A70-B105; A70-B106; A70-B107; A70-B108; A70-B109; A70-B110; A70-B111; A70-B112; A70-B113; A70-B114; A70-B115; A70-B116; A70-B117; A70-B118; A70-B119; A70-B120; A70-B121; A70-B122; A70-B123; A70-B124; A70-.B125; A70-B126; A70-B127; A70-B128; A70-B129; A70-B130; A70-B131; A70-B132; A70-B133; A70-B134; A70-B135; A70-B136; A70-B137; A70-B138; A70-B139; A70-B140; A70-B141; A70-B142; A70-B143; A70-B144; A70-B145; A70-B146; A70-B147; A70-B148; A70-B149; A70-B150; A70-B151; A70-B152; A70-B153; A70-B154; A70-B155; A70-B156; A70-B157; A70-B158; A70-B159; I A70-B160; A70-B161; A70-B162; A70-B163; A70-B164; A70-B165; A70-B166; A70-B167; A70-B168; A70-B169; A71-B1; A71-B2; A71-B3; A71-B4; A71-B5; A71-B6; A71-B7; A71-B8; A71-B9; A71-B10; A71-B11; 'A71-B12; A71-B13; A71-B14; A71-B15; A71-B16; A71-B17; "A71-B18; A71-B19; A71-B20; A71-B21; A71-B22; A71-B23; A71-B24; A71-B25; A71-B26; A71-B27; A71-B28; A71-B29; A71-B30; A71-B31; A71-B32; A71-B33; A71-B34; A71-B35; A71-B36; A71-B37; A71-B38; A71-B39; A71-B40; A71-B41; A71-B42; A71-B43; A71-B44; A71-B45; A71-B46; A71-B47; A71-B48; A71-B49; A71-B50; A71-B51; A71-B52; A71-B53; A71-B54; A71-B55; A71-B56; A71-B57; A71-B58; A71-B59; A71-B60; A71-B61; A71-B62; A71-B63; A71-B64; A71-B65; A71-B66; A71-B67; A71-B68; A71-B69; A71-B70; A71-B71; A71-B72; A71-B73; A71-B74; A71-B75; A71-B76; A71-B77; A71-B78; A71-B79; A71-B80; A71-B81; A71-B82; A71-B83; A71-B84; A71-B85; A71-B86; A71-B87; A71-B88; A71-B89; 'A71-B90; A71-B91; A71-B92; A71-B93; A71-B94; A71-B95; A71-B96; A71-B97; A71-B98; A71-B99; A71-B100; A71-B † 01; A71-B102; A71-B103; A71-B104; A71-B105; A71-B106; A71-B107; A71-B108; A71-B109; A71-B110; A71-B111; A71-B112; A71-B113; A71-B114; A71-B115; A71-B116; A71-B117; A71-B118; A71-B119; A71-B120; A71-B121; A71-B122; A71-B123; A71-B124; A71-B125; A71-B126; A71-B127; A71-B128; A71-B129; A71-B130; A71-B131; A71-B132; A71-B133; A71-B134; A71-B135; A71-B136; A71-B137; A71-B138; A71-B139; A71-B140; A71-B1 1; A71-B142; A71-B143; A71-B144; A71-B145; A71-B146; A71-B147; A71-B148; A71-B149; A71-B150; A71-B151; A71-B152; A71-B153; A71-B154; ? 71 - ?? 55; A71-B156; A71-B157; A71-B158; A71-B159; A71-B160; A71-B161; A71-B162; A71-B163; A71-B164; A71-B165; A71-B166; A71-B167; A71-B168; A71-B169; A72-B1; A72-B2; A72-B3; A72-B4; A72-B5; A72-B6; A72-B7; A72-B8; A72-B9; A72-B10; A72-B11; A72-B12; A72-B13; A72-B14; A72-B15; A72-B16; A72-B17; A72-B18; A72-B19; A72-B20; A72-B21; A72-B22-, A72-B23; A72-B24; A72-B25; A72-B26; A72-B27; A72-B28; A72-B29; A72-B30; A72-B31; A72-B32; A72-B33; A72-B34; A72-B35; A72-B36; A72-B37; A72-B38; A72-B39; A72-B40; A72-B41; A72-B42; A72-B43; A72-B44; A72-B45; A72-B46; A72-B47; A72-B48; A72-B49; A72-B50; A72-B51; A72-B52; A72-B53; A72-B54; A72-B55; A72-B56; A72-B57; A72-B58; A72-B59; A72-B60; A72-B61; A72-B62; A72-B63; A72-B64; A72-B65; A72-B66; A72-B67; A72-B68; A72-B69; A72-B70; A72-B71; A72-B72; A72-B73; A72-B74; A72-B75; A72-B76; A72-B77; A72-B78; A72-B79; A72-B80; A72-B81; A72-B82; A72-B83; A72-B84; A72-B85; A72-B86; A72-B87; A72-B88; 'A72-B89; A72-B90; A72-B91; A72-B92; A72-B93; A72-B94; A72-B95; A72-B96; A72-B97; A72-B98; A72-B99; A72-B100; A72-B101; A72-B102; A72-B103; A72-B104; A72-B105; A72-B106; A72-B107; A72-B108; A72-B109; A72-B110; A72-B111; A72-B112; A72-B113; A72-B114; A72-B115; A72-B116; A72-B117; A72-B118; A72-B119; A72-B120; A72-B121; A72-B122; A72-B123; A72-B124; A72-B125; A72-B126; A72-B127; A72-B128; A72-B129; A72-B130; A72-B131; A72-B132; A72-B133; A72-B134; A72-B135; A72-B136; A72-B137; A72-B138; A72-B139; A72-B140; A72-B141; A72-B1 2; A72-B143; A72-B144; A72-B145; A72-B146; A72-B147; A72-B148; A72-B149; A72-B150; A72-B151; A72-B152; A72-B153; A72-B154; A72-B155; A72-B156; A72-B157; A72-B158; A72-B159; A72-B160; A72-B161; A72-B162; A72-B163; A72-B164; A72-B165; A72-B166; A72-B167; A72-B168; A72-B169; A73-B1; A73-B2; A73-B3; A73-B4; A73-B5; A73-B6; A73-B7; A73-B8; A73-B9; A73-B10; A73-B11; A73-B12; A73-B13; A73-B14; A73-B15; A73-B16; A73-B17; A73-B18; A73-B19; A73-B20; A73-B21; A73-B22; A73-B23; A73-B24; A73-B25; A73-B26; A73-B27; A73-B28; A73-B29; A73-B30; A73-B31; A73-B32; A73-B33; A73-B34; A73-B35; A73-B36; A73-B37; A73-B38; A73-B39; A73-B40; A73-B41; A73-B42; A73-B43; A73-B44; A73-B45; A73-B46; A73-B47; A73-B48; A73-B49; A73-B50; A73-B51; A73-B52; A73-B53; A73-B54; A73-B55; A73-B56; A73-B57; A73-B58; A73-B59; A73-B60; A73-B61; A73-B62; A73-B63; A73-B64; A73-B65; A73-B66; A73-B67; A73-B68; A73-B69; A73-B70; A73-B71; A73-B72; A73-B73; A73-B74; A73-B75; ¾ A73-B76; A73-B77; A73-B78; A73-B79; A73-B80; A73-B81; A73-B82; A73-B83; A73-B84; A73-B85; A73-B86; A73-B87; A73-B88; A73-B89; A73-B90; A73-B91; A73-B92; A73-B93; A73-B94; A73-B95; A73-B96; A73-B97; A73-B98; A73-B99; A73-B100; A73-B101; A73-B102; A73-B103; A73-B104; A73-B105; A73-B106; A73-B107; A73-B108; A73-B109; A73-B110; A73-B111; A73-B112; A73-B113; A73-B114; A73-B115; A73-B116; A73-B117; A73-B118; A73-B119; A73-B120; A73-B121; A73-B122; A73-B123; A73-B124; A73-B125; A73-B126; A73-B127; A73-B128; A73-B129; A73-B130; A73-B131; A73-B132; A73-B133; A73-B134; A73-B135; A73-B136; A73-B137; A73-B138; A73-B139; A73-B140; A73-B141; A73-B142; A73-B143; A73-B144; A73-B145; A73-B146; A73-B147; A73-B148; A73-B149; A73-B150; A73-B151; A73-B152; A73-B153; A73-B154; A73-B155; A73-B156; A73-B157; A73-B158; A73-B159; A73-B160; A73-B161; A73-B162; A73-B163; A73-B164; A73-B165; A73-B166; A73-B167; A73-B168; A73-B169; A74-B1; A74-B2; A74-B3; A74-B4; A74-B5; A74-B6; A74-B7; A74-B8; A74-B9; A74-B10; A74-B11; A74-B12; A74-B13; A74-B14; A74-B15; A74-B16; A74-B17; A74-B18; A74-B19; A74-B20; A74-B21; A74-B22; A74-B23; A74-B24; A74-B25; A74-B26; A74-B27; A74-B28; A74-B29; A74-B30; A74-B31; A74-B32; A74-B33; A74-B34; A74-B35; A74-B36; A74-B37; A74-B38; A74-B39; A74-B40; A74-B41; A74-B42; A74-B43; A74-B44; A74-B45; A74-B46; A74-B47; A74-B48; A74-B49; A74-B50; A74-B51; A74-B52; A74-B53; A74-B54; A74-B55; A74-B56; A74-B57; A74-B58; A74-B59; A74-B60; A74-B61; A74-B62; A74-B63; A74-B64; A74-B65; A74-B66; A74-B67; A74-B68; A74-B69; A74-B70; A74-B71; A74-B72; A74-B73; A74-B74; A74-B75; A74-B76; A74-B77; A74-B78; A74-B79; A74-B80; A74-B81; A74-B82; A74-B83; A74-B84; A74-B85; A74-B86; A74-B87; A74-B88; A74-B89; A74-B90; A74-B91; A74-B92; A74-B93; A74-B94; A74-B95; A74-B96; A74-B97; A74-B98; A74-B99; A74-B100; A74-B101; A74-B102; A74-B103; A74-B104; A74-B105; A74-B106; A74-B107; A74-B108; A74-B109; A74-B110; A74-B11 1; A74-B112; A74-B113; A74-B114; A74-B115; A74-B1 16; A74-B117; A74-B118; A74-B119; A74-B120; A74-B121; A74-B122; A74-B123; A74-B124; A74-B125; A74-B126; A74-B127; A74-B128; A74-B129; A74-B130; A74-B131; A74-B132; A74-B133; A74-B134; A74-B135; A74-B136; A74-B137; A74-B138; A74-B139; A74-B140; 'A74-B141; A74-B142; A74-B143; A74-B144; A74-B145; A74-B146; A74-B147; A74-B148; A74-B149; A74-B150; A74-B151; A74-B152; A74-B153; A74-B154; A74-B155; A74-B156; A74-B157; A74-B158; A74-B159; A74-B160; A74-B161; A74-B162; A74-B163; A74-B164; A74-B165; A74-B166; A74-B167; A74-B168; A74-B169; A75-B1; . A75-B2; A75-B3; A75-B4; A75-B5; A75-B6; A75-B7; A75-B8; A75-B9; A75-B10; A75-B11; A75-B12; A75-B13; A75-B14; A75-B15; A75-B16; A75-B17; A75-B18; A75-B19; 'A75-B20; A75-B21; A75-B22; A75-B23; A75-B24; A75-B25; A75-B26; A75-B27; A75-B28; A75-B29; A75-B30; A75-B31; A75-B32; A75-B33; A75-B34; A75-B35; A75-B36; A75-B37; A75-B38; A75-B39; A75-B40; A75-B41; A75-B42; A75-B43; A75-B44; A75-B45; A75-B46; A75-B47; A75-B48; A75-B49; A75-B50; A75-B51; A75-B52; A75-B53; A75-B54; A75-B55; A75-B56; A75-B57; A75-B58; A75-B59; A75-B60; A75-B61; A75-B62; A75-B63; A75-B64; A75-B65; A75-B66; A75-B67; A75-B68; A75-B69; A75-B70; A75-B71; A75-B72; A75-B73; A75-B74; A75-B75; A75-B76; A75-B77; A75-B78; A75-B79; A75-B80; A75-B81; A75-B82; A75-B83; A75-B84; A75-B85; A75-B86; A75-B87; A75-B88; A75-B89; A75-B90; A75-B91; A75-B92; A75-B93; A75-B94; A75-B95; A75-B96; A75-B97; A75-B98; A75-B99; A75-B100; A75-B101; A75-B102; A75-B1P3; A75-B104; A75-B105; A75-B106; A75-B107; A75-B108; A75-B109; A75-B110; A75-B111; A75-B112; A75-B113; A75-B114; A75-B115; A75-B116; A75-B117; A75-B118; A75-B119; A75-B120; A75-B121; A75-B122; A75-B123; A75-B124; A75-B125; A75-B126; A75-B127; A75-B128; A75-B129; A75-B130; A75-B131; A75-B132; A75-B133; A75-B134; A75-B135; A75-B136; A75-B137; A75-B138; A75-B139; A75-B140; A75-B141; A75-B142; A75-B143; A75-B144; A75-B145; A75-B146; A75-B147; A75-B148; A75-B149; A75-B150; A75-B151; A75-B152; A75-B153; A75-B154; A75-B155; A75-B156; A75-B157; A75-B158; A75-B159; A75-B160; A75-B161; A75-B162; A75-B163; A75-B164; A75-B165; A75-B166; A75-B167; A75-B168; A75-B169; A76-B1; A76-B2; A76-B3; A76-B4; A76-B5; A76-B6; A76-B7; A76-B8; A76-B9; A76-B10; A76-B11; A76-B12; A76-B13; A76-B14; A76-B15; A76-B16; A76-B17; A76-B18; A76-B19; ^ A76-B20; A76-B21; A76-B22; A76-B23; A76-B24; A76-B25; A76-B26; A76-B27; A76-B28; A76-B29; A76-B30; A76-B31; A76-B32; A76-B33; A76-B34; A76-B35; A76-B36; A76-B37; A76-B38; A76-B39; A76-B40; A76-B41; A76-B42; A76-B43; A76-B44; A76-B45; A76-B46; A76-B47; A76-B48; A76-B49; A76-B50; A76-B51; A76-B52; A76-B53; A76-B54; 'A76-B55; A76-B56; A76-B57; A76-B58; A76-B59; A76-B60; A76-B61; A76-B62; A76-B63; A76-B64; A76-B65; A76-B66; A76-B67; A76-B68; A76-B69; A76-B70; A76-B71; A76-B72; A76-B73; A76-B74; A76-B75; A76-B76; A76-B77; A76-B78; A76-B79; A76-B80; A76-B81; A76-B82; A76-B83; A76-B84; A76-B85; A76-B86; A76-B87; A76-B88; A76-B89; A76-B90; A76-B91; A76-B92; A76-B93; A76-B94; A76-B95; A76-B96; A76-B97; A76-B98; A76-B99; A76-B100; A76-B101; A76-B102; A76-B103; A76-B104; A76-B105; A76-B106; A76-B107; A76-B108; A76-B109; A76-B110; A76-B111; A76-B112; A76-B113; A76-B114; A76-B115; A76-B116; A76-B117; A76-B118; A76-B119; A76-B120; . A76-B121; A76-B122; A76-B123; A76-B124; A76-B125; A76-B126; A76-B127; A76-B128; A76-B129; A76-B130; A76-B131; A76-B132; A76-B133; A76-B134; A76-B135; A76-B136; A76-B137; A76-B138; A76-B139; A76-B140; A76-B141; A76-B142; A76-B143; A76-B144; A76-B145; A76-B146; A76-B147; A76-B148; A76-B149; A76-B150; A76-B151; A76-B152; A76-B153; A76-B154; A76-B155; A76-B156; A76-B157; A76-B158; A76-B159; A76-B160; A76-B161; A76-B162; A76-B163; A76-B164; A76-B165; A76-B166; A76-B167; A76-B168; A76-B169; A77-B1; A77-B2; A77-B3; A77-B4; A77-B5; A77-B6; A77-B7; A77-B8; A77-B9; A77-B10; A77-B11; A77-B12; A77-B13; A77-B14; A77-B15; A77-B16; A77-B17; A77-B18; A77-B19; A77-B20; A77-B21; A77-B22; A77-B23; A77-B24; A77-B25; A77-B26; A77-B27; A77-B28; A77-B29; A77-B30; A77-B31; A77-B32; A77-B33; A77-B34; A77-B35; A77-B36; A77-B37; A77-B38; A77-B39; A77-B40; A77-B41; A77-B42; A77-B43; A77-B44; A77-B45; A77-B46; A77-B47; A77-B48; A77-B49; A77-B50; A77-B51; A77-B52; A77-B53; A77-B54; A77-B55; A77-B56; A77-B57; A77-B58; A77-B59; A77-B60; A77-B61; A77-B62; A77-B63; A77-B64; A77-B65; A77-B66; A77-B67; A77-B68; A77-B69; A77-B70; A77-B71; 'A77-B72; A77-B73; A77-B74; A77-B75; A77-B76; A77-B77; A77-B78; A77-B79; A77-B80; A77-B81; A77-B82; A77-B83; A77-B84; A77-B85; A77-B86; A77-B87; A77-B88; A77-B89; A77-B90; · A77-B91; A77-B92; A77-B93; A77-B94; A77-B95; A77-B96; A77-B97; A77-B98; A77-B99; A77-B100; A77-B101; A77-B102; A77-B103; A77-B104; A77-B105; A77-B106; A77-B107; A77-B108; A77-B109; A77-B110; A77-B111; A77-B112; A77-B113; A77-B114; A77-B115; A77-B11B; A77-B117; A77-B118; A77-B119; A77-B120; A77-B121; A77-B122; A77-B123; A77-B124; A77-B125; A77-B126; A77-B127; A77-B128; A77-B129; A77-B130; A77-B131; A77-B132; A77-B133; A77-B134; A77-B135; A77-B136; A77-B137; A77-B138; A77-B139; A77-B140; A77-B141; A77-B142; A77-B143; A77-B144; A77-B145; A77-B146; A77-B147; A77-B148; A77-B149; A77-B150; A77-B151; A77-B152; A77-B153; A77-B154; A77-B155; A77-B156; A77-B157; A77-B158; A77-B159; A77-B160; A77-BT61; A77-B162; A77-B163; A77-B164; A77-B165; A77-B166; A77-B167; A77-B168; A77-B169; A78-B1; A78-B2; A78-B3; A78-B4; A78-B5; A78-B6; A78-B7; A78-B8; A78-B9; A78-B10; A78-B11; A78-B12; A78-B13; A78-B14; A78-B15; A78-B16; A78-B17; A78-B18; A78-B19; A78-B20; A78-B21; A78-B22; A78-B23; A78-B24; A78-B25; A78-B26; A78-B27; A78-B28; A78-B29; A78-B30; A78-B31; A78-B32; A78-B33; A78-B34; A78-B35; A78-B36; A78-B37; A78-B38; A78-B39; A78-B40; A78-B41; A78-B42; A78-B43; A78-B44; A78-B45; A78-B46; A78-B47; A78-B48; A78-B49; A78-B50; A78-B51; A78-B52; A78-B53; A78-B54; A78-B55; A78-B56; A78-B57; A78-B58; A78-B59; A78-B60; A78-B61; A78-B62; A78-B63; A78-B64; A78-B65; A78-B66; A78-B67; A78-B68; A78-B69; A78-B70; A78-B71; A78-B72; A78-B73; A78-B74; A78-B75; A78-B76; A78-B77; A78-B78; A78-B79; A78-B80; A78-B81; A78-B82; A78-B83; A78-B84; A78-B85; A78-B86; A78-B87; A78-B8.8; A78-B89; A78-B90; A78-B91; A78-B92; A78-B93; A78-B94; A78-B95; A78-B96; A78-B97; A78-B98; A78-B99; A78-B100; A78-B101; A78-B102; A78-B103; A78-B104; A78-B105; A78-B106; A78-B107; A78-B108; A78-B109; A78-B110; A78-B111; A78-B112; A78-B113; A78-B114; A78-B115; A78-B116; A78-B117; A78-B118; A78-B119; A78-B120; A78-B121; A78-B122; A78-B123; A78-B124; A78-B125; A78-B126; A78-B127; A7S-B128; A78-B129; A78-B130; A78-B131; A78-B132; A78-B133; A78-B134; A78-B135; A78-B136; A78-B137; A78-B138; A78-B139; A78-B140; A78-B141; A78-B142; · A78-B143; A78-B144; A78-B145; A78-B146; A78-B147; A78-B148; A78-B149; A78-B150; A78-B151; A78-B152; A78-B153; A78-B154; A78-B155; A78-B156; A78-B157; A78-B158; A78-B159; A78-B160; A78-B161; A78-B162; A78-B163; A78-B164; A78-B165; A78-B166; A78-B167; A78-B168; A78-B169; A79-B1; A79-B2; A79-B3; A79-B4; A79-B5; A79-B6; A79-B7; A79-B8; A79-B9; A79-B10; A79-B11; A79-B12; A79-B13; A79-B14; A79-B15; | A79-B16; A79-B17; A79-B18; A79-B19; A79-B20; A79-B21; A79-B22; A79-B23; A79-B24; A79-B25; A79-B26; A79-B27; · A79-B28; A79-B29; A79-B30; A79-B31; A79-B32; A79-B33; A79-B34; A79-B35; A79-B36; A79-B37; A79-B38; A79-B39; A79-B40; A79-B41; A79-B42; A79-B43; A79-B44; A79-B45; A79-B46; A79-B47; A79-B48; A79-B49; A79-B50; A79-B51; A79-B52; A79-B53; A79-B54; A79-B55; A79-B56; A79-B57; A79-B58; A79-B59; A79-B60; A79-B61; A79-B62; A79-B63; · A79-B64; A79-B65; A79-B66; A79-B67; A79-B68; A79-B69; A79-B70; A79-B71; A79-B72; A79-B73; A79-B74; A79-B75; A79-B76; A79-B77; A79-B78; A79-B79; A79-B80; A79-B81; A79-B82; A79-B83; A79-B84; A79-B85; A79-B86; A79-B87; A79-B88; A79-B89; A79-B90; A79-B91; A79-B92; A79-B93; A79-B94; A79-B95; A79-B96; A79-B97; A79-B98; A79-B99; A79-B100; A79-B101; A79-B102; A79-B103; A79-B104; A79-B105; A79-B106; A79-B107; A79-B108; A79-B109; A79-B110; A79-B1 11; _ A79-B1 12; A79-B113; A79-B114; A79-B1 15; A79-B116; A79-B117; A79-B118; A79-B1 19; A79-B120; A79-B121; A79-B122; A79-B123; A79-B124; A79-B125; A79-B126; A79-B127; A79-B128; A79-B129; A79-B130; A79-B131; A79-B132; A79-B133; A79-B134; A79-B135; A79-B136; A79-B137; A79-B138; A79-B139; A79-B140; A79-B141; A79-B142; A79-B143; A79-B144; A79-B145; A79-B146; A79-B147; A79-B148; A79-B149, A79-B150; A79-B151; A79-B152; . A79-B153; A79-B154; A79-B155; A79-B156; A79-B157; A79-B158; A79-B159; A79-B160; A79-B161; A79-B162; A79-B163; A79-B164; A79-B165; A79-B166; A79-B167; A79-B168; A79-B169; A80-B1; A80-B2; . A80-B3; A80-B4; A80-B5; A80-B6; A80-B7; A80-B8; A80-B9; A80-B10; A80-B1 1; A80-B12; A80-B13; A80-B14; A80-B15; A80-B16; A80-B17; A80-B18; A80-B19; A80-B20; A80-B21; A80-B22; A80-B23; A80-B24; A80-B25; A80-B26; A80-B27; A80-B28; A80-B29; A80-B30; A80-B31; A80-B32; A80-B33; A80-B34; A80-B35; A80-B36; A80-B37; A80-B38; A80-B39; A80-B40; A80-B41; A80-B42; A80-B43; A80-B44; A80-B45; A80-B46; A80-B47; A80-B48; A80-B49; A80-B50; A80-B51; A80-B52; A80-B53; A80-B54; A80-B55; A80-B56; 'A80-B57; A80-B58; A80-B59; A80-B60; A80-B61; A80-B62; A80-B63; A80-B64; A80-B65; A80-B66; A80-B67; A80-B68; A80-B69; A80-B70; A80-B71; A80-B72; A80-B73; A80-B74; A80-B75; A80-B76; A80-B77; A80-B78; A80-B79; A80-B80; A80-B81; A80-B82; A80-B83; A80-B84; A80-B85; A80-B86; A80-B87; A80-B88; A80-B89; A80-B90; A80-B91; A80-B92; A80-B93; A80-B94; A80-B95; A80-B96; A80-B97; A80-B98; · A80-B99; A80-B100; A80-B101; A80-B102; A80-B103; A80-B104; A8C-B105; A80-B106; A80-B107; A80-B108; A80-B109; A80-B110; A80-B111; A80-B112; A80-B113; A80-B1 14; A80-B115; A80-B116; A80-B117; A80-B118; A80-B119; A80-B120; A80-B121; A80-B122; A80-B123; A80-B124: A80-B125; A80-B126; A80-B127; A80-B128; A80-B129; A80-B130; A80-B131; A80-B132; A80-B133; A80-B134; A80-B135; A80-B136; A80-B137; A80-B138; A80-B139; A80-B140; A80-B141; A80-B142; A80-B143; A80-B144; A80-B145; A80-B146; A80-B147; A80-B148; A80-B149; A80-B150; A80-B151; A80-B152; A80-B153; A80-B154; A80-B155; A80-B156; A80-B157; A80-B158; A80-B159; A80-B160; A80-B161; A80-B162; A80-B163; A80-B164; 'A80-B165; A80-B166; A80-B167; A80-B168; A80-B169; A81-B1; A81-B2; A81-B3; A81-B4; A81-B5; A81-B6; A81-B7; A81-B8; A81-B9; A81-B10; A81-B11; A81-B12; A81-B13; · A81-B14; A81-B15; A81-B16; A81-B17; A81-B18; A81-B19; A81-B20; A81-B21; A81-B22; A81-B23; A81-B24; A81-B25; A81-B26; A81-B27; A81-B28; A81-B29; A81-B30; A81-B31; A81-B32; A81-B33; A81-B34; A81-B35; A81-B36; A81-B37; A81-B38; A81-B39; A81-B40; A81-B41; A81-B42; A81-B43; A81-B44; A81-B45; A81-B46; A81-B47; A81-B48; A81-B49; A81-B50; A81-B51; A81-B52; A81-B53; A81-B54; A81-B55; A81-B56; A81-B57; A81-B58; A81-B59; A81-B60; A81-B61; A81-B62; A81-B63; A81-B64; A81-B65; A81-B66; A81-B67; A81-B68; A81-B69; A81-B70; A81-B71; A81-B72; A81-B73; A81-B74; A81-B75; A81-B76; A81-B77; A81-B78; A81-B79; A81-B80; A81-B81; A81-B82; A81-B83; A81-B84; A81-B85; A81-B86; A81-B87; A81-B88; A81-B89; A81-B90; A81-B91; A81-B92; A81-B93; A81-B94; A81-B95; A81-B96; A81-B97; A81-B98; A81-B99; A81-B100; A81-B101; A81-B102; A81-B103; A81-B104; A81-B105; A81-B106; A81-B107; A81-B108; A81-B109; · A81-B110; A81-B111; A81-B112; A81-B113; A81-B114; A81-B115; A81-B116; A81-B117; A81-B118; A81-B119; A81-B120; A81-B121; A81-B122; A81-B123; A81-B124; A81-B125; A81-B126; A81-B127; A81-B128; A81-B129; A81-B130; A81-B131; A81-B132; A81-B133; A81-B134; A81-B135; A81-B136; A81-B137; A81-B138; A81-B139; A81-B140; A81-B141; A81-B142; A81-B143; A81-B144; A81-B145; A81-B146; A81-B147; A81-B148; A81-B149; A81-B150; A81-B151; A81-B152; A81-B153; A81-B154; A81-B155; A81-B156; A81-B157; A81-B158; A81-B159; A81 -B160; A81-B161; A81-B162; A81-B163; A81-B164; A81-B165; A81-B166; A81-B167; A81-B168; A81-B169; A82-B1; A82-B2; A82-B3; A82-B4; A82-B5; A82-B6; A82-B7; A82-B8; A82-B9; A82-B10; A82-B11; A82-B12; . A82-B13; A82-B14; A82-B15; A82-B16; A82-B17; A82-B18; A82-B19; A82-B20; A82-B21; A82-B22; A82-B23; A82-B24; A82-B25; A82-B26; A82-B27; A82-B28; A82-B29; A82-B30; A82-B31; A82-B32; A82-B33; A82-B34; A82-B35; A82-B36; A82-B37; A82-B38; A82-B39; A82-B40; A82-B41; A82-B42; A82-B43; A82-B44; A82-B45; A82-B46; A82-B47; A82-B48; A82-B49; A82-B50; A82-B51; A82-B52; A82-B53; A82-B54; A82-B55; A82-B56; A82-B57; A82-B58; A82-B59; A82-B60; A82-B61; A82-B62; A82-B63; A82-B64; A82-B65; A82-B66; A82-B67; A82-B68; A82-B69; A82-B70; A82-B71; A82-B72; A82-B73; A82-B74; A82-B75; A82-B76; A82-B77; A82-B78; A82-B79; A82-B80; A82-B81; A82-B82; A82-B83; A82-B84; A82-B85; A82-B86; A82-B87; A82-B88; A82-B89; A82-B90; A82-B91; A82-B92; A82-B93; A82-B94; A82-B95; A82-B96; A82-B97; A82-B98; A82-B99; A82-B100; A82-B101; A82-B102; A82-B103; A82-B104; A82-B105; A82-B106; A82-B107; A82-B108; A82-B109; A82-B110; A82 B111; A82-B112; A82-B113; A82-B114; A82-B115; A82-B116; A82-B117; A82-B118; A82-B1 -19; A82-B120; A82-B121; A82-B122; A82-B123; A82-B124; A82-B125; A82-B126; A82-B127; A82-B128; A82-B129; A82-B130; A82-B131; A82-B132; . A82-B133; A82-B134; A82-B135; A82-B136; A82-B137; A82-B138; A82-B139; A82-B140; A82-B141; |? 82-? 142; A82-B143; A82-B144; A82-B145; A82-B146; A82-B147; A82-B148; A82-B149; A82-B150; A82-B151; A82-B152; A82-B153; A82-B154; A82-B155; A82-B156; A82-B157; A82-B158; A82-B159; A82-B160; A82-B161; A82-B162; A82-B163; A82-B164; A82-B165; A82-B166; A82-B167; A82-B168; A82-B169; A83-B1; A83-B2; A83-B3; A83-B4; A83-B5; A83-B6; A83-B7; A83-B8; A83-B9; A83-B10; A83-B11; A83-B12; A83-B13; A83-B14; A83-B15; A83-B16; A83-B17; A83-B18; A83-B19; A83-B20; A83-B21; A83-B22; A83-B23; A83-B24; A83-B25; A83-B26; A83-B27; A83-B28; A83-B29; A83-B30; A83-B31; A83-B32; A83-B33; A83-B34; A83-B35; A83-B36; A83-B37; A83-B38; A83-B39; A83-B40; A83-B41; A83-B42; A83-B43; A83-B44; A83-B45; A83-B46; A83-B47; A83-B48; ? 83-? 49 ·; A83-B50; A83-B51; A83-B52; A83-B53; A83-B54; A83-B55; A83-B56; A83B57; A83-B58; A83-B59; A83-B60; A83-B61; A83-B62; A83-B63; A83-B64; A83-B65; . A83-B66; A83-B67; A83-B68; A83-B69; A83-B70; A83-B71; ·· A83-B72; A83-B73; A83-B74; A83-B75; A83-B76; A83-B77; .. A83-B78; A83-B79; A83-B80; A83-B81; A83-B82; A83-B83; A83-B84; A83-B85; A83-B86; A83-B87; A83-B88; A83-B89; A83-B90; A83-B91; A83-B92; A83-B93; A83-B94; A83-B95; A83-B96; A83-B97; A83-B98; A83-B99; A83-B100; ? 83-? 1? 1; A83-B102; A83-B103; A83-B104; A83-B105; A83-B106; A83-B1Q7; A83-B108; A83-B109; A83-B110; A83-B11 1; A83-B112; A83-B113; A83-B114; A83-B1 15; A83-B116; A83-B117; A83-B118; A83-B119; A83-B120; A83-B121; A83-B122; A83-B123; A83-B124; A83-B125; A83-B126; A83-B127; A83-B128; A83-B129; A83-B130; A83-B131; A83-B132; A83-B133; ? 83G? 134; A83-B135; A83-B136; A83-B137; A83-B138; A83-B139; ? 83-? 1 0; A83-B141; A83-B142; A83-B143; A83-B144; A83-B145; ? 83-? 146; A83-B147; A83-B148; A83-B149; -. A83-B150; A83-B151; ? 83-? 152; A83-B153; A83-B154; A83-B155; A83-B156; A83-B157; ? 83-? 158; A83-B159; A83-B160; A83-B161; A83-B162; A83-B163; ? 83-? 164; A83-B165; A83-B166; A83-B167; A83-B168; A83-B169; ? 84-? 1; A84-B2; A84-B3; A84-B4; A84-B5; A84-B6; ? 84-? 7; A84-B8; A84-B9; A84-B10; A84-B11; A84-B12; ? 84-? 13; A84-B14; A84-B15; A84-B16; A84-B17; A84-B18; ? 84-? 19; A84-B20; A84-B21; A84-B22; A84-B23; A84-B24; ? 84-? 25; A84-B26; A84-B27; A84-B28; · A84-B29; A84-B30; ? 84-? 31; A84-B32; A84-B33; A84-B34; A84-B35; A84-B36; ? 84-? 37; A84-B38; A84-B39; A84-B40; A84-B41; A84-B42; A84-B43; A84-B44; A84-B45; A84-B46; A84-B47; A84-B48; A84-B49; A84-B50; A84-B51; A84-B52; A84-B53; A84-B54; A84-B55; A84-B56; A84-B57; A84-B58; A84-B59; A84-B60; A84-B61; A84-B62; A84-B63; A84-B64; A84-B65; A84-B66; A84-B67; A84-B68; A84-B69; A84-B70; A84-B71; A84-B72; A84-B73; A84-B74; A84-B75; A84-B76; A84-B77; A84-B78; A84-B79; A84-B80; A84-B81; A84-B82; - A84-B83; A84-B84; A84-B85; A84-B86; A84-B87; A84-B88; A84-B89; A84-B90; A84-B91; A84-B92; A84-B93; A84-B94; A84-B95; A84-B96; A84-B97; A84-B98; A84-B99; A84-B100; A84-B101; A84-B102; A84-B103; A84-B104; A84-B105; A84-B106; A84-B107; A84-B108; A84-B109; A84-B110; A84-B1 11; A84-B112; A84-B113; A84-B114; A84-B115; A84-B116; A84-B117; A84-B118; A84-B119; A84-B120; A84-B121; A84-B122; A84-B123; A84-B124; A84-B125; A84-B126; A84-B127; A84-B128; A84-B129; A84-B130; A84-B131; A84-B132; A84-B133; A84-B134; A84-B135; A84-B136; A84-B 37; A84-B138; A84-B139; A84-B140; A84-B141; A84-B142; A84-B143; A84-B144; A84-B145; A84-B1 6; A84-B147; A84-B148; A84-B149; A84-B150; A84-B151; A84-B152; A84-B153; A84-B154; A84-B155; A84-B156; A84-B157; A84-B1S8; A84-B159; A84-B160; A84-B161; A84-B162; A84-B163; A84-B164; A84-B165; A84-B166; A84-B167; A84-B168; A84-B169; A85-B1; A85-B2; A85-B3; A85-B4; A85-B5; A85-B6; A85-B7; A85-B8; A85-B9; A85-B10; A85-B11; A85-B12; A85-B13; A85-B14; A85-B15; A85-B16; A85-B17; A85-B18; A85-B19; A85-B20; A85-B21; A85-B22; A85-B23; A85-B24; A85-B25; A85-B26; A85-B27; A85-B28; A85-B29; A85-B30; A85-B31; A85-B32; A85-B33; A85-B34; A85-B35; A85-B36; A85-B37; A85-B38; A85-B39; A85-B40; A85-B41; A85-B42; A85-B43; A85-B44; A85-B45; A85-B46; A85-B47; A85-B48; A85-B49; A85-B50; A85-B51; A85-B52; A85-B53; A85-B54; A85-B55; A85-B56; A85-B57; A85-B58; A85-B59; A85-B60; A85-B61; A85-B62; A85-B63; A85-B64; A85-B65; A85-B66; A85-B67; A85-B68; A85-B69; A85-B70; A85-B71; A85-B72; A85-B73; A85-B74; A85-B75; A85-B76; A85-B77; A85-B78; A85-B79; A85-B80; A85-B81; A85-B82; A85-B83; A85-B84; A85-B85; A85-B86; A85-B87; A85-B88; A85-B89; A85-B90; A85-B91; A85-B92; A85-B93; A85-B94; A85-B95; A85-B96; A85-B97; A85-B98; A85-B99; A85-B100; A85-B101; A85-B102; A85-B103; A85-B104; A85-B105; A85-B106; A85-B107; A85-B108; A85-B109; A85-B110; A85-B111; A85-B112; A85-B113; A85-B114; A85-B115; A85-B116; A85-B117; A85-B118; A85-B119; A85-B120; A85-B121; A85-B122; A85-B123; A85-B124; A85-B125; A85-B126; A85-B127; A85-B128; A85-B129; A85-B130; A85-B131; A85-B132; A85-B133; A85-B134; A85-B135; A85-B136; A85-B137; A85-B138; A85-B139; A85-B140; A85-B141; A85-B142; A85-B143; A85-B144; A85-B145; A85-B146; A85-B147; A85-B148; A85-B149; A85-B150; A85-B151; A85-B152; A85-B153; A85-B154; A85-B155; A85-B156; A85-B157; A85-B158; A85-B159; A85-B160; A85-B161; A85-B162; A85-B163; A85-B164; A85-B165; A85-B166; A85-B167; A85-B 68; A85-B169; A86-B1; A86-B2; A86-B3; A86-B4; A86-B5; A86-B6; A86-B7; A86-B8; A86-B9; A86-B10; A86-B11; A86-B12; A86-B13; A86-B14; A86-B15; A86-B16; A86-B17; A86-B18; A86-B19; A86-B20; 'A86-B21; A86-B22; A86-B23; A86-B24; A86-B25; A86-B26; A86-B27; A86-B28; A86-B29; A86-B30; A86-B31; A86-B32; A86-B33; A86-B34; A86-B35; A86-B36; A86-B37; A86-B38; A86-B39; A86-B40; A86-B41; A86-B42; A86-B43; A86-B44; A86-B45; A86-B46; A86-B47; A86-B48; A86-B49; A86-B50; A86-B51; A86-B52; A86-B53; A86-B54; A86-B55; A86-B56; A86-B57; A86-B58; A86-B59; A86-B60; A86-B61; A86-B62; A86-B63; A86-B64; A86-B65; A86-B66; A86-B67; A86-B68; A86-B69; A86-B70; A86-B71; A86-B72; A86-B73; A86-B74; |? 86-? 75; A86-B76; A86-B77; A86-B78; A86-B79; A86-B80; A86-B81; A86-B82; A86-B83; A86-B84; A86-B85; A86-B86; A86-B87; A86-B88; A86-B89; A86-B90; A86-B91; A86-B92; A86-B93; A86-B94; A86-B95; A86-B96; A86-B97; A86-B98; A86-B99; A86-B100; A86-B101; A86-B102; A86-B103; A86-B104; A86-B105; A86-B106; A86-B107; A86-B108; A86-B109; A86-B110; A86-B111; A86-B112; A86-B113; A86-B1 14; A86-B115; A86-B116; A86-B11; A86-B118; A86-B119; A86-B120; A86-B121; A86-B122; A86-B123; A86-B124; A86-B125; A86-B126; A86-B127; A86-B128; A86-B129; A86-B130; A86-B131; A86-B132; A86-B133; A86-B134; A86-B135; A86-B136; A86-B137; A86-B138; A86-B139; A86-B140; A86-B141; A8S-B142; A86-B143; A86-B144; A86-B145; A86-B146; A86-B147; A86-B148; A86-B149; A86-B150; A86-B151; A86-B152; A86-B153; A86-B154; A86-B155; A86-B156; A86-B157; A86-B158; A86-B159; A86-B160; A86-B161; A86-B162; A86-B163; A86-B164; A86-B165; A86-B166; A86-B167; A86-B168; A86-B169; A87-B1; A87-B2; A87-B3; A87-B4; A87-B5; A87-B6; A87-B7; A87-B8; A87-B9; A87-B10; A87-B11; A87-B12; A87-B13; A87-B14; A87-B15; A87-B16; A87-B17; A87-B18; A87-B19; · A87-B20; A87-B21; A87-B22; A87-B23; A87-B24; A87-B25; A87-B26; A87-B27; A87-B28; A87-B29; A87-B30; A87-B31; A87-B32; A87-B33; A87-B34; A87-B35; A87-B36; A87-B37; A87-B38; A87-B39; A87-B40; A87-B41; A87-B42; A87-B43; A87-B44; A87-B45; A87-B46; A87-B47; A87-B48; A87-B49; A87-B50; A87-B51; A87-B52; A87-B53; A87-B54; A87-B55; A87-B56; A87-B57; A87-B58; A87-B59; A87-B60; A87-B61; A87-B62; A87-B63; A87-B64; A87-B65; A87-B66; A87-B67; A87-B68; A87-B69; A87-B70; A87-B71; A87-B72; A87-B73; A87-B74; A87-B75; A87-B76; A87-B77; A87-B78; A87-B79; A87-B80; A87-B81; A87-B82; A87-B83; A87-B84; A87-B85; A87-B86; A87-B87; A87-B88; A87-B89; A87-B90; A87-B91; A87-B92; A87-B93; A87-B94; A87-B95; A87-B96; A87-B97; A87-B98; A87-B99; A87-B100; A87-B101; A87-B102; A87-B103; A87-B104; A87-B105; A87-B106; A87-B107; A87-B108; A87-B109; A87-B110; A87-B111; A87-B112; A87-B113; A87-B114; A87-B115; A87-B116; A87-B117; A87-B118; A87-B119; A87-B120; A87-B121; A87-B122; A87-B123; A87-B124; A87-B125; A87-B126; A87-B 127; A87-B128; A87-B129; A87-B 30; A87-B131; A87-B132; A87-B133; A87-B134; A87-B135; A87-B136; A87-B137; A87-B138; A87-B139; A87-B140; A87-B141; A87-B142; A87-B143; A87-B144; A87-B145; A87-B146; A87-B147; A87-B148; A87-B149; A87-B150; A87-B151; A87-B152; A87-B153; A87-B154; A87-B155; A87-B156; A87-B157; A87-B158; A87-B159; A87-B160; A87-B161; A87-B162; A87-B163; A87-B164; A87-B165; A87-B166; A87-B167; A87-B168; A87-B169; A88-B1; A88-B2; A88-B3; A88-B4; A88-B5; A88-B6; A88-B7; A88-B8; A88-B9; A88-B10; A88-B11; A88-B12; A88-B13; A88-B14; A88-B15; A88-B16; A88-B17; A88-B18; A88-B19; A88-B20; A88-B21; A88-B22; A88-B23; A88-B24; A88-B25; A88-B26; A88-B27; A88-B28; A88-B29; A88-B30; A88-B31; A88-B32; A88-B33; A88-B34; A88-B35; A88-B36; A88-B37; A88-B38; A88-B39; A88-B40; A88-B41; A88-B42; A88-B43; A88-B44; A88-B45; A88-B46; A88-B47; A88-B48; A88-B49; A88-B50; A88-B51; A88-B52; A88-B53; A88-B54; A88-B55; A88-B56; A88-B57; A88-B58; A88-B59; A88-B60; A88-B61; A88-B62; A88-B63; A88-B64; A88-B65; A88-B66; A88-B67; A88-B68; A88-B69; A88-B70; A88-B71; A88-B72; · A88-B73; A88-B74; A88-B75; A88-B76; A88-B77; A88-378; A88-B79; A88-B80; A88-B81; A88-B82; A88-B83; A88-B84; A88-B85; A88-B86; A88-B87; A88-B88; A88-B89; A88-B90; A88-B91; A88-B92; A88-B93; A88-B94; A88-B95; A88-B96; A88-B97; A88-B98; A88-B99; A88-B100; A88-B101; A88-B102; A88-B103; A88-B104; A88-B105; A88-B106; A88-B107; A88-B108; A88-B109; A88-B110; A88-B111; A88-B112; A88-B113; ? 88-? 114; ? 88-? 115; ? 88-? 116; ? 88-? 117; A88-B1 18; A88-B119; ? 88-? 120; ? 88-? 121; ? 88-? 122; ? 88-? 123; A88-B124; A88-B125; 88- 126; ? 88-? 127; ? 88-? 128; ? 88-? 129; A88-B130; A88-B131; ? 88-? 132; ? 88-? 133; ? 88-? 134; ? 88-? 135; A88-B136; A88-B137; 88- 138; ? 88-? 139; ? 88-? 140; ? 88-? 141; A88-B142; A88-B143; ? 88-? 144; ? 88-? 145; ? 88-? 146; ? 88-? 147; A88-B148; A88-B149; ? 88-? 150; ? 88-? 151; ? 88-? 152; ? 88-? 153; A88-B154; A88-B155; 88- 156; ? 88-? 157; 88- 158; ? 88-? 159; A88-B160; A88-B161; ? 88-? 162; ? 88-? 163; ? 88-? 164; 88- 165; A88-B166; A88-B167; ? 88-? 168; ? 88-? 169; ? 89-? 1; ? 89-? 2; A89-B3; A89-B4; ? 89-? 5; ? 89-? 6; ? 89-? 7; ? 89-? 8; A89-B9; A89-B10; ? 89-? 11; '? 89-? 12; ? 89-? 13; ? 89-? 14; A89-B15; A89-B16; ? 89-? 17; ? 89-? 18; ? 89-? 19; ? 89-? 20; A89-B21; A89-B22; ? 89-? 23; ? 89-? 24; ? 89-? 25; ? 89-? 26; A89-B27; A89-B28; ? 89-? 29; ? 89-? 30; ? 89-? 31; ? 89-? 32; A89-B33; A89-B34; ? 89-? 35; ? 89-? 36; ? 89-? 37; ? 89-? 38; A89-B39; A89-B40; ? 89-? 41; ? 89-? 42; ? 89-? 43; ? 89-? 44; A89-B45; A89-B46; ? 89-? 47; ? 89-? 48; ? 89-? 49; . ? 89-? 50; A89-B51; A89-B52; ? 89-? 53; ? 89-? 54; ? 89-? 55; ? 89-? 56; A89-B57; A89-B58; ? 89-? 59; ? 89-? 60; ? 89-? 61; ? 89-? 62; A89-B63; A89-B64; ? 89-? 65; ? 89-? 66; ? 89-? 67; ? 89-? 68; A89-B69; A89-B70; ,? 89-? 71; ? 89-? 72; ? 89-? 73; ? 89-? 74; A89-B75; ? 89-? 76; ? 89-? 77; ? 89-? 78; ? 89-? 79; ? 89-? 80; A89-B81; ? 89-? 82; ? 89-? 83; ? 89-? 84; ? 89 -? 85; ? 89-? 86; A89-B87; ? 89-? 88; ? 89-? 89; ? 89-? 90; ? 89-? 91; ? 89-? 92; A89-B93; A89-B94; A89-B95; A89-B96; A89-B97; A89-B98; A89-B99; A89-B100; A89-B101; A89-B102; A89-B103; A89-B104; A89-B105; A89-B106; A89-B107; A89-B108; A89-B109; A89-B110; A89-B111; A89-B112; A89-B113; A89-B114; A89-B115; A89-B116; A89-B117; A89-B118; A89-B119; 'A89-B120; A89-B121; A89-B122; A89-B123; A89-B124; A89-B125; A89-B126; A89-B127; A89-B128; A89-B129; A89-B130; A89-B131; A89-B132; A89-B133; A89-B134; A89-B135; A89-B136; A89-B137; A89-B138; A89-B139; A89-B140; A89-B141; A89-B142; A89-B143; A89-B144; A89-B145; A89-B146; A89-B147; A89-B148; A89-B149; A89-B150; A89-B151; A89-B152; A89-B153; A89-B154; A89-B155; A89-B156; A89-B157; A89-B158; A89-B159; A89-B160; A89-B161; A89-B162; A89-B163; A89-B164; A89-B165; A89-B166; A89-B167; A89-B168; A89-B169; A90-B1; A90-B2; A90-B3; A90-B4; A90-B5; A90-B6; A90-B7; A90-B8; A90-B9; A90-B10; A90-B11; A90-B12; A90-B13; A90-B14; A90-B15; A90-B16; A90-B17; A90-B18; A90-B19; A90-B20; A90-B21; A90-B22; A90-B23; A90-B24; A90-B25; A90-B26; A90-B27; A90-B28; A90-B29; A90-B30; A90-B31; A90-B32; A90-B33; A90-B34; A90-B35; A90-B36; A90-B37; A90-B38; A90-B39; A90-B40; A90-B41; A90-B42; A90-B43; A90-B44; A90-B45; A90-B46; A90-B47; A90-B48; A90-B49; A90-B50; A90-B51; A90-B52; A90-B53; A90-B54; A90-B55; A90-B56; A90-B57; A90-B58; A90-B59; A90-B60; A90-B61; A90-B62; A90-B63; A90-B64; A90-B65; A90-B66; A90-B67; A90-B68; A90-B69; A90-B70; A90-B71; A90-B72; A90-B73; A90-B74; A90-B75; A90-B76; A90-B77; A90-B78; A90-B79; A90-B80; A90-B81; A90-B82; A90-B83; A90-B84; A90-B85; A90-B86; A90-B87; A90-B88; A90-B89; A90-B90; A90-B91; A90-B92; A90-B93; A90-B94; A90-B95; A90-B96; A90-B97; A90-B98; A90-B99; A90-B100; A90-B101; A90-B102; A90-B103; A90-B104; A90-B105; A90-B106; A90-B107; A90-B108; A90-B109; A90-B1 10; A90-B111; A90-B112; A90-B113; A90-B114; A90-B115; A90-B1 16; A90-B117; A90-B118; A90-B119; A90-B120; A90-B121; A90-B122; A90-B123; A90-B124; A90-B125; A90-B126; A90-B127; A90-B128; A90-B129; A90-B130; A90-B131; A90-B132; A90-B133; A90-B134; A90-B135; A90-B136; A90-B137; A90-B138; A90-B139; A90-B140; A90-B141; A90-B142; A90-B143; A90-B144; A90-B 45; A90-B146; A90-B147; A90-B148; A90-B149; A90-B150; A90-B151; A90-B152; A90-B153; A90-B154; 'A90-B155; A90-B156; A90-B157; A90-B158; A90-B159; A90-B160; A90-B161; A90-B162; A90-B163; A90-B164; A90-B165; A90-B166; A90-B167; A90-B168; A90-B169; A91-B1; A91-B2; A91-B3; A91-B4; A91-B5; A91-B6; A91-B7; A91-B8; A91-B9; A91-B10; A91-B11; A91-B12; A91-B13; A91-B14; A91-B15; A91-B16; A91-B17; A91-B18; A91-B19; A91-B20; A91-B21; A91-B22; A91-B23; A91-B24; A91-B25; A91-B26; A91-B27; A91-B28; A91-B29; A91-B30; A91-B31; A91-B32; A91-B33; A91-B34; A91-B35; ? 91-? 3ß; A91-B37; A91-B38; A91-B39; A91-B40; A91-B41; 91-42; A91-B43; A91-B44; A91-B45; A91-B46; A91-B47; 91-? 48; A91-B49; A91-B50; A91-B51; "A91-B52; A91-B53;? 91-? 54; j A91-B55; A91-B56; A91-B57; A91-B58; A91-B59; A91-B60; A91-B61; A91-B62; A91-B63; A91-B64; A91-B65; A91-B66; A91-B67; A91-B68; A91-B69; A91-B70; A91-B71; A91-B72; A91 -B73; A91-B74; A91-B75; A91-B76; A91-B77; A91-B78; A91-B79; A91-B80; A91-B81; A91-B82; A91-B83; A91-B84; A91-B85; A91-B86; A91-B87; A91-B88; A91-B89; A91-B90; A91-B91; A91-B92; A91-B93; A91-B94; A91-B95; A91-B96; A91-B97; A91-B98; A91-B99; A91-B100; A91-B101; A91-B102; A91-B103; A91-B104; A91-B105; 'A91-B106; A91-B107; A91-B108; A91-B109; A91-B110; A91-B111; A91-B112; A91-B113; A91-B114; A91-B115; A91-B116; A91-B117; A91-B118; A91-B119; A91-B120; A91-B121; A91-B122; A91-B123; A91-B124; A91-B125; A91-B126; A91-B127; A91-B128; A91-B129; A91-B130; A91-B131; A91-B132; A91-B133; A91-B134; A91-B135; A91-B136; A91-B137; A91-B138; A91-B139; A91-B140; A91-B141; A91-B142; A91-B143; A91-B144; A91-B145; A91-B146; A91-B147; A91-B148; A91-B149; A91-B150; A91-B151; A91-B152; A91-B153; A91-B154; A91-B155; A91-B156; A91-B157; A91-B158; A91-B159; A91-B160; A91-B161; A91-B162; A91-B163; A91-B164; A91-B165; A91-B166; A91-B167; A91-B168; A91-B169; A92-B1; A92-B2; A92-B3; A92-B4; A92-B5; A92-B6; A92-B7; A92-B8; A92-B9; A92-B10; A92-B11; A92-B12; A92-B13; A92-B14; A92-B15; A92-B16; A92-B17; A92-B18; A92-B19; A92-B20; A92-B21; A92-B22; A92-B23; A92-B24; A92-B25; A92-B26; A92-B27; A92-B28; A92-B29 * A92-B30; A92-B31; A92-B32; A92-B33; A92-B34; A92-B35; A92-B36; A92-B37; A92-B38; A92-B39; A92-B40; A92-B41; A92-B42; A92-B43; A92-B44; A92-B45; A92-B46; A92-B47; A92-B48; A92-B49; A92-B50; A92-B51; A92-B52; A92-B53; A92-B54; | A92-B55; A92-B56; A92-B57; A92-B58; A92-B59; A92-B60; A92-B61; A92-B62; A92-B63; A92-B64; A92-B65; A92-B66; A92-B67; A92-B68; A92-B69; A92-B70; A92-B71; A92-B72; A92-B73; A92-B74; A92-B75; A92-B76; A92-B77; A92-B78; A92-B79; A92-B80; A92-B81; A92-B82; A92-B83; A92-B84; A92-B85; A92-B86; A92-B87; A92-B88; A92-B89; A92-B90; A92-B91; A92-B92; · A92-B93; A92-B94; A92-B95; A92-B96; A92-B97; A92-B98; A92-B99; A92-B100; A92-B101; A92-B102; A92-B103; A92-B104; A92-B105; A92-B106; A92-B107; A92-B108; A92-B109; A92-B110; A92-B111; A92-B112; A92-B113; A92-B114; A92-B115; A92-B1 16; A92-B117; A92-B118; A92-B119; A92-B120; A92-B121; A92-B122; A92-B123; A92-B124; A92-B125; A92-B126; A92-B127; A92-B128; A92-B129; A92-B130; A92-B131; A92-B132; A92-B133; A92-B134; A92-B135; A92-B136; A92-B137; A92-B138; A92-B139; A92-B140; A92-B141; A92-B142; A92-B143; A92-B144; A92-B145; A92-B146; A92-B147; A92-B148; A92-B149; A92-B150; A92-B151; A92-B152; A92-B153; A92-B154; A92-B155; A92-B156; A92-B157; A92-B158; A92-B159; A92-B160; A92-B161; A92-B162; A92-B163; A92-B164; A92-B165; A92-B166; A92-B167; A92-B168; A92-B169; A93-B1; A93-B2; A93-B3; A93-B4; A93-B5; A93-B6; A93-B7; A93-B8; »A93-B9; A93-B10; A93-B11; A93-B12; A93-B13; A93-B14; A93-B15; A93-B16; A93-B17; A93-B18; A93-B19; A93-B20; A93-B21; A93-B22; A93-B23; A93-B24; A93-B25; A93-B26; A93-B27; A93-B28; A93-B29; A93-B30; A93-B31; A93-B32; A93-B33; A93-B34; A93-B35; A93-B36; A93-B37; A93-B38; A93-B39; A93-B40; A93-B41; A93-B42; A93-B43; A93-B44; A93-B45; A93-B46; A93-B47; A93-B48; A93-B49; A93-B50; A93-B51; A93-B52; A93-B53; A93-B54; A93-B55; A93-B56; A93-B57; A93-B58; A93-B59; A93-B60; A93-B61; · A93-B62; A93-B63; A93-B64; A93-B65; A93-B66; A93-B67; A93-B68; A93-B69; A93-B70; A93-B71; A93-B72; A93-B73; A93-B74; A93-B75; A93-B76; A93-B77; A93-B78; A93-B79; A93-B80; A93-B81; A93-B82; A93-B83; A93-B84; A93-B85; A93-B86; A93-B87; A93-B88; A93-B89; A93-B90; A93-B91; A93-B92; A93-B93; 'A93-B94; A93-B95; A93-B96; A93-B97; A93-B98; A93-B99; A93-B100; A93-B101; A93-B102; A93-B103; A93-B104; A93-B105; A93-B106; A93-B107; A93-B108; A93-B109; A93-B110; A93-B111; A93-B112; A93-B113; A93-B114; A93-B115; A93-B116; A93-B117; A93-B118; A93-B119; A93-B120; A93-B121; A93-B122; A93-B123; A93-B124; A93-B125; A93-B126; A93-B127; . A93-B128; A93-B129; A93-B130; A93-B131; A93-B132; A93-B133; A93-B134; A93-B135; A93-B136; A93-B137; A93-B138; A93-B139; A93-B140; A93-B141; A93-B142; A93-B143; A93-B144; A93-B145; A93-B146; A93-B147; A93-B148; A93-B149; A93-B150; A93-B151; A93-B152; A93-B153; A93-B154; A93-B155; A93-B156; A93-B157; A93-B158; A93-B159; A93-B160; A93-B161; A93-B162; A93-B163; A93-B164; A93-B165; A93-B166; A93-B167; A93-B168; A93-B169; A94-B1; A94-B2; A94-B3; A94-B4; A94-B5; A94-B6; A94-B7; A94-B8; A94-B9; A94-B10; A94-B11; A94-B12; · A94-B13; A94-B14; A94-B15; A94-B16; A94-B17; A94-B18; A94-B19; A94-B20; A94-B21; A94-B22; A94-B23; A94-B24; A94-B25; A94-B26; A94-B27; A94-B28; A94-B29; A94-B30; A94-B31; A94-B32; A94-B33; A94-B34; A94-B35; A94-B36; A94-B37; A94-B38; A94-B39; A94-B40; A94-B41; A94-B42; A94-B43; A94-B44; A94-B45; A94-B46; A94-B47; A94-B48; A94-B49; A94-B50; A94-B51; A94-B52; A94-B53; A94-B54; · A94-B55; A94-B56; A94-B57; A94-B58; A94-B59; A94-B60; A94-B61; A94-B62; A94-B63; A94-B64; 'A94-B65; A94-B66; A94-B67; A94-B68; A94-B69; A94-B70; A94-B71; A94-B72; A94-B73; A94-B74; A94-B75; A94-B76; A94-B77; A94-B78; A94-B79; A94-B80; A94-B81; A94-B82; A94-B83; A94-B84; A94-B85; A94-B86; A94-B87; A94-B88; A94-B89; A94-B90; A94-B91; A94-B92; A94-B93; A94-B94; A94-B95; A94-B96; A94-B97; A94-B98; A94-B99; A94-B100; A94-B101; A94-B102; A94-B103; A94-B104; A94-B105; A94-B106; A94-B107; A94-B108; A94-B109; A94-B110; A94-B111; A94-B112; A94-B113; A94-B114; A94-B115; A94-B116; A94-B117; A94-B118; A94-B119; A94-B120; A94-B121; A94-B122; A94-B123; A94-B124; A94-B125; A94-B126; A94-B127; A94-B128; A94-B129; A94-B130; A94-B131; A94-B132; A94-B133; A94-B134; A94-B135; A94-B136; A94-B137; A94-B138; A94-B139; A94-B140; A94-B141; A94-B142; A94-B143; A94-B144; A94-B145; A94-B146; A94-B147; A94-B148; A94-B149; A94-B150; A94-B151; A94-B152; A94-B153; A94-B154; A94-B155; A94-B156; A94-B157; A94-B158; A94-B159; A94-B160; A94-B161; A94-B162; A94-B163; A94-B164; A94-B165; A94-B166; A94-B167; A94-B168; A94-B169; A95-B1; A95-B2; A95-B3; A95-B4; A95-B5; A95-B6; A95-B7; A95-B8; A95-B9; A95-B10; A95-B11; A95-B12; A95-B13; A95-B14; A95-B15; A95-B16; A95-B17; A95-B18; A95-B19; A95-B20; A95-B21; A95-B22; A95-B23; A95-B24; A95-B25; A95-B26; A95-B27; A95-B28; A95-B29; A95-B30; A95-B31; A95-B32; A95-B33; A95-B34; A95-B35; A95-B36; A95-B37; A95-B38; A95-B39; A95-B40; A95-B41; A95-B42; A95-B43; A95-B44; A95-B45; A95-B46; A95-B47; A95-B48; A95-B49; A95-B50; A95-B51; A95-B52; A95-B53; A95-B54; A95-B55; A95-B56; A95-B57; A95-B58; A95-B59; A95-B60; A95-B61; A95-B62; A95-B63; A95-B64; A95-B65; A95-B66; A95-B67; A95-B68; A95-B69; A95-B70; A95-B71; A95-B72; A95-B73; A95-B74; A95-B75; A95-B76; A95-B77; A95-B78; A95-B79; A95-B80; A95-B81; A95-B82; A95-B83; . A95-B84; A95-B85; A95-B86; A95-B87; A95-B88; A95-B89; A95-B90; A95-B91; A95-B92; A95-B93; A95-B94; A95-B95; A95-B96; A95-B97; A95-B98; A95-B99; A95-B100; A95-B101; A95-B102; A95-B103; A95-B104; A95-B105; A95-B106; A95-B107; A95-B108; A95-B109; A95-B110; A95-B111; A95-B112; A95-B113; A95-B114; A95-B115; A95-B116; A95-B117; A95-B118; A95-B119; A95-B120; A95-B121; A95-B122; A95-B123; A95-B124; A95-B125; A95-B126; A95-B127; A95-B128; A95-B129; A95-B130; A95-B131; A95-B132; A95-B133; A95-B134; A95-B135; A95-B136; A95-B137; 'A95-B138; A95-B139; A95-B140; A95-B141; A95-B142; A95-B143; A95-B144; A95-B145; A95-B146; A95-B147; A95-B148; A95-B149; A95-B150; A95-B151; A95-B152; A95-B153; A95-B154; A95-B155; A95-B156; A95-B157; A95-B158; A95-B159; A95-B160; A95-B161; A95-B162; A95-B163; A95-B164; A95-B165; A95-B166; A95-B167; 'A95-B168; A95-B169; A9S-B1; A96-B2; A96-B3; A96-B4; A96-B5; A96-B6; A96-B7; A96-B8; A96-B9; A96-B10; A96-B11; A96-B12; A96-B13; A96-B14; A96-B15; A96-B16; A96-B17; A96-B18; A9S-B19; A96-B20; A96-B21; A96-B22; A96-B23; A96-B24; A96-B25; A96-B26; A96-B27; A96-B28; A96-B29; A96-B30; A96-B31; A96-B32; A96-B33; A96-B34; A96-B35; A96-B36; A96-B37; A96-B38; A96-B39; A96-B40; A96-B41; A96-B42; A96-B43; A96-B44; A96-B45; A96-B46; A96-B47; A96-B48; A96-B49; A96-B50; A96-B51; A96-B52; A96-B53; A96-B54; A96-B55; A96-B56; A96-B57; A96-B58; A96-B59; A96-B60; A96-B61; A96-B62; A96-B63; A96-B64; A96-B65; A96-B66; A96-B67; A96-B68; A96-B69; A96-B70; A96-B71; A96-B72; A96-B73; A96-B74; A96-B75; A96-B76; A96-B77; A96-B78; A96-B79; A96-B80; . A96-B81; A96-B82; A96-B83; A96-B84; A96-B85; A96-B86; A96-B87; A96-B88; A96-B89; A96-B90; A96-B91; A96-B92; A96-B93; A96-B94; A96-B95; A96-B96; A96-B97; A96-B98; A96-B99; A96-B100; A96-B101; A96-B102; A96-B103; A96-B104; A96-B105; A96-B106; A96-B107; A96-B108; A96-B109; A96-B110; A96-B11 1; A96-B112; A96-B113; A96-B114; A96-B115; A96-B116; A96-B117; A96-B18; A96-B119; A96-B120; A96-B121; A96-B122; A96-B123; A96-B124; A96-B125; A9S-B126; A96-B127; A96-B128; A96-B129; A96-B130; A96-B131; A96-B132; A96-B133; A96-B134; A96-B135; A96-B136; A96-B137; A96-B138; A96-B139; A96-B140; A96-B141; A96-B142; A96-B143; A96-B144; A96-B145; A96-B146; A96-B 47; A96-B148; A96-B149; A96-B150; A96-B151; A96-B152; A96-B153; A96-B154; A96-B155; A96-B156; A96-B157; A96-B158; A96-B159; A96-B160; A96-B161; A96-B162; A96-B163; A96-B164; A96-B165; A96-B166; A96-B167; A96-B168; A96-B169; A97-B1; A97-B2; A97-B3; A97-B4; A97-B5; A97-B6; A97-B7; A97-B8; A97-B9; A97-B10; A97-B11; A97-B12; A97-B13; A97-B14; A97-B15; A97-B16; A97-B17; A97-B18; A97-B19; A97-B20; A97-B21; A97-B22; A97-B23; A97-B24; A97-B25; A97-B26; A97-B27; A97-B28; A97-B29; A97-B30; A97-B31; A97-B32; A97-B33; A97-B34; A97-B35; A97-B36; A97-B37; A97-B38; A97-B39; A97-B40; A97-B41; A97-B42; A97-B43; A97-B44; A97-B45; A97-B46; A97-B47; A97-B48; A97-B49; A97-B50; A97-B51; A97-B52; A97-B53; A97-B54; A97-B55; A97-B56; A97-B57; A97-B58; A97-B59; A97-B60; A97-B61; A97-B62; A97-B63; A97-B64; A97-B65; A97-B66; A97-B67; A97-B68; A97-B69; A97-B70; A97-B71; A97-B72; A97-B73; A97-B74; A97-B75; A97-B76; A97-B77; A97-B78; A97-B79; A97-B80; A97-B81; A97-B82; A97-B83; A97-B84; A97-B85; A97-B86; A97-B87; ? 97-? 88; ? 97-? 89; ? 97-? 90; A97-B91; A97-B92; A97-B93; ? 97-? 94; ? 97-? 95; ? 97-? 96; A97-B97; A97-B98; A97-B99; ? 97-? 100; ? 97-? 101; 97-? 102; A97-B103; A97-B104; A97-B105; ? 97-? 106; 97-? 107; 97-? 108; A97-B109; A97-B110; A97-B1 11; ? 97-? 112; ? 97-? 113; ? 97-? 114; A97-B115; A97-B116; A97-B117; '? 97-? 118; 97-? 119; ? 97-? 120; A97-B121; A97-B122; A97-B123; 97-? 124; ? 97-? 125; ? 97-? 126; A97-B127; A97-B128; A97-B129; ? 97-? 130; 97-? 131; 97- 132; A97-B133; A97-B134; A97-B135; 97-? 136; ? 97-? 137; 97-? 138; A97-B139; A97-B140; A97-B141; 97-? 142; ? 97-? 143; 97-? 144; A97-B1 5; A97-B146; A97-B147; 97-? 148; ? 97-? 149; ? 97-? 150; A97-B151; A97-B152; A97-B153; ? 97-? 154; ? 97-? 155; 97- 156; A97-B157; A97-B158; A97-B159; ? 97-? 160; ? 97-? 161; ? 97-? 162; A97-B163; A97-B164; A97-B165; ? 97-? 166; ? 97-? 167; ? 97-? 168; A97-B169; A98-B1; A98-B2; ? 98-? 3; ? 98-? 4; ? 98-? 5; A98-B6; A98-B7; A98-B8; ? 98-? 9; ? 98-? 10; ? 98-? 11; A98-B12; A98-B13; A98-B14; ? 98-? 15; ? 98-? 16; ? 98-? 17; A98-B18; A98-B19; A98-B20; ? 98-? 21; ? 98-? 22; ? 98-? 23; A98-B24; A98-B25; A98-B26; ? 98-? 27; ? 98-? 28; ? 98-? 29; A98-B30; A98-B31; A98-B32; ? 98-? 33; ? 98-? 34; ? 98-? 35; A98-B36; A98-B37; A98-B38; ? 98-? 39; ? 98-? 40; ? 98-? 41; A98-B42; A98-B43; A98-B44; ? 98-? 45; ? 98-? 46; ? 98-? 47; A98-B48; A98-B49; A98-B50; ? 98-? 51; ? 98-? 52; ? 98-? 53; A98-B54; A98-B55; A98-B56; ? 98-? 57; ? 98-? 58; ? 98-? 59; A98-B60; A98-B61; A98-B62; ,? 98-? 63; ? 98-? 64; ? 98-? 65; A98-B66; A98-B67; ? 98-? 68; ? 98-? 69; ? 98-? 70; ? 98-? 71; A98-B72; A98-B73; ? 98-? 74; ? 98-? 75; ? 98-? 76; ? 98-? 77; A98-B78; A98-B79; ? 98-? 80; ? 98-? 81; ? 98-? 82; ? 98-? 83; A98-B84; A98-B85; ? 98-? 86; ? 98-? 87; ? 98-? 88; ? 98-? 89; A98-B90; A98-B91; ? 98-? 92; ? 98-? 93; ? 98-? 94; ? 98-? 95; A98-B96; A98-B97; ? 98-? 98; ? 98-? 99; ? 98-? 100; ? 98-? 101; A98-B102; A98-B103; 98-? 104; 98-? 105; ? 98-? 106; 98-? 107; A98-B108; A98-B109; ? 98-? 110; ? 98-? 111; 98-? 112; ? 98-? 113; A98-B114; A98-B115; ? 98-? 116; ? 98-? 117; ? 98-? 1 18; 98-? 119; A98-B120; A98-B121; ? 98-? 122; |? 98-? 123; 98-? 124; ? 98-? 125; A98-B126; A98-B127; ? 98-? 128; ? 98-? 129; ? 98-? 130; ? 98-? 131; A98-B132; A98-B133; ? 98-? 134; ? 98-? 135; ? 98-? 136; ? 98-? 137; A98-B138; A98-B139; ? 98-? 140; ? 98-? 141; ? 98-? 142; ? 98-? 143; A98-B144; A98-B145; 98-? 146; ? 98-? 147; ? 98-? 148; ? 98-? 149; A98-B150; A98-B151; ? 98-? 152; ? 98-? 153; 98-? 154; 98-? 155; A98-B156; A98-B157; ? 98-? 158; ? 98-? 159; ? 98-? 160; ? 98-? 161; A98-B162; A98-B163; 98-? 164; ? 98-? 165; ? 98-? 166; ? 98-? 167; A98-B168; A98-B169; 99-? 1; ? 99-? 2; ? 99-? 3; 99-? 4; A99-B5; A99-B6; ? 99-? 7; ? 99-? 8; ? 99-? 9; ? 99-? 10; A99-B11; A99-B12; ? 99-? 13; 99-? 14; ? 99-? 15; ? 99-? 16; A99-B17; A99-B18; ? 99-? 19; ? 99-? 20; ? 99-? 21; 99-? 22; A99-B23; A99-B24; ,? 99-? 25; ? 99-? 26; ? 99-? 27; 99-? 28; A99-B29; ? 99-? 30; ? 99-? 31; ? 99-? 32; 99-? 33; 99-? 34; A99-B35; ? 99-? 36; ? 99-? 37; ? 99-? 38; ? 99-? 39; ? 99-? 40; A99-B41; ? 99-? 42; ? 99-? 43; ? 99-? 44; ? 99-? 45; ? 99-? 46; A99-B47; A99-B48; A99-B49; A99-B50; A99-B51; A99-B52; A99-B53; A99-B54; A99-B55; A99-B56; A99-B57; A99-B58; A99-B59; A99-B60; A99-B61; A99-B62; A99-B63; A99-B64; A99-B65; A99-B66; A99-B67; A99-B68; A99-B69; A99-B70; A99-B71; A99-B72; A99-B73; A99-B74; A99-B75; A99-B76; A99-B77; A99-B78; A99-B79; A99-B80; A99-B81; A99-B82; A99-B83; A99-B84; A99-B85; A99-B86; A99-B87; A99-B88; A99-B89; A99-B90; A99-B91; A99-B92; A99-B93; A99-B94; A99-B95; A99-B96; A99-B97; A99-B98; A99-B99; A99-B100; A99-B101; A99-B102; A99-B103; A99-B104; A99-B105; A99-B106; A99-B107; A99-B 08; A99-B109; A99-B110; A99-B1 11; A99-B112; A99-B113; A99-B114; A99-B115; A99-B116; A99-B117; A99-B118; A99-B119; A99-B120; A99-B121; A99-B122; A99-B123; A99-B124; A99-B125; A99-B126; A99-B127; A99-B128; A99-B129; A99-B130; A99-B131; A99-B132; A99-B133; A99-B134; A99-B135; A99-B136; A99-B137; A99-B138; A99-B139; A99-B140; A99-B141; A99-B142; A99-B143; A99-B144; A99-B145; A99-B146; A99-B147; A99-B148; A99-B149; A99-B150; A99-B151; A99-B152; A99-B153; A99-B154; A99-B155; A99-B156; A99-B157; A99-B158; A99-B159; A99-B160; A99-B161; A99-B162; A99-B163; A99-B164; A99-B165; A99-B166; A99-B167; A99-B168; A99-B169; A100-B1; A100-B2; A100-B3; A100-B4; A100-B5; A100-B6; A100-B7; A100-B8; A100-B9; A100-B10; A100-B11; A100-B12; A100-B13; A100-B14; A100-B15; A100-B16; A100-B17; A 00- 18; 'A100-B19; A100-B20; A100-B21; A100-B22; A100-B23; A100-B24; A100-B25; A100-B26; A100-B27; A100-B28; A100-B29; A100-B30; A100-B31; A100-B32; A100-B33; A100-B34; A100-B35; A100-B36; A100-B37; A100-B38; A100-B39; A100-B40; A100-B41; A100-B42; A100-B43; A100-B44; A100-B45; A100-B46; A100-B47; A100-B48; A100-B49; A100-B50; A100-B51; A100-B52; A100-B53; A100-B54; A100-B55; A100-B56; A100-B57; A100-B58; A100-B59; A100-B60; A100-B61; A100-B62; A100-B63; A100-B64; A100-B65; A100-B66; A100-BS7; A100-B68; A100-B69; A100-B70; A100-B71; A100-B72; A100-B73; A100-B74; A100-B75; A100-B76; A100-B77; A100-B78; A100-B79; A100-B80; A100-B81; A100-B82; A100-B83; A100-B84; A100-B85; A100-B86; A100-B87; A100-B88; A100-B89; A100-B90; A100-B91; A100-B92; A100-B93; A100-B94; A100-B95; A100-B96; A100-B97; A100-B98; A100-B99; A100-B100; A100-B101; A100-B102; A100-B103; A100-B104; A100-B105; A100-B106; A100-B107; A100-B108; A100-B109; A100-B110; A100-B111; A100-B112; A100-B113; A100-B114; A100-B115; A100-B116; A100-B117; A100-B118; A100-B119; A100-B120; A100-B121; A100-B122; A100-B123; A100-B124; A100-B125; A100-B126; A100-B127; A100-B128; A100-B129; A100-B130; A100-B131; A100-B132; A100-B133; A100-B134; A100-B135; A100-B136; A100-B137; A100-B138; A100-B139; A100-B140; A100-B141; A100-B142; A100-B143; A100-B144; A100-B145; A100-B146; A100-B147; A100-B148; A100-B149; A100-B150; A100-B151; A100-B152; A100-B153; A100-B154; A100-B155; A100-B156; A100-B157; A100-B158; A100-B159; A100-B160; A100-B161; A100-B162; A100-B163; A100-B164; A100-B165; A100-B166; A100-B167; A100-B168; A100-B169; A101-B1; A101-B2; A101-B3; A101-B4; A101-B5; A101-B6; A101-B7; A101-B8; A101-B9; A101-B10; A101-B11; A101-B12; A101-B13; A101-B14; A101-B15; A101-B16; A101-B17; A101-B18; A101-B19; A101-B20; A101-B21; A101-B22; A101-B23; A101 -B24; A101-B25; A101-B26; A101-B27; A101-B28; A101-B29; A101-B30; A101-B31; A101-B32; A101-B33; A101-B34; A101-B35; A101-B36; A101-B37; A101-B38; A101-B39; A101-B40; A101-B41; A101-B42; A101-B43; A101-B44; A101-B45; A101-B46; A101-B47; A101-B48; A101-B49; A101-B50; A101-B51; A101-B52; A101-B53; A101-B54; A101-B55; A101-B56; A101-B57; A101-B58; A101-B59; A101-B60; A101-B61; A101-B62; A101-B63; A101-B64; A101-B65; A101-B66; A101-B67; A101-B68; A101-B69; A101-B70; A101-B71; A101-B72; A101-B73; A101-B74; A101-B75; A101-B76; A101-B77; A101-B78; A101-B79; A101-B80; A101-B81; A101-B82; A101-B83; A101-B84; A101-B85; A101-B86; A101-B87; A101-B88; A101-B89; A101-B90; A101-B91; A101-B92; A101-B93; A101-B94; A101-B95; A101-B96; A101-B97; A101-B98; A101-B99; A101-B100; A101-B101; A101-B102; A101-B103; A101-B104; A101-B105; A101-B106; A101-B107; A101-B108; A101-B109; A101-B110; A101-B111; A101-B112; A101-B113; A101-B114; A101-B115; A101-B116; A101-B117; A101-B118; A101-B119; A101-B120; A101-B121; A101-B122; A101-B123; A101-B124; A101-B125; A101-B126; A101-B127; A101-B128; A101-B129; A101-B130; A101-B131; A101-B132; A101-B133; A101-B134; A101-B135; A101-B136; A101-B137; A101-B138; A101-B139; A101-B140; A101-B141; A101-B142; A101-B143; A101-B144; A101-B145; A101-B146; A101-B147; A101-B148; A101-B149; A101-B150; A101-B151; A101-B152; A101-B153; A101-B154; A101-B155; A101-B156; A101-B157; A101-B158; A101-B159; A101-B160; ? 101-? 161; ? 101-? 162; ? 101-? 163; ? 101-? 164; ' A101-B165; A101-B166; ? 101-? 167; ? 101-? 168; ? 101-? 169; 102-? 1; A102-B2; A102-B3; 102-? 4; ? 102-? 5; ? 102-? 6; ? 102-? 7; A102-B8; A102-B9; 102-? 10; 102-? 11; 102-? 12; ? 102-? 13; A102-B14; A102-B15; 102-? 16; 102-? 17; ? 102-? 18; ? 102-? 19; A102-B20; A102-B21; 102-? 22; 102-? 23; 102-? 24; 102-? 25; A102-B26; A102-B27; 102-? 28; 102-? 29; ? 102-? 30; ? 102-? 31; A102-B32; A102-B33; 102-? 34; 102-? 35; 102-? 36; ? 102-? 37; A102-B38; A102-B39; ? 102-? 40; 102-? 41; 102-? 42; ? 102-? 43; A102-B44; A102-B45; 102-? 46; 102-? 47; 102-? 48; 102-? 49; A102-B50; A102-B51; 102-? 52; 102-? 53; 102-? 54; ? 102-? 55; A102-B56; A102-B57; 102-? 58; ? 102-? 59; ? 102-? 60; 102-? 61; A102-B62; A102-B63; 102-? 64; ? 102-? 65; 102-66; 102-? 67; A102-B68; A102-B69; ? 102-? 70; ? 102-? 71; ? 102-? 72; 102-? 73; A102-B74; A102-B75; 102-? 76; 102-? 77; 102-? 78; ? 102-? 79; A102-B80; A102-B81; ? 102-? 82; ? 102-? 83; 102-? 84; ? 102-? 85; A102-B86; A102-B87; 102-? 88; 102-? 89; ? 102-? 90; ? 102-? 91; A102-B92; A102-B93; 102-? 94; ? 102-? 95; ? 102-? 96; 102-? 97; A102-B98; A102-B99; ? 102-? 100; 102-? 101; 102-? 102; 102-? 103; A102-B104; A102-B105; 102-? 106; 102-? 107; 102-? 108; 102-? 109; A102-B110; A102-B111; 102-? 112; 102-? 113; 102-? 114; 102-? 115; A102-B116; , A102-B1 17; 102-? 118; 102-? 119; 102-? 120; 102-? 121; A102-B122; ? 102-? 123; 102-? 124; ? 102-? 125; 102-? 126; ? 102-? 127; A102-B128; ? 102-? 129; 102-? 130; 102-? 131; 102-? 132; 102-? 133; A102-B134; 102-? 135; 102-? 136; 102-? 137; 102-? 138; 102-? 139; A102-B140; A102-B141; A102-B142; A102-B143; A102-B144; A102-B145; A102-B146; A102-B147; A102-B148; A102-B149; A102-B150; A102-B151; A102-B152; A102-B153; A102-B154; A102-B155; A102-B156; A102-B157; A102-B158; A102-B159; A102-B160; A102-B161; A102-B162; A102-B163; A102-B164; A102-B165; A102-B166; A102-B167; A102-B168; A102-B169; A103-B1; A103-B2; A103-B3; A103-B4; A103-B5; A103-B6; A103-B7; A103-B8; A103-B9; A103-B10; A103-B1 1; A103-B12; A103-B13; A103-B14; A103-B15; A103-B16; A103-B17; A103-B18; A103-B19; A103-B20; A103-B21; A103-B22; A103-B23; A103-B24; A103-B25; A103-B26; A103.B27; A103-B28; A103-B29; A1 O3-B30; A103-B31; A103-B32; A103-B33; A103-B34; A103-B35; A103-B36; A103-B37; A103-B38; A103-B39; A103-B40; A103-B41; A103-B42; A103-B43; A103-B44; A103-B45; A103-B46; A103-B47; A103-B48; A103-B49; A103-B50; A103-B51; A103-B52; A103-B53; A103-B54; A103-B55; A103-B56; A103-B57; · A103-B58; A103-B59; A103-B60; A103-B61; A103-B62; A103-B63; A103-B64; A103-B65; A103-B66; A103-B67; A103-B68; A103-B69; A103-B70; A103-B71; A103-B72; A103-B73; A103-B74; A103-B75; A103-B76; A103-B77; A103-B78; A103-B79; A103-B80; A103-B81; . A103-B82; A103-B83; A103-B84; A103-B85; A103-B86; A103-B87; A103-B88; A103-B89; A103-B90; A103-B91; A103-B92; A103-B93; A103-B94; A103-B95; A103-B96; A103-B97; A103-B98; A103-B99; A103-B100; A103-B101; A103-B102; A103-B103; A103-B104; A103-B105; A103-B106; A103-B107; A103-B108; A103-B109; A103 - B110; A103-B11 1; A103-B1 12; A103-B113; A103-B114; A103-B115; A103-B116; A103-B117; A103-B118; A103-B119; A103-B120; A103-B121; A103-B122; A103-B123; A103-B124; A103-B125; A103-B126; A103-B127; A103-B128; A103-B129; A103-B130; A103-B131; A103-B132; A103-B133; A103-B134; A103-B135; A103-B136; A103-B137; A103-B138; A103-B139; A103-B140; A103-B141; A103-B142; A103-B143; A103-B144; A103-B145; A103-B146; A103-B147; A103-B148; A103-B149; A103-B150; A103-B151; A103-B152; A103-B153; A103-B154; A103-B155; A103-B156; A103-B157; A103-B158; A103-B159; A103-B160; A103-B161; A103-B162; A103-B163; A103-B164; A103-B165; A103-B166; A103-B167; A103-B168; A103-B169; A104-B1; A104-B2; A104-B3; A104-B4; A104-B5; A104-B6; A104-B7; A104-B8; A104-B9; A104-B10; A104-B11; A104-B12; A104-B13; A104-B14; A104-B15; A104-B16; A104-B17; A104-B18; A104-B19; A104-B20; A104-B21; A104-B22; A104-B23; A104-B24; A104-B25; A104-B26; A104-B27; A104-B28; A104-B29; A104-B30; A104-B31; A104-B32; A104-B33; A104-B34; A104-B35; A104-B36; A104-B37; A104-B38; A104-B39; A104-B40; A104-B41; A104-B42; A104-B43; A104-B44; A104-B45; A104-B46; A104-B47; A104-B48; A104-B49; A104-B50; A104-B51; A104-B52; A104-B53; A104-B54; A104-B55; A104-B56; A104-B57; A104-B58; A104-B59; A104-B60; A104-B61; A104-B62; A104-B63; A104-B64; A104-B65; A104-B66; A104-B67; A104-B68; A104-B69; A104-B70; A104-B71; A104-B72; A104-B73; A104-B74; A104-B75; A104-B76; A104-B77; A104-B78; A104-B79; A104-B80; A104-B81; A104-B82; A104-B83; A104-B84; A104-B85; A104-B86; A104-B87; A104-B88; A104-B89; A104-B90; A104-B91; A104-B92; A104-B93; A104-B94; A104-B95; A104-B96; A104-B97; A104-B98; A104-B99; A104-B100; A104-B101; A104-B102; A104-B103; A104-B104; A104-B105; A104-B106; A104-B107; A104-B108; A104-B109; A104-B110; A104-B111; A104-B112; A104-B113; A104-B114; A104-B1 15; A104-B116; A104-B117; A104-B118; A104-B119; A104-B120; A104-B121; A104-B122; A104-B123; A104-B124; A104-B125; A104-B126; A104-B127; A104-B128; A104-B129; A104-B130; A104-B131; A104-B132; A104-B133; 104-? 134; · A104-B135; A104-B136; A104-B137; A104-B138; A104-B139; A104-B140; A104-B141; A104-B142; A104-B143; A104-B144; A104-B145; A104-B146; ' A104-B147; A104-B148; A104-B149; A104-B150; A104-B151; A104-B152; A104-B153; A104-B154; A104-B155; A104-B156; A104-B157; A104-B158; A104-B159; A104-B160; A104-B161; A104-B 62; A104-B163; A104-B164; A104-B165; A104-B166; · A104-B167; A104-B168; A104-B169; A105-B1; A105-B2; A105-B3; A105-B4; A 05-B5; A105-B6; A105-B7; A105-B8; A105-B9; A105-B10; A105-B11; A105-B12; A105-B13; A105-B14; A105-B15; A105-B16; A105-B17; A105-B18; A105-B19; A105-B20; A105-B21; . A105-B22; A105-B23; A105-B24; A105-B25; A105-B26; A105-B27; A105-B28; A105-B29; A105-B30; A105-B31; A105-B32; A105-B33; A105-B34; A105-B35; A105-B36; A105-B37; A105-B38; A105-B39; A105-B40; A105-B41; A105-B42; A105-B43; A105-B44; A105-B45; A105-B46; A105-B47; A105-B48; A105-B49; A105-B50; A105-B51; A105-B52; A105-B53; A105-B54; A105-B55; A105-B56; A105-B57; A105-B58; A105-B59; A105-B60; A105-B61; A105-B62; A105-B63; A105-B64; A105-B65; A105-B66; A105-B67; A105-B68; A105-B69; A105-B70; A105-B71; A105-B72; A105-B73; A105-B74; A105-B75; A105-B76; A105-B77; A105-B78; A105-B79; A105-B80; A105-B81; A105-B82; A105-B83; A105-B84; A105-B85; A105-B86; A105-B87; A105-B88; A105-B89; A105-B90; A105-B91; A105-B92; A105-B93; A105-B94; A105-B95; A105-B96; A105-B97; A105-B98; A105-B99; A105-B100; A105-B101; A105-B102; A105-B103; A105-B104; A105-B105; A105-B106; A105-B107; A105-B108; A105-B109; A105-B110; A105-B111; A105-B112; A105-B1 13; A105-B114; A105-B115; A105-B116; A105-B117; A105-B118; A105-B119; A105-B120; A105-B121; A105-B122; A105-B123; A105-B124; A105-B125; A105-B126; A105-B127; A105-B128; A105-B129; A105-B130; A105-B131; A105-B132; A105-B133; A105-B134; A105-B135; A105-B136; A105-B137; A105-B138; A105-B139; A105-B140; A105-B141; A105-B142; A105-B143; A105-B144; A105-B145; A105-B146; A105-B147; A105-B148; A105-B149; A105-B150; A105-B151; A105-B152; A105-B153; A105-B154; A105-B155; A105-B156; A105-B157; A105-B158; A105-B159; A105-B160; A105-B161; A105-B162; A105-B163; A105-B164; A105-B165; A105-B166; A105-B167; A105-B168; A105-B169; A106-B1; A106-B2; A106-B3; A106-B4; A106-B5; A106-B6; A106-B7; A106-B8; A106-B9; A106-B10; A106-B11; A106-B12; "A106-B13; A106-B14; A106-B15; A106-B16; A106-B17; A106-B18; A106-B19; A106-B20; A106-B21; A106-B22; A106-B23; A106-B24; A106-B25; A106-B26; A106-B27; A106-B28; A106-B29; A106-B30; A106-B31; A106-B32; A106-B33; A106-B34; A106-B35; A106-B36; A106-B37; A106-B38; A106-B39; A106-B40; A106-B41; A106-B42; · A106-B43; A106-B44; A106-B45; A106-B46; A106-B47; A106-B48; A106-B49; A106-B50; A106-B51; A106-B52; A106-B53; A106-B54; A106-B55; A106-B56; A106-B57; A106-B58; A106-B59; A106-B60; A106-B61; A106-B62; A106-B63; A106-B64; A106-B65; A106-B66; A106-B67; A106-B68; A106-B69; A106-B70; A106-B71; A106-B72; A106-B73; A106-B74; A106-B75; A106-B76; A106-B77; A106-B78; A106-B79; A106-B80; A106-B81; A106-B82; A106-B83; A106-B84; A106-B85; A106-B86; A106-B87; A106-B88; A106-B89; A106-B90; A106-B91; A106-B92; A106-B93; A106-B94; A106-B95; A106-B96; A106-B97; A106-B98; A106-B99; A106-B100; A106-B101; A106-B102; A106-B103; A106-B104; A106-B105; A106-B106; A106-B107; ? 106- ?? 08; A106-B109; A106-B110; A106-B111; A106-B112; A106-B113; A106-B114; A106-B115; A106-B116; A106-B117; A106-B118; A106-B119; A106-B120; A106-B121; A106-B122; A106-B123; A106-B 24; A106-B125; A106-B126; A106-B127; A106-B128; A106-B129; A106-B130; A106-B131; A106-B132; A106-B133; A106-B134; A106-B135; A106-B136; A106-B137; A106-B138; A106-B139; A106-B140; A106-B141; A106-B142; A106-B143; A106-B144; A106-B145; A106-B146; A106-B147; A106-B148; A106-B149; A106-B150; A106-B151; A106-B152; A106-B153; A106-B154; A106-B155; A106-B156; A106-B157; A106-B158; A106-B159; A106-B160; A106-B161; A106-B162; A106-B163; A106-B164; A106-B165; A106-B166; A106-B167; A106-B168; A106-B169; A107-B1; A107-B2; A107-B3; A107-B4; A107-B5; A107-B6; A107-B7; A107-B8; A107-B9; A107-B10; A107-B.11; A107-B12; A107-B13; A 07-B14; A107-B15; A107-B16; A107-B17; A107-B18; A107-B19; A107-B20; A107-B21; A107-B22; A107-B23; A107-B24; A107-B25; A107-B26; A107-B27; A107-B28; A107-B29; A107-B30; A107-B31; A107-B32; A107-B33; A107-B34; A107-B35; A107-B36; A107-B37; A107-B38; A107-B39; A107-B40; A107-B41; A107-B42; A107-B43; A107-B44; A107-B45; A107-B46; A107-B47; A107-B48; A107-B49; A107-B50; A107-B51; A107-B52; A107-B53; A107-B54; A107-B55; A107-B56; A107-B57; A107-B58; A107-B59; A107-B60; A107-B61; A107-B62; A107-B63; A107-B64; A107-B65; A107-B66; A107-B67; A107-B68; A107-B69; A107-B70; A107-B71; A107-B72; A107-B73; A107-B74; A107-B75; A107-B76; A107-B77; A107-B78; A107-B79; A107-B80; A107-B81; A107-B82; A107-B83; A107-B84; A107-B85; A107-B86; A107-B87; A107-B88; A107-B89; A107-B90; A107-B91; A107-B92; A107-B93; A107-B94; A107-B95; A107-B96; A107-B97; A107-B98; A107-B99; A107-B100; A107-B101; A107-B102; A107-B103; A107-B104; A107-B105; A1O7-B106; A107-B107; A107-B108; A107-B109; A107-B110; A107-B111; A107-B112; A107-B113; A107-B114; A107-B115; A107-B116; A107-B117; A107-B118; A107-B119; A107-B120; A107-B121; A107-B122; A107-B123; A107-B124; A107-B125; A107-B126; A107-B127; A107-B128; A107-B129; A107-B130; A107-B131; A107-B132; A107-B133; A107-B134; A107-B135; A107-B136; A107-B137; A107-B138; A107-B139; A107-B140; A107-B141; A107-B142; A107-B143; A107-B144; A107-B145; A107-B146; A107-B147; A107-B148; A107-B149; A107-B150; A107-B151; A107-B152; A107-B153; A107-B154; A107-B155; A107-B156; A107-B157; A107-B158; A107-B159; A107-B160; A107-B161; A107-B162; A107-B163; A107-B164; A107-B165; A107-B166; A107-B167; A107-B168 '; A107-B169; A108-B1; A108-B2; A108-B3; A108-B4; A108-B5; A108-B6; A108-B7; A108-B8; A108-B9; A108-B10; A108-B11; A108-B12; A108-B13; A108-B14; A108-B15; A108-B16; A108-B17; A108-B18; A108-B19; A108-B20; A108-B21; A108-B22; A108-B23; A108-B24; A108-B25; A108-B26; A108-B27; A108-B28; A108-B29; A108-B30; A108-B31; A108-B32; A108-B33; A108-B34; A108-B35; A108-B36; A108-B37; A108-B38; A108-B39; A108-B40; A108-B41; A108-B42; A108-B43; A108-B44; A108-B45; A108-B46; A108-B47; A108-B48; A108-B49; A108-B50; A108-B51; A108-B52; A108-B53; A108-B54; A108-B55; A108-B56; A108-B57; A108-B58; A108-B59; A108-B60; A108-B61; A108-B62; A108-B63; A108-B64; A108-B65; A108-B66; A108-B67; A108-B68; A108-B69; A108-B70; A108-B71; A108-B72; A108-B73; A108-B74; A108-B75; A108-B76; A108-B77; A108-B78; A108-B79; A108-B80; A108-B81; A108-B82; A108-B83; A108-B84; A108-B85; A108-B86; A108-B87; A108-B88; A108-B89; A108-B90; A108-B91; A108-B92; A108-B93; A108-B94; A108-B95; A108-B96; A108-B97; A108-B98; A108-B99; A108-B100; A108-B101; A108-B102; A108-B103; A108-B104; A108-B105; A108-B106; A108-B107; A108-B108; A108-B109; A108-B1 10; A108-B111; A108-B112; A108-B113; A108-B114; A108-B115; A108-B116; A108-B117; A108-B118; A108-B119; A108-B120; A108-B121; A108-B122; A108-B123; A108-B124; A108-B125; A108-B126; A108-B127; A108-B128; A108-B129; A108-B130; A108-B131; A108-B132; A108-B133; A108-B134; A108-B135; A108-B136; A108-B137; A108-B138; A108-B139; A108-B140; A108-B141; A108-B142; A108-B143; A108-B144; A108-B145; A108-B146; A108-B147; A108-B148; A108-B149; A108-B150; A108-B151; A108-B152; A108-B153; A108-B154; A108-B155; A108-B156; A108-B157; A108-B158; A108-B159; A108-B160; A108-B161; A108-B162; A108-B163; A108-B164; A108-B165; A108-B166; A108-B167; A108-B168; A108-B169; A109-B1; A109-B2; A109-B3; A109-B4; A109-B5; A109-B6; A109-B7; A109-B8; A109-B9; A109-B10; A109-B1 1; A109-B12; A109-B13; A109-B14; A109-B15; A109-B16; A109-B17; A109-B18; A109-B19; A109-B20; A109-B21; A109-B22; A109-B23; A109-B24; A109-B25; A109-B26; A109-B27; A109-B28; A109-B29; A109-B30; A109-B31; A109-B32; A109-B33; A109-B34; A109-B35; A109-B36; A109-B37; A109-B38; A109-B39; A109-B40; A109-B41; A109-B42; A109-B43; A109-B44; A109-B45; A109-B46; A109-B47; A109-B48; A109-B49; A109-B50; A109-B51; A109-B52; A109-B53; A109-B54; A109-B55; A109-B56; A109-B57; A109-B58; A109-B59; A109-B60; A109-B61; A109-B62; A109-B63; A109-B64; A109-B65; A109-B66; A109-B67; A109-B68; A109-B69; A109-B70; A109-B71; A109-B72; A109-B73; A109-B74; A109-B75; A109-B76; A109-B77; A109-B78; A109-B79; A109-B80; A109-B81; A109-B82; A109-B83; A109-B84; A109-B85; A109-B86; A109-B87; A109-B88; A109-B89; A109-B90; A109-B91; A109-B92; A109-B93; . A109-B94; A109-B95; A109-B96; A109-B97; A109-B98; A109-B99; A109-B100; A109-B101; A109-B102; A109-B103; A109-B104; A109-B105; A109-B106; A109-B107; A109-B108; A109-B109; A109-B110; A109-B111; A109-B112; A109-B113; A109-B114; A109-B115; A109-B116; A109-B117; A109-B118; A109-B119; A109-B120; A109-B121; A109-B122; A109-B123; A109-B124; A109-B125; A109-B126; A109-B127; A109-B128; A109-B129; A109-B130; A109-B131; A109-B132; A109-B133; A109-B134; A109-B135; A109-B136; A109-B137; A109-B138; A109-B139; A109-B140; A109-B141; A109-B142; A109-B143; A109-B144; A109-B145; A109-B146; A109-B147; A109-B148; A109-B149; A109-B150; A109-B151; A109-B152; A109-B153; A109-B154; A109-B155; A109-B156; A109-B157; A109-B158; A109-B159; A109-B160; A109-B161; A109-B162; A109-B163; A109-B164; A109-B165; A109-B166; A109-B167; A109-B168; A109-B169; A110-B1; A110-B2; A110-B3; A1 10-B4; A110-B5; A110-B6; A110-B7; A110-B8; A110-B9; A1 10-B10; A110-B11; A110-B12; A110-B13; A110-B14; A110-B15; A1 10-B16; A110-B17; A110-B18; A110-B19; A110-B20; A110-B21; A110-B22; A110-B23; A110-B24; A110-B25; A110-B26; A110-B27; A110-B28; A110-B29; A110-B30; A110-B31; A110-B32; A110-B33; A1 10-B34; A110-B35; A110-B36; A110-B37; A110-B38; A110-B39; A1 10-B40; A110-B41; A110-B42; A110-B43; A110-B44; A110-B45; A110-B46; A110-B47; A110-B48; A110-B49; A110-B50; A110-B51; A1 10-B52; A110-B53; A110-B54; A110-B55; A110-B56; A110-B57; A110-B58; A110-B59; A110-B60; A110-B61; A110-B62; A110-B63; A110-B64; A110-B65; A110-B66; A110-B67; A110-B68; A110-B69; A110-B70; A110-B71; A110-B72; A110-B73; A110-B74; A110-B75; A1 10-B76; A110-B77; A110-B78; A110-B79; A110-B80; A110-B81; A1 10-B82; A110-B83; A110-B84; A110-B85; A110-B86; A110-B87; A110-B88; A110-B89; A110-B90; A110-B91; A110-B92; A110-B93; A110-B94; A110-B95; A110-B96; A110-B97; A110-B98; A110-B99; A110-B100; A110-B101; A110-B102; A110-B103; A110-B104; A110-B105; A110-B106; A110-B107; A110-B108; A110-B109; A110-B110; A110-B1 11; A110-B112; A110-B113; A110-B114; A110-B115; A1 10-B116; A110-B1 17; A110-B118; A110-B1 19; A110-B120; A110-B121; A110-B122; A110-B123; A110-B124; A110-B125; A110-B126; A110-B127; A110-B128; A110-B129; A110-B130; A110-B131; A110-B132; A110-B133; A110-B134; A110-B135; A110-B136; A110-B137; A110-B138; A110-B139; A1 10-B140; A110-B141; A110-B142; A110-B143; A110-B144; A1 10-B145; A110-B146; A110-B147; A110-B1 8; A110-B149; A110-B150; A1 10-B151; A110-B152; A1 10-B153; A110-B154; A110-B155; A110-B156; A110-B157; A1 10-B158; A110-B159; A110-B160; A110-B161; A110-B162; A1 10-B163; A110-B164; A110-B165; A1 10-B166; A110-B167; A110-B168; A110-B169.
Thus, for example, in the above list, the compound indicated as A9-B9 is the product of the combination of group A9 in Table 1 and B9 in Table 2, namely Example 230 (a) described later. The particular compounds of the invention of formula (Ix) for the inhibition of Syk are: 2- (1 H-indazol-3-iI) -1 H-benzimidazole-5-carboxylic acid benzylamide N-methylamide of. 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2- (1 H-indazol-3-yl) -1 H-benzamidazole-5-carboxylic acid N-isopropylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide; S.e-dimethyl-^ - IS-methylsulfanyl-1 H-pyrazole-S-i-1 H-benzoimidazole; 6-Chloro-5-methyl-2- (5-methylsulfanyl-1 H-pyrazol-3-yl) -1 H -benzoimidazole; 6-chloro-2- (5-eti! Sulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole; 2- (5-cyclopropylmethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole; 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 5,6-dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole; 5- fluoro-2- [5-methylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole; 5,6-dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-ii) -1H-benzoimidazole; 4- methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dimethyl-2- (5-benzylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6- chloro-5-methyl-2- (5-morpholin-4-yl-1 H-pyrazol-3-yl) -1 H-benzoimidazole; 5,6-Dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1 H -pyrazol-3-ylJ-1 H-benzoimidazole; 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methoxy-1 H-benzoimidazole hydrochloride; 5- methyl-2- (5-methylsulfanyl-4-propyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (5- (4-methoxy-benzyl-sulfanyl) -4-propyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-benzylsulfanyl-4-isopropyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole 2- (5-methylsulfanyl-4-methyl-1 H-pyrazole-3-yl); l) -5-methoxy-1 H-benzoimidazole; 2- (5-Methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methyl-1H-benzoimidazole; 3- (5-Chloro-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5,6-dichloro-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5,6-dimethyI-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine; 3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-ethoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine; 3- (5-trifluoromethoxy-1H-benzoimidazol-2-y) -1 H-pyrazol-4-ylamine; 3- (5-trifluorometn-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine; 2- (4-amino-1 H-pyrazolo-3-yl) -1 H-benzoimidazole-5-carboxylic acid methyl ester; 3- (1 H-benzoimidazol-2-iI) -1 H-indazole; 3- (5-methoxy-1 H -benzo.imidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenyl-methanone; 2- (1 H-indazol-3-yl) -3H-benzoimidazol-4-ol; 2- phenyl-1 H -amidazo [4,5-b] pyrazine; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (1 H-indazol-3-yl) -3 H -amidazo [4,5-c] pyridine; - (1 H-indazol-3-yl) -3H-imidazo [4,5-b] pyridine; - (1 H-pyrazol-3I) -1 H-benzoimidazole; - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazoi; - (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -5-methoxy-1 H-indazole; - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-fluoro-1 H-indazole; - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-fluoro-1 H-indazole; - (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-1 H-indazole; - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-methoxy-1 H-indazole; , 6-dimethyl-2- (4-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; - (5-ethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-isopropyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-bromo-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (3-cyano) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H-indazole; - (6-methyl-5-phenyl-1 H-benzoimidazol-2-yl) -1 H -indazole; - (5-phenyl-1 H -benzoimidazol-2-yl) -1 H -indazole; - (5- (2-fluoro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (5,6-methylenedioxy) phenyl-1 H -benzoimidazol-2-yl) -1 H-indazole; - (5- (2-methoxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (4-chloro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (4-methyl) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-benzyloxy-1 H-benzoimidazol-2-yl) -1 H -ndazole; 3- (5,6-methylenedioxy-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethoxy-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-diethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (4,5-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carbonitrile; 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-ethoxy-1 H-indazole; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -pyrazol-4-carboxylic acid methyl ester; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid methyl ester; cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazole-4-carboxylic acid; 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-y) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- [5- (2-morpholin-4-yl-ethoxy) -1 H -benzoimidazol-2-yl] -1 H-indazole; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide; 3- (5,6-Dimetii-1H-benzoimidazoI-2-yl) -1H-pyrazole-4-carboxylic acid propylamide; 3- (5,6-Dimethyl-1 H -benzoimidazoi-2-yl) -1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide; 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carbonitrile; 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; 3- (6-ethyl-5-methoxy-1 H-benzoimidazoI-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile; 2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (5-ethoxy-1 H-pyrazol-3-ii) -1 H-benzoimidazole; 2- (5-methylsulfanyl-isoxazol-3-yl) -1 H-benzoimidazole; 5-chloro-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dichloro-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole; (benzoimidazol-2-yl) -5-methylthio-3-pyrazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-indazole; 2- (5-isopropyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 2- (5-ethyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 5,6-dimethyl-2- (1, 4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1 H -benzoimidazole; 3- (5,6-dimethyl-1 H-benzoimidazol-2-ii) -4-fluoro-1 H-indazole; 4- chloro-3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-chloro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazoI-5-??; 3- (5-n-propyl-1 H-benzoimidazoI-2-yl) -1 H-indazole; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-sulfonic acid benzylamide; 3- (5-methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1H-benzoimidazoI-5-yl] -phenyl-methanol; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid; [2- (Ndazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid methylamide; [2- (Ndazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid dimethylamide; . [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid isopropylamide; 1 H-benzoimidazol-5-yl] -carboxylic acid benzylamide; [2- (ndazol-3-yl) -1H-benzoimidazoI-5-yl] -carboxylic acid benzamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; 2- (1H-IndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methyl-benzyl amide; 4- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methyl-benzyl amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-morpholin-4-ii-ethyl) -amide; 2- (1H-Indazoi-3-yl) -1H-benzoimidazoi-5-carboxylic acid (2-methoxy-ethyl) -amide; 2- (1H-IndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl) -amide; 2- (1 H-indazol-3-y!) - 1 H-benzoimidazo I-5-carboxylic acid (2-hydroxy-1, 1-dimethylalkyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-imidazoI-1-yl-propyl) -amide; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazoyl-4-carboxylic acid isobutyl-amide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide; 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide; [2- (indazol-3-yl) -1H-benzoimidazoI-5-yl] -carboxylic acid; 3- (5,6-dimethyl-1 H-benzoimidazol-5-yl) -pyrazol-4-carboxylic acid; 2- (4-isopropylcarbamoii-1 H-pyrazolo-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid; - N- [3- (5,6-dimethyI-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-phenyl-acetamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of ci-clopropanecarboxylic acid; [3- (5,6-d.methyl-1 H -benzoamidol-2-yl) -1 H-pyrrazol-4-yl] -amide of methoxyacetic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of ci-clopentanecarboxylic acid; [3- (5,6-dimethyl-1 H -benzoimidazoi-2-yl) -1H-pyrazol-4-yl] -amide of trimethylacetic acid; [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -amide of urea-butylacetic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of butanoic acid; [3- (5,6-dimethyl-1H-benzoin-iidazol-2-yl) -1H-pyrazol-4-yl] -amide of isoxazole-5-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanoic acid; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (6-Chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1H-pyrazoloi-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (6-chloro-5-methioxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethylurea; [3- (5-methoxy-1 H-benzoimidazoI-2-yl) -1 H-pyrrazol-4-yl] -amide of ci-clopropanecarboxylic acid; [3- (5-ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ii] -cyclopropanecarboxylic acid amide; [3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; N- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 3,5-dimethyl-isoxazole-4-carboxylic acid; N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -acetamide; [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of furan-3-carboxylic acid; N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -4-methyl-benzamide; 5,6-dimethyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazoI; 5-ethyl-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6- chloro-5-meioxy-2- (4-nitro-1H-pi'razol-3-yl) -1 H -benzoimidazole; 5-fluoro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (4-Nitro-1 H -pyrazol-3-yl) -5-trifluoromethoxy-1 H-benzoimidazole; 2- (4-Nitro-1 H -pyrazol-3-yl) -5-trifluoromethyl-1H-benzoimidazole; 5-Chloro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (4-Nitro-1H-pyrazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methyl ester; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide; Cyclopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazole or [4,3-c] pyridin-5-yl] -metanone; isopropyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; 1- [3- (5,6-dimethyl-1 H-benzoimidazole ^ -i-l ^ .ej-tetrahydro-pyrazolo ^. S c] pyridin-5-yl] -2,2-dimethyl-propan-1-one 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester; 5,6-dimethyl-1H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H -pyrazolo [4,3-c] pyridine; 3- (5-chloro-6-methyl) -1H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-pyrazoo [4,3-c] pyridine; 3- [5- (2-morpholin-4-yl-ethoxy) -1 H -benzoimidazo! -2-yl] -4,5,6,7-tetrahydro-1 H- pyrazolo [4,3-c] pyrid Na 3- (5-trifluoromethyl-1H-benzoimidazol-2-y [(4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine; 3- (5,6-dimethyl-1 H -benzoimidazol-2-y!) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester; 5-methoxy-2- (4-nitro-1 H-pyrazole-3Ti) -1 H-benzoimidazole; 5-ethoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 3- (5-Cloco-6-methyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] tert-butyl ester ] pyridine-5-carboxylic acid; 3- (5,6-D-methyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyran [4,3-cjpyrazole; 3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-morpholin-4-yl-acetamide; 2-dimethylamino-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2- (1 H-1, 2,3,4-tetraazole-1 - il) -aceta mid a; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isonicotinamide; 2- cyclopropyl-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; 1 - [3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol! -4-yl] -3-methu-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyl-urea; 1 - . 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea; 1-benzyl-3- [3- (5,6-d'metl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazoo [4,3-c] pyridin-5-carboxylic acid isopropylamide; [3- (5-Ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] amide of cyclopropanecarboxylic acid; 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazol-4-ylamine; 4-methyl-piperazin-1-carboxylic acid 3- (1, 5,6,7-teirahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide; 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H -pyrazol-4-yl] -urea; [3- (6-Ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1 H-pyrrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-ethoxy-5-fIuoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide tetrahydropyran-4-carboxylic acid; [3- (6-Ethoxy-5-fiuoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] amide of morpholino-4-carboxylic acid; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-4-carboxylic acid amide; 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethylurea; 5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; [3- (5,6-Dimethyl-1H-benzoimidazol-2-y!) - 1 H -pyrazol-4-ylmethyl] -amide of morpholino-4-carboxylic acid; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide; [3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-iridazin-2-yl) -1H-pyrazolo-4-ii] cyclopropanecarboxylic acid amide; [3- (1, 5,6,7-tetra idro-1,3-diaza-s-indacen-2-yl) -1H-pyrazolo-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-Methoxy-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid; 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazole-4-H] -1,1-dimethyl-urea; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide; 3- [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -dimethyl urea; [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyridinidin-1-yl -metanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1- il-methanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4-yl -metanone; 3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid diethylamide; [3- (5,6-Dimethyl-1H-benzoimidazo! -2-yl) -1H-pyrazol-4-yl] -amido of morpholino-4-carboxylic acid; [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [5- (2-morfoin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridylamide ridino-5-carboxylic; 3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [2- (2H-tetrazoi-5-yl) -ethyl] -amide; 1-cyclopropyI-3- [3- (5-ethyl-6-methyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 4-Methyl-piperazin-1-carboxylic acid [3- (5-etiI-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of piperidino-1-carboxylic acid; 1 - [3- (5-Fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methu-urea; [3- (5-fIuoro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-fIuoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazolo-4-yl] -amide of 4-methyl-piperazino-1-carboxylic acid; 1-methyl-3- [3- (5-trifiuoromethyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5-Chloro-6-methyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-y!) - 1 H -pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; 1-tert-butyl-3- [3- (5,6-dimethyI-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 1- [3- (5,6-d.methyl-1 H -benzoimidazof-2-yl) -1 H-pyrrazol-4-yl] -3-etii-urea; 4-methyl-piperazin-1-carboxylic acid [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; 1-cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-ii] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isobutyl-urea; 1- cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -indazole-5-carboxylic acid; 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1 H -benzoimidazoi-5-carboxylic acid; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; 3- (5-nitro-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1H-lndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-etyl) -amide; (2- (1 H-lndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; 2- (1 H-lndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide; N- [2- (1 H-ldazol-3-y!) -1 H -benzoimidazol-5-yl] -isobutyramide; N- [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-piperidin-1-yl-acetamide; 2- (1 H-indazoI-3-ii) -3H-benzoimidazol-5-amine; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid; and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The compounds of formula (Ixa) of the invention for the inhibition of SYK are: 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-methylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 1M-isopropylamide of 2- (1 H-indazoI-3-yl) -1 H-benzimidazole-5-carboxylic acid; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazo I; 6-Chloro-5-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-Chloro-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-methylsufanyl-1H-pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole; 2- (5-cyclopropylmethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole; 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 5,6-dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole; 5-fluoro-2- [5-methylsulfanyl) -1H-pyrazol-3-yl] -1 H -benzoimidazole; 5,6-Dimethyl-2- (5-phenethylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 4- methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzoimidazole; 5,6-dimethyl-2- (5-benzylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-Dimeti-2- [5- (thiophen-2-ylmethylsulfanyl) -1H-pyrazol-3-yl] -1H-benzoimidazole; 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methoxy-1H-benzoimidazole hydrochloride; 5- methyl-2- (5-methylsulfani-4-propyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1 H -pyrazol-3-yl) -5-met "il-1 H-benzoimidazole; 2- (5-benzylsulfanyl-4-isopropyl-1) H-prazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-methylsulfanyl-4-methyl-1H-pyrazol-3-yl) -5-methoxy-1 H-benzoimidazole; 2- ( 5-methylsulfanyl-4-methyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 3- (5-clbro-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4 -amylamine: 3- (5,6-dichloro-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine; 5,6-dimethyl-2- (4-phenylM H -pyrazol-3-yl; ) -1 H-benzoimidazole; 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; acid isopropylamide 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid; (2- (5,6-D-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxy-etiI) -amide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid propylamide; (3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid tetrahydro-pyrano-4-yl) -amide; 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 2- (5-ethoxy-1 H -pyrazol-3-yl) -1H-benzoimidazole; (benzoimidazol-2-yl) -5-methylthio-3-pyrazole; 2- (5-isopropyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazoI; 2- (5-ethyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl] -1H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isobutyl-amide; 3- (5,6-dimethyI-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-phenyl-acetamide; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of ci-clopropanecarboxylic acid; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-yl] -amide of methoxyacetic acid; [3- (5,6-D-methyl-1H-benzoimidazoI-2-yl) -H-pyrazol-4-yl] -amide of ci-clopentanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -amide of trimethylacetic acid; [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -amide of urea-butylacetic acid; [3- (5,6-dimethyl-1H-benzoimidazoI-2-ii) -1H-pyrazol-4-yl] -amide of butanoic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of isoxazole-5-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanoic acid; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-Chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazolo-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (6-chloro-5-methoxy-1 H -benzoimidazol-2-y!) - 1 H -pyrazol-4-yl] -1, 1-dimethylurea; [3- (5-Methoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -amide of ci-clopropanecarboxylic acid; [3- (5-ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; N- [3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -isobutyramide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 3,5-dimethyl-isoxazole-4-carboxylic acid; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of furan-3-carboxylic acid; N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -4-methylene-benzamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-morpholin-4-yl-acetamide; 2-dimethylamino-N- [3- (5,6-dimethyl-1 H -benzo: midazol-2-yl) -1 H -pyrazI-4-yl] -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2- (1 H-1, 2,3,4-tetraazole-1) -yl) -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ii] -isonicotinamide; 2- cyclopropyl-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide; 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyl-urea; 1 - . 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea; 1-benzyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; [3- (5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] 4-me yl-piperazin-1-carboxylic acid amide; 1, 1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H -pyrazol-4-yl] urea; [3- (6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1H-benzimidazol-2-ii) -1H-pyrazol-4-yl] -amide tetrahydropyran-4-carboxylic acid; [3- (6-Ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] -morpholino-4-carboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-4-carboxylic acid amide; 3- [6-ethoxy-5-fluoro-1 H-benzimidazdl-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide of morfoin-4-carboxylic acid; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -1, 1-diethyl urea; [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide; [3- (6-Chloro-5-methoxy-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-Methoxy-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid; 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazol! -4-yl] -1, 1-dimethyl-urea; [3- (5-Etii-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (5-fluoro-6-methy [-1 H-benzoimidazol-2-y1) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 1-cyclopropyl-3- [3- (5-etl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea; 1 - [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; [3- (5-fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazl-4-yl] -amide of piperidino-1-carboxylic acid; 1 - [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -3-methyl-urea; [3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of morpholino-4-carboxylic acid; 4-Methyl-1-piperazine-1-carboxylic acid [3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide; 1-methyl-3- [3- (5-trifluoromethyl-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -urea; 1 - . 1 - . 1 - [3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-yl] -amide of 4-methyl-piperazine-1-carboxylic acid; 1-tert-butyl-3- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea; 4-methyl-piperazin-1-carboxylic acid 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; 1-Cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isobutyl-urea; 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea; 2- (1H-Indazoi-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; N- [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl] -isobutyramide; N- [3- (5,6-dimethy1-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-piperidn-1-yl-acetamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-morpholinoamide; N- (N'-methylpiperazino) 2- (1 H -indazol-3-yl) -1H-benzimidazoi-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; N- (isobutyl) 2- (1 H -indazol-3-yl) -1H-benzimidazole-5-carboxylic acid amide; N- (cyclohexylmethyl) 2- (1 H -indazoI-3-yl) -1H-benzimidazole-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide; 2- (1 H -ndazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl ester; 5,6-dimethyl-2- (1 H-indazoI-3-yl) -1 H-benzimidazole; 2- (1 H -ndazol-3-yl) -3H-benzyldazole-4-carboxylic acid; 2- (5-ethoxy-2H-pyrazol-3-yl) -1 H -benzimidazole-4-carboxylic acid; 5,6-Dimethyl-2- (5-methyI-2H-pyrazol-3-yl) -1 H-benzimidazole; 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1 H -benzimidazole; 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimetii-1 H-benzimidazole; 2- (5-etiI-2H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzimidazole; 2- (5-etiI-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1 H-benzimidazoI; 2- (5-etiI-2H-pyrazol-3-yl) -5-methoxy-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1 H-benzimidazole; and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Particularly preferred compounds of formula (Ixa) of the invention for the inhibition of SYK are: 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid benziamide, Example 1; 2- (1 H -indazol-3-yl) -1 H-benzimidazo I-5-carboxylic acid N-methylamide, Example 2; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide, Example 3; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide, Example 4; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide, Example 5; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide, Example 6 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) ) -1 H-benzoimidazole, (compound designated A9-B9), Example 230 (a); 6-chloro-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole, (compound designated A12-B9), Example 230 (b); 6-Chloro-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole, (compound designated A12-B10), Example 230 (c); 2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole, (compound designated A4-B9), Example 230 (d); 2- (5-cyclopropylmethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole, (compound designated A9-B11), Example 230 (e); 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole, (compound designated A9-B10), Example 230 (f); 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ah); 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid sopropylamide, Example 235 (ai); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide, Example 235 (ak); 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazo-4-carboxylic acid propylamide, Example 235 (al); 3- (5,6-Dimethyl-1 H -benzoimidazoI-2-yl) -1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide, Example 235 (a); 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid sopropylamide, Example 235 (ao); 3- (5-difluoromethoxy-1H-benzoamidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ap); 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazoyl-4-carboxylic acid sopropylamide, Example 235 (aq); 2- (5-isopropyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole, (compound designated A9-B83), Example 241 (b); 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid sopropylamide (compound designated A9-B106), Example 246 (g); (2-hydroxy-1,1-dimethyl-ethyl) -amide of 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid, (compound designated A9-B25), Example 246 (h); 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide, (compound designated A40-B106), Example 246 (i); 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide (compound designated A9-B105), Example 246 (j); 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid phenylmethyl-amide, (compound designated A17-B106), Example 246 (k); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246 (v); 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 246 (w); 3- (5,6'-dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethylidene, Example 246 (x); 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide, Example 246 (y); 2- (4-Isobutyricamino-1 H -pyrazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid benzylamide, Example 246 (aa); N- [3- (5,6-Dimeti! -1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide, (compound designated A9-B85), Example 248 (a); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide, (compound designated A9-B86), Example 248 (b ); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of N- [3- (5,6-dimethyl-1 H- benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-phenyl-acetamide, (compound designated A9-B36), Example 248 (c); cyclopropanecarboxylic, (compound designated A9-B89), Example 248 (d); [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazl-4-yl] -amide of methoxyacetic acid, (compound designated A9-B94), Example 248 (e); [3- (5,6-D-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of ci-clopentanecarboxylic acid, (compound designated A9-B87), Example 248 ( F); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of trimethylacetic acid, (compound designated A9-B88), Example 248 (g); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of urea-butylacetic acid, (compound designated A9-B90), Example 248 (h ); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of butanoic acid, (compound designated A9-B91), Example 248 (i); Isoxazole-5-carboxylic acid 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (compound designated A9-B96), Example 248 ( j); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanoic acid, (compound designated A9-B93), Example 248 (k); [3- (5-Ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide, (compound designated A55-B89), Example 248 (1 ); [3- (6-Chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid, Example 248 (m); 3- [3- (6-chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethylurea, Example 248 (n); [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of ci-clopropanecarboxylic acid, Example 248 (o); [3- (5-Ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (p); [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (q); [3- (5-trifluoromethoxy-1H-benzoimidazoi-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (r); [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (s); N- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -isobutyramide, Example 248 (t); [3- (5-Chloro-6-methyl-1H-benzoimidazoi-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (u); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 3,5-dimethyl-isoxazole-4-carboxylic acid, Example 248 (v) ); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide, Example 248 (w); [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of furan-3-carboxylic acid, Example 248 (x); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -4-methyl-benzamide, Example 248 (y); N- [3- (5,6-D -methyl-1 H -benzoimidazol-2-yl) -H-pyrazol-4-yl] -2-morpholin-4-yl-acetamide, (compound designated A9- B99), Example 253; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2- (1 H-1, 2,3,4-tetraazole-1- il) -acetamide, (compound designated A9-B97), Example 254 (a); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isonicotinamida; Example 254 (b); 2-Cyclopropyl-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; Example 254 (c); 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl-3-methyl-urea, (compound designated A9-B38), Example 255 (a); 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyl-urea, (compound designated A9-B103), Example 255 (b ); 1 - [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea, (compound designated A9-B40), Example 255 (c); 1-Benzyl-3- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea, (compound designated A9-B39), Example 255 (d); Cyclopropanecarboxylic acid [3- (5-ethoxy-6-ethyl-1H-benzoimidazoI-2-yl) -1H-pyrazolo-4-yl] -amide, Example 256 (a); 4-methyl-piperazine-1-carboxylic acid 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazol-4-yl] -amide , Example 256 (c); 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1H-pyrazol-4-yl] urea, Example 256 ( d); [3- (6-Ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid, Example 257 (a); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -hydroxy-4-carboxylic acid, Example 257 (b); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] morpholino-4-carboxylic acid amide, Example 257 (c); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] piperidino-4-carboxylic acid amide, Example 257 (d); 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea, Example 257 (e); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-methylmethyl] -amidocarbomethyl-4-carboxylic acid, Example 257 (g); 3- [3- (5-difluoromethoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazI-4-yl] -1,1 -diethi-urea, Example 257 (h); [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 257 (i); [3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 258 (a); [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid, Example 258 (b); [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid, Example 258 (c); [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid, Example 258 (d); 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea, Example 258 (e); [3- (5-etiI-6-methyl-1 H-benzoimidazoI-2-yl) -1 H -pyrazole-4-y [] - piperidino-1-carboxylic acid amide, Example 258 (f); 3- [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (g); [3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido morpholino-4-carboxylic acid, Example 258 (h); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid, Example 258 (n); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-p¡razol-4-yl] -amide of piperidino-1-carboxylic acid, Example 258 (o); 1-cyclopropyI-3- [3- (5-etiI-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (a); 1 - [3- (5-eti-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea, Example 260 (b); 4-Methyl-piperazine-1-carboxylic acid 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide, (c); [3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide, Example 260 (d); 1 - [3- (5-Fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazI-4-yl] -3-methyl-urea, Example 260 (e); [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid, Example 260 (f); 4-methyl-piperazine-1-carboxylic acid 3- (5-fluoro-6-methyl-1-H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide g); 1-methyl-3- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-yl] -urea, Example 260 (h); 1 - [3- (5-Chloro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea, Example 260 (i); [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of 4-methyl-piperazine-1-carboxylic acid, Example 260 (j); 1-tert-butyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (k); 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea, Example 260 (1); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazine-1-carboxylic acid, Example 260 (m); 1-cyclopropyl-3- [3- (5,6-d-methyI-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (n); 3- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H -pyrazI-4-yl] -1,1-diethylurea, Example 260 (o); 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isobutyl-urea, Example 260 (p); 1-cyclopropylmethyl-3- [3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (q); 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (r); 2- (1H-lndazol-3-yl) -1-hibenzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide, Example 246 (ab); 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide, Example 246 (aq); N- [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -2-piperidin-1-yl-acetamide, Example 253 (c); and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Especially preferred compounds of formula (Ixa), referred to as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of SYK are: cyclopropylamide of 3- (1, 5) acid , 6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazole-4-carboxylic acid, Example 235 (ah); 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ai); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide, Example 235 (ak); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazole-4-carboxylic acid propylamide, Example 235 (al); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide, Example 235 (am); 3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (ao); 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ap); 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide, Example 235 (aq); 3- (5,6-Dimethyl-1H-benzoamidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide (compound designated A9-B106), Example 246 (g); 3- (5,6-Dimeti-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide, (compound named A9-B25), Example 246 (h); 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide, (compound designated A40-B106), Example 246 (f); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H -pyrazole-4-carboxylic acid cyclopropylamide (compound designated A9-B105), Example 246 (j); 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide, (compound designated A17-B106), Example 246 (k); 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246 (v); 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid sopropylamide, Example 246 (w); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide, Example 246 (x); 3- (5,6-Dimethyl-1 H -benzoimidazoI-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide, Example 246 (y); 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide, Example 246 (aa); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide, (compound designated A9-B85), Example 248 (a); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide, (compound designated A9-B86), Example 248 (b ); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cycloalkanecarboxylic acid amide, (compound designated A9-B89), Example 248 (d ); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of methoxyacetic acid, (compound designated A9-B94), Example 248 (e); [3- (5,6-Dimethyl-1H-benzoamidazol-2-yl) -1H-pyrazolo-4-yl] -amide of cyclopentanecarboxylic acid, (compound designated A9-B87), Example 248 ( F); [3- (5,6-dimethyl-1H-benzoimidazo! -2-yl) -1H-pyrazol-4-yl] -amide of trimethylacetic acid, (compound designated A9-B88), Example 248 (g); [3- (5,6-Dimethyl-1H-benzoamidazol-2-N) -1H-pyrazol-4-yl] -amide of urea-butylacetic acid 3- (5,6-dimethyl-1H- benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -amide, (compound designated A9-B90), Example 248 (h); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of butanoic acid, (compound designated A9-B91), Example 248 (i); Isoxazole-5-carboxylic acid 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide (compound named A9-B96), Example 248 ( j); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanoic acid, (compound designated A9-B93 ), Example 248 (k); [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amidopropanecarboxylic acid amide, (compound designated A55-B89), Example 248 (1); [3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 248 (m); 3- [3- (6-chloro-5-methoxy-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethylurea, Example 248 (n); [3- (5-Methoxy-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -amidopropanecarboxylic acid amide, Example 248 (o); [3- (5-Ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cidopropanecarboxylic acid, Example 248 (p); [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-ii) -1H-pyrazolo-4-yl] -cyclopropanecarboxylic acid amide, Example 248 (); [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (s); N- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazI-4-yl] -isobutyramide, Example 248 (t); [3- (5-Chloro-6-methyl-1H-benzoimidazoi-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 248 (u); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 3,5-dimethyl-isoxazole-4-carboxylic acid, Example 248 (v); [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of furan-3-carboxylic acid, Example 248 (x); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-morpholin-4-yl-acetamide, (compound designated A9-B99), Example 253; N- [3- (5,6-dimethyl-H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2- (1 H-1, 2,3,4-tetraazol-1-yl) ) -acetamide, (compound designated A9-B97), Example 254 (a); N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isonicotinamide; Example 254 (b); 2-Cyclopropyl-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; Example 254 (c); 1 - [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea, (compound designated A9-B38), Example 255 (a ); 1 - . 1 - . 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyI-urea, (compound designated A9-B103), Example 255 (b ); 1 - [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea, (compound designated A9-B40), Example 255 (c ); 1-Benzyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, (compound designated A9-B39), Example 255 (d); [3- (5-Ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide, Example 256 (a); 4-methyl-piperazin-1-carboxylic acid 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H -pyrazl-4-yl] -amide , Example 256 (c); 1, 1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H -pyrazol-4-yl] urea, Example 256 (d); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide, Example 257 (a); [3- (6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] acid amide [3- (6-ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1 H -pyrazol-4-yl] -amide tetrahydropyraz-4-carboxylic acid, Example 257 (b); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amino-4-carboxylic acid amide, Example 257 (c); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] piperidino-4-carboxylic acid amide, Example 257 (d); 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea, Example 257 (e); 3- [3- (5-difluoromethoxy-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea, Example 257 (h); [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 257 (i); [3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid, Example 258 (a); [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid, Example 258 (b); [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-prazol-4-if] -amido morpholine-4-carboxylic acid, Example 258 (c); [3- (5-Methoxy-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid, Example 258 (d); 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazl-4-yl] -1,1-dimethyl-urea, Example 258 (e); [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-icarboxylic acid, Example 258 (f); 3- [3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (g); [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid, Example 258 (h); [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid, Example 258 (n); [3- (5,6-dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 258 (o); 1-cyc! Opropyl-3- [3- (5-etiI-6-methyI-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (a); 1 - [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea, Example 260 (b); [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazine-1-carboxylic acid, Example 260 (c); [3- (5-fluoro-6-methyl-1-H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 260 (d); 1- [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea, Example 260 (e); [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid, Example 260 (f); 1-methyl-3- [3- (5-trifluoromethyl-1H-benzoimidazoI-2-yl) -1 H-pyrrazol-4-yl] -urea, Example 260 (h); 1- [3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -3-methyl-urea, Example 260 (i); [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid, Example 2600); 1-tert-Butyl-3- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (k); 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea, Example 260 (1); [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazine-1-carboxylic acid, Example 260 (m); 1-cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (n); 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea, Example 260 (o); 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isobutyl-urea, Example 260 (p); 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (q); 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea, (compound designated A9-B142), Example 258 (r); and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The more especially preferred compounds of formula (Ixa) of the invention for the inhibition of SYK are: 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide , Example 235 (ai); 3- (1, 5,6,7-tetrahydro-, 3-diaza-s-indacen-2-yl) -1 H -pyrazole-4-carboxylic acid cyclopropylamide, Example 235 (ah); (tetrahydro-pyran-4-y!) - 3- (5,6-dimethyI-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid amide, Example 235 (a); 3- (5,6-dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide, Example 246 (v); [3- (5-Ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide, Example 256 (a); 1, 1-dimethyI-3- [3- (1,5,6,7-tetrahydro-s-indacen-2-yl) -1H-pyrazol-4-yl] urea, Example 256 (d); [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] piperidino-4-carboxylic acid, Example 257 (d); 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H-pyrazol-4-yl] -1,1-diethylurea, Example 257 (e); 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea, Example 257 (h); [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 257 (¡); [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid, Example 258 (b); [3- (5-Methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 258 (d); [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 258 (f); [3- (5,6-dimethy1-1H-benzoimidazoI-2-yl) -1H-pyrrazol-4-yl] -amide of piperidino-1-carboxylic acid, Example 258 (o); 1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea, Example 260 (a); [3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide, Example 260 (d); 1-tert-butyl-3- [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (k); 1-cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (n); 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-diethylurea, Example 260 (o); 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea, Example 260 (q); 3- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea, Example 258 (r); and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The preferred compounds of formula (Ixb) of the invention for the inhibition of SYK are: 3- (1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenyl-methanone; 2- (1 H-indazol-3-yl) -3H-benzoimidazol-4-ol; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -3H-imidazo [4,5-c] pyridine; 2- (1 H-indazoi-3-yl) -3H-imidazo [4,5-b] pyridine; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-fluoro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-fluoro-1 H-indazole; 3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-methoxy-1 H-indazole; 3- (5-ethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-isopropyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-bromo-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (3-cyano) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (6-methyl-5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (2-fluoro) phenyl-1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (5- (5,6-methylenedioxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (2-methoxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (4-chloro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (4-metii) pheni! -1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-benzyloxy-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-methylenedioxy-1 H -benzoimidazoI-2-yl) -1 H-indazole; 3- (5,6-dimethoxy-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-diethyl-1 H-benzoimidazol-2-yl) -1 H-indázol; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carbonitrile; 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H -indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-ethoxy-1 H-indazole; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1 H -indazole; 3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carbonitrile; 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H -indazole-5-carbonitrile; '3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4-fluoro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-chloro-1 H-indazole; 3- (5-n-propyI-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-sulfonic acid benzylamide; 3- (5-methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -phenyl-methanol; [2- (Ndazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid methylamide; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid dimethylamide; [2- (indazol-3-yl) -1H-benzoimidazoI-5-yl] - isopropylamide [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid benzylamide; [2- (indazol-3-yl) -1H-benzoimidazol-5-ii] -carboxylic acid benzamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methy-benzylamide; 4- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide; 2- (1 H -indazo! -3-yl) -1 H -benzoimidazo I-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide; (2- (1-H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-cyano-etiI) -amide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; 2- (1 H-lndazol-3-ii) -1 H-benzoimidazole-5-carboxylic acid (3-imidazol-1-l-propyI) -amide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole-5-carboxylic acid dimethylamide; [2- (Ndazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid amide dihydrochloride; and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Particularly preferred compounds of formula (Ixb), referred to as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of SYK are: 3- (1 H-benzoimidazole-2) -yl) -1 H-indazole, (compound designated A1-B63), Example 234 (a); 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A6-B63), Example 234 (b); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound denominated A9-B63), Example 234 (f); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methoxy-1 H-indazole, (compound designated A9-B68), Example 235 (b); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-fluoro-1 H-indazole, (compound designated A9-B70), Example 235 (d); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -6-fluoro-1 H-indazole, (compound designated A9-B71), Example 235 (e); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-1 H-indazole, (compound designated A9-B64), Example 235 (f); 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-methoxy-1 H-indazole, (compound designated A9-B69), Example 235 (g); 3- (5-ethyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A27-B63), Example 235 (i); 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-iI) -1 H-indazole, (compound designated A55-B63), Example 2350); 3- (5-isopropyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A54-B63), Example 235 (k); 3- (5-bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H -indazole, (compound of-nominated A58-B63), Example 235 (1); 3- (5-Bromo-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A32-B63), Example 235 (m); 3- (5- (3-cyano) phenyl-1 H-benzoimidazol-2-yl) -1 H -indazole, (compound designated A58-B63), Example 235 (n); 3- (5- (pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H -indazole, (compound designated A69-B63), Example 235 (o); 3- (6-methyl-5-phenyl-1 H-benzoimidazol-2-yl) -1 H -indazole, (compound designated A57-B63), Example 235 (p); 3- (5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A60-B63), Example 235 (q); 3- (5- (2-fluoro) phenyl-1 H-benzoimidazol-2-yl) -1 H -indazole, (compound designated A65-B63), Example 235 (r); 3- (5- (3,4-methylenedioxy) phenyl-1 H-benzoimidazol-2-yl) -1 H -indazole, (compound designated A66-B63), Example 235 (s); 3- (5-benzyloxy-1 H-benzoimidazol-2-yl) -1 H -ndazole, (compound designated A74-B63), Example 235 (w); 3- (5,6-methylenedioxy-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A22-B63), Example 235 (x); 3- (5,6-dimethoxy-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A23-B63), Example 235 (y); 3- (5,6-diethyl-1 H-benzoimidazoi-2-yl) -1 H-indazole, (compound designated A56-B63), Example 235 (z); 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carbonitrile, (compound designated A33-B63), Example 235 (ab); 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A35-B63), Example 235 (aq); 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-ethoxy-1H-indazole, (compound designated A9-B63), (compound designated A9-B112), Example 235 (ad); 3- [5- (2-morpholin-4-yl-ethoxy) -1 H -benzoimidazol-2-yl] -1 H -indazole, Example 235 (aj); 3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile, Example 235 (an); 3- (5,6-DimetiI-1 H-benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile, Example 235 (ar); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -4-fluoro-1 H-indazole, (compound designated A9-B110), Example 242 (a); 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-chloro-1 H-indazole, (compound designated A9-B109), Example 242 (c); , 3- (5-n-propyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A28-B63), Example 244 (a); 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-sulfonic acid benzylamide, Example 244 (b); 3- (5-methanesulfonyl-1H-benzoimidazol-2-yl) '- 1 H-indazole; Example 244 (c) [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -phenyl-methanol, (compound designated A34-B63), Example 245; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid, ethylamide, (compound designated A36-B63), Example 246 (a); [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid methylamide, (compound designated A15-B63), Example 246 (b); [2- (ndazoI-3-yl) -1H-benzoimidazoI-5-yl] -carboxylic acid isopropylamide, (compound designated A16-B63), Example 246 (d); [2- (ndazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid benzylamide, (compound designated A17-B63), Example 246 (e); [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid benzamide acid benzamide, (compound designated A52-B63), Example 246 (f); 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide (pyridin-3-ylmethyl) -amide, Example 246 (m); 3- 2- (1 H -indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid methylbenzyl amide, Example 246 (n); 4- 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl-benzylamide, Example 246 (o); 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide, Example 246 (p); 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide, Example 246 (q); 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide, Example 246 (r); (2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-cyano-etiI) -amide, Example 246 (s); 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide, Example 246 (t); 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide, example 246 (u), 3- (dimethylamide 5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid, Example 246 (x); [2- (Ndazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid, (compound designated A14-B63), Example 247 (a); 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole-5-carboxylic acid amide dihydrochloride, Example 262; and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Especially preferred compounds of formula (Ixb) of the invention for the inhibition of SYK are: 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methoxy-1 H-indazole, (compound designated A9-B68), Example 235 (b); 3- (5-ethyl-6-methyl-1 H-benzoimidazoI-2-it) -1 H-indazole, (compound designated A55-B63), Example 235Q); 3- (5,6-diethyl-1H-benzoimidazol-2-yl) ^ 1 H-indazole, (compound designated A56-B63), Example 235 (z); 3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1 H-indazoy-5-carboxylic acid dimethylamide, Example 246 (x); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The preferred compounds of formula (Ixc) of the invention for the inhibition of SYK are: 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-indazole; 5,6-DimetiI-2- (1, 4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1 H -benzoimidazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,5,6,7,8-hexahydro-cycloheptapyrazole; and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Particularly preferred compounds of formula (Ixc), designated as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of SYK are: 3- (5,6 -dimethyl-1 H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-indazole, (compound designated A9-B59), Example 241 (a); 5,6-dimethyl-2- (1, 4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1-hibenzoimidazole, (compound designated A9-B56), Example 241 (d); and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Preferred compounds of formula (Ixd) of the invention for the inhibition of SYK are: 3- (5,6-dimethyl-1 H-benzoimidazole-2-yl) -1,4,6,7-tetrahydro- isopropylamide pyrazolo [4,3-c] pyridino-5-carboxylic acid; cyclopropyl- [3- (5,6-dimethyl-hi-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; isopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -ethanone; 1 - . 1 - [3- (5,6-Di-methyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-ii] -2- methyl-propan-1 -one; 3- (5,6-Dimetyl! -1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridinium-5-carboxylic acid methyl ester; 3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -3- methi-butan-1-one; 1 - [3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazoo [4,3-c] pyridin-5-yl] -2.2 -dimethyl-propan-1-one; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid methyl ester; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl -metanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1-yl -metanone; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4-yl- methanone; 3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -l ^ .e.y-tetrahydro-pyrazolo ^. S-cJp'iridino-S-carboxylic acid diethylamide; 3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 1 - [3- (5,6-Dimeti! -1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazoo [4,3-c] pyridin-5-yl] -2, 2-dimethyl-propan-1-one; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5- (propane-2-sulfonyl) -4,5,6,7-tetrahydro-1 Hp-arazoo [4,3- c] pyridine; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Particularly preferred compounds of formula (Ixd), referred to as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of SYK are: 3- (5,6-isopropylamide) -Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid, (compound designated A9-B 21), Example 250 (a ); CyclopropyI- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone, ( compound named A9-B122); isopropyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrrazolo [4,3-c] pyridin-5-yl ] -metanone; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2.2 -dimethyl-propan-1-one; 3- (5,6-Dimethyl-1H-benzoimidazol-2-ii) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester; 3- (5,6-dimethyl-1H-benzoimidazoI-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide; 26 (e) prepared diethylamide of 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyro D-N-5-carboxylic acid; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin- 1-l-methanone; [3- (5,6-D -methyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin -1-yl-methanone; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morfoin -4-yl-methanone; 3- (5-chloro-6-methyl-1H-benzoimidazoI-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 3- [5- (2-morfoyl-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-tetrahjdro-pyrazolo [4,3-c] pyridin-5-diethylamide -carboxylic; 3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 3- (5,6-dimethyl-H-benzoimidazol-2-yl) -, 4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide, (compound designated A9-B119 ); 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-p¡razolo [4,3-c] pyridin-5-yl] -2 -methyl-propan-1-one, (compound designated A9-B117); 3- (5,6-Dimethyl-1H-benzoimidazole-2-ii) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester (compound named A9-B120); 1- [3- (5,6-Dimetii-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-p¡razolo [4,3-c] pyridin-5-yl] -3-methyl-butan-1-one, (compound designated A9-B118); 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2.2 -dimethyl-propan-1-one, (compound designated A9-B123); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Especially preferred compounds of formula (Ixd), designated as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of SYK are: 3- (5,6-dimethyl-1 H -benzoimidazol-2-iI) -1,4,6,7-tetrahydro-pyrazolo [3- (5,6-dimethyl-1H-isopropylamide]] 4,3-c] pyridine-5-carboxylic acid, (compound designated A9-B121), Example 250 (a); Cyclopropyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone, ( compound named A9-B122); Example 250 (b); 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-cjpyridino-5-carboxylic acid isopropylamide, Example 255 (e ); prepared 3- (5,6-dimethyI-1H-benzoimidazol-2-yl) -1 ^ .ej-tetrahydro-pyrazolo ^. S-cjpyridine-S-carboxylic acid diethylamide, Example 258 (i); [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyridinidin-1-yl -metanone, Example 2580); [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1,4,6,7-tetrahydro-pyrazoo [4,3-cjpyridin-5-ylj-piperidin-1-yl-methanone] Example 258 (k); 3- (5-chloro-6-methyl-1H-benzoimidazoI-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide, Example 258 ( m); 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide (compound named A9- B119); and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The particular compounds of formula (Ix) of the invention for the inhibition of KDR are: 2- (1 H-indazol-3-yl) -1 H -benzimidazo I-5-carboxylic acid benzylamide; N-methylamide of 2- (1H-indazol-3-iI) -1 H-benzimidazole-5- acid carboxylic; 2- (1H-IndazoI-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide; 2- (1 H-indazql-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (1 H -ndazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenethylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-morpholinoamide; N- (N'-methylpiperazino) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid amide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; N- (isobutyl) 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid amide; N- (2-, 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid cyclohexyl) amide; N- (2-furfuriI) 2- (1 H -indazol-3-yl) -1H-benzimidazole-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl ester; 5,6-dimethyl-2- (1 H -indazol-3-yl) -1 H-benzimidazole; 5-methoxy-2- (1 H-indazoI-3-yl) -1 H -benzimidazole; 2- (1 H-indazol-3-yl) -3H-benzimidazo I-4-carboxylic acid; 5-bromo 2- (1 H-indazol-3-yl) -3H-benzimidazole; 2- (5-ethoxy-2H-pyrazolo-3-yl) -1H-benzimidazole-4-carboxylic acid; 5,6-dimethyl-2- (5-methyI-2H-pyrazol-3-yl) -1 H -benzimidazole; 5,6-DimetiI-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazo I; 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1 H-benzimidazo I; 2- (5-etiI-2H-pyrazol-3-yl) -5-methoxy-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1 H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1 H-benzimidazole; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-ethoxy-propii) -amide; 2- (1H-IndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid-4-methanesulfonyl-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (naphthalene-l-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl) -amide; . 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-parboxylic acid 4-dimethylamino-benzylamide; 4- ( { [2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carbonyl] -amino} -methyl) -piperidino-1-tert-butyl ester carboxylic; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; (2- (1H-indazol-3-yl) -1H-benzoimidazoi-5-carboxylic acid (pyridin-3-ylmethi) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylamide; (2- (1 H-indazoI-3-yl) -1H-benzoimidazo I-5-carboxylic acid benzo [1,3] dioxol-5-ymethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (1,3-dimethyl-1 H-pyrazol-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 3- (1 H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1H-IndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (1-methyl-1 H -pyrazol-4-ylmethyl) -amide; 4- 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid isopropyI-benzamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-2-ylmethyl) -amide; [3- (3-acetylamino-phenoxy) -propyl] -amide of 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; (2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid ([2,2] -thiiophenyl-5-ylmethyl) -amide; (2,3-Dihydro-benzofuran-5-ylmethyl) -amide of 2- (1 H -indazol-3-yl) -1 H -benzoimidazo I-5-carboxylic acid; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid 4-cyano-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (5-chloro-benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methylsuiphanyl-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid (tetrahydro-pyrano-4-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzo [1] 4] dioxin-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid nitro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (thiophen-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide; 2- (1 H -indazo! -3-yl) -1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-benzoimidazol-2-ylmethyl) -amide; 3- (1H-indazol-3-yl) -1H-benzoamidazole-5-carboxylic acid methyl-benzylamide; 3- 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid chloro-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-sulfamoyl-benzylamide; 2- (1 H -ndazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (3-ethoxy-propyl) -amide; 4- (1H-indazoI-3-yl) -3H-benzoimidazole-4-carboxylic acid bromo-benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (naphthalene-l-ylmethyl) -amide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid thiophen-2-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-dimethylaminobenzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazo [4-carboxylic acid; 4-nitro-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H -indadazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3-bromo-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3-methoxy-benzylamide; 2- (1H-IndazoI-3-yl) -3H-benzoimidazole-4-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-phenoxy-benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazo I-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; 2- (1H-indazol-3-ii) -3H-benzoimidazole-4-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid trifluoromethyl-benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; (furan-3-ylmethyl) 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid amide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid nitro-benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide; 3- 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid chloro-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid phenylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid phenethyl-amide; 3- (6-phenyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (2,4-dichloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-naphthalen-1-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (4-fluoro-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-chloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-methoxy-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; - [6- (3-chloro-4-fluoro-phenyl) -1H-benzoimidazol-2-yl] -2H-indazoI; - [6- (3,5-dichloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; - (6-thiantren-1 H-benzoimidazol-2-yl) -2H-indazoI; - (6-biphenyl-4-yl-1H-benzoimidazol-2-yl) -2H-indazoi; - (6-p-tolyl-1 H-benzoimidazol-2-yl) -2H-indazoi; - (6-m-tolyl-1H-benzoimidazol-2-y!) - 2H-indazole; - (6-o-tolyl-1H-benzoimidazol-2-yl) -2H-indazole; - (6-thiophen-3-yl-1H-benzoimidazol-2-yl) -2H-indazoI; - [6- (3-trifluoromethyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; - [6- (4-trifluoromethyl-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; - [6- (3-chloro-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; - [6- (3-methoxy-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; - [6- (3,5-dimethyl-phenyl) -1H-benzoimidazol-2-ylJ-2H-indazole; - [6- (3,4-dimethyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; - (6-benzo [1,3] dioxol-5-yl-1H-benzoimidazoI-2-yl) -2H-indazoI; - [6- (4-tert-butyl! -phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; - (6-hex-1-enyI-1H-benzoimidazol-2-yl) -2H-indazole; - [6- (3,4-dimethoxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; - [2- (2H-indazol-3-yl) -3H-benzoimidazo! -5-yl] -phenol; - [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenol; - [6- (3,4-dic! Gold-phenyl) -1 H -benzoirr (idazoI-2-yl] -2H-indazole; - [6- (4-trifluoromethoxy-phenyl) -1 H -benzoimidazole-2 -yl] -2H-indazoI; - { 4- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenyl} -ethanone; 3- (6-benzo [b] thiophen-2-yl-1H-benzoimidazoi-2-yl.} -2H-indazole; 3- [6- (3,4,5-trimethoxy-phenyl) -1 H- benzolamdazol-2-yl] -2H-indazoI; 1-. {5- [2- (2 H -indazol-3-yl) -3 H -benzoimidazol-5-yl] -thiophen-2-yl il.} - ethanone; 1- {3- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenyl} -ethanone; 3- [6- (4 -benzyloxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (2-fIuoro-biphenyl-4-ii) -1 H -benzoimidazol-2-yl] -2H -indazole; 3- (6-benzo [b] thiophen-3-yl-1H-benzoimidazol-2-yl) -2 H -ndazole; .3- [2- (2H-indazol-3-yl) - 3 H -benzoimidazol-5-yl] -phenyl.} - methane I, 3- [6- (4-ethylsulfanii-phenyl) -1 H -benzoimidazol-2-yl] -2 H -ndazole; - [6- (2,4-difluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazoi; 3- [6- (3-trifluoromethoxy-phenyI) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-fIuoro-2-methyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazoI; 3- { 6- [2- (4- fIuoro-phenyl] -vinyl] -1H-benzoimidazol-2-yl.} -2H-indazole; 3- {6- [2- (4-chloro-phenyl) -vinyl] -1H -benzoimidazol-2-yl.} -2H-indazole; 3- {4- [2- (2H-indazole)} l-3-ii) -3H-benzoimidazol-5-yl] -phenyl} -propionic; . { 4- [2- (2 H -ndazol-3-yl) -3 H -benzoimidazol-5-yl] -phenyl} -methanol; 3- (6-furan-2-yl-1 H-benzoimidazol-2-yl) -2H-indazoI; 3- [6- (3-benzyloxy-phenyl) -1 H -benzoimidazol-2-yl] -2 H -ndazole; 3- [6- (4-isopropyl-phen] [- 1 H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-methanesulfonyl-phenyl) -1 H -benzoimidazol-2-yl] -2 H -ndazole; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (t6trah! dro-pyrano-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-acetylaminobenzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazo! -5-carboxylic acid isopropylamide; [2- (1 H-indazol-3-yl) -1 H -benzoimidazo [-5-yl] -morfoin-4-yl-methanone; [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl] - (4-methyl-piperazin-1-yl) -methanone; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid benzyl-methyl-amide; 3- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid nitrobenzamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid bromo-2-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxy (4-bromo-2-fluoro-benzylamide of 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid, 2- (1 H-indazoI-3-yl) -1 H-benzoimidazoi-5-carboxylic acid 3,4,5-trifluoro-benzylamide; 2- (1 H -indazoI-3-yl) -1 H -benzoimidazole-5-carboxylic acid (4'-chloro-biphenyl-4-ylmethyl) -amide; (S'-S'-dichloro-biphenyl-methyl-2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid amide: (4'-fluoro-biphenyl-4-ylmethyl) ) 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid amide: 2- (1 H-indazol-3-yl) -1-f! uoro-benzylamide H-benzoimidazole-5-carboxylic acid, 2- (1 H-indazol-3-yl) -1 H- 'benzoimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide; 2,4-dichloro- 2- (1 H-indazol-3-yl) -1 H-benzoimidazo I-5-carboxylic acid benzylamide; 2- (1 H-indazo! -3-yl) -1 H-benzoim acid 4-chloro-benzylamide 4-dazole-5-carboxylic acid: 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid: chloro-2-methyl-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2'-chloro-biphenii-4-ylmethyl) -amide. 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -amide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carbopylic acid (3-imidazol-1-yl-propyl) -amide; 4- [2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carbonyl!] -piperazine-1-carboxylic acid tert -butyl ester; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-cyclo-6-methyl-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide; 2- [5- (benzyloxy) -2H-pyrazol-3-ii] -1H-benzoimidazole; 2- [5- (3-phenyl-allyloxy) 2 H -pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (2-methyl-allyloxy) 2 H-pyrrazol-3-yl] -1H-benzoimidazole; 2- [5- (3J-dimethyl-octa-2,6-dienyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (3-bromo-benzyloxy) -2H-pyrazol-3-ii] -1 H-benzoimidazole; 3- [5- (1 H -benzoimidazol-2-yl) -1H-pyrazol-3-yloxymethyl] -benzonitrile; 2- [5- (4-yl-Ivoromethyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (3,4-dichloro-benzyloxy) -2 H-pyrrazol-3-yl] -1H-benzoimidazole; 2- [5-pentafluorophenylmethoxy] -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (4-ferc-butyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (2-benzenesulfonylmethyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 4- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxymethyl] -benzonitin; 2- [5- (biphenyl-4-ylmethoxy) -2 H-pyrrazol-3-yl] -1 H -benzoimidazole; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-ylco acid 2,3-dichioro-benzenesulfonic acid ester; 2- [5- (2-morpholin-4-yl-ethoxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (2-piperidin-1-yl-ethoxy) -2 H -pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (3-methoxy-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1-p-tolyl-ethanone; 1- [5- (1 H -benzoimidazol-2-yl) -1H-pyrazol-3-ylox-3,3,4,4,4-pentafluoro-butan-2-one; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1-biphenyl-4-yl-ethanone; 1 - [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -butan-2-one; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1- (4-dimethylamino-phenyl) -ethanone; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1- (3-phenyl-isoxazol-5-yl) -ethanone; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -N-phenyl-acetamide; 1- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -3,3-dimethyl-2-butan-2-one; 1 -adamantan-1 -yl-2- [5- (1 H-benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -ethanone; 2- [5- (1 H -benzoimidazoI-2-yl) -1 H -pyrazol-3-yloxy] -1-naphthalene-2-yl-ethanone; 4- . { 2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -acetyl} -benzonitrile; 6- { 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -acetyl} -3,4-dihydro-1 H-quinolin-2-one; 2- [5- (1 H -benzoimidazole-2-y!) -1 H-pyrazol! -3-yloxy] -1 - (4-trifluoromethoxy-phenyl) -ethanone; 5- . { 2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -acetyl} -2-chloro-benzenesulfonamide; 2- [5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yloxy] -1- (4-methoxy-phenyl) -ethanone; 2- [5- (1 H-benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1-cyclopropyl-ethanone; 5- (1H-benzoimidazol-2-yl) -1H-p -razol-3-yl ester of isonicotinic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of 2,2-dimethyl-propionic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazoyl-3-yl ester of benzyloxy-acetic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazolo-3-yl ester of 4-methoxy-benzoic acid; 5- (1 H-benzoimidazol-2-yl) -1 H-pyrazoyl-3-yl ester of phenyl-acetic acid; 5- (1H-benzoimidazoI-2-yl) -1H-pyrazol-3-yl ester of 2,3,4,5,6-petaphluoro-benzoic acid; 5- (1H-benzoimidazoI-2-yl) -1H-pyrazole-3-yl ester of cyclopropane carboxylic acid; 2- (1 H-benzoimidazol-2-yl) -1 H-pyrazol-3-yl ester of 2,2,3,3,4,4,4-heptafluoro-butyric acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of cyclopentane carboxylic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of 3-phenyl-propionic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazolo-3-yl ester of biphenyl-4-carboxylic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of 3,5-bis-trifluoromethyl-benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of 4-trifluoromethyl-benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of thiophene-2-carboxylic acid; and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Preferred compounds of formula (Ixa), named as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of KDR are: 2- (5-ethyl-2H-pyrazole -3-yl) -5,6-dimethyl-1H-benzimidazole, (compound designated A9-B3); 2- (5-methyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole (compound designated A9-B2); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The preferred compounds of formula (Ixb), referred to as the product of the combination of group A1 in Table 1 and B1 in Table 2, of the invention for the inhibition of KDR are: 2- (1 H-indazo! -3-yl) -1 H-benzimidazole-5-carboxylic acid benzylamide, (compound designated A17-B63); 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-methylamide (compound designated A15-B63); 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide, (compound designated A36-B63); 2- (1 H-ndazo! -3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide, (compound designated A37-B63); N-phenylamide of 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid, (compound designated A52-B63); 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide, (compound designated A51-B63); N-morpholinoamide of 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid, (compound designated A92-B63); N- (N'-methylpiperazino) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide, (compound designated A93-B63); N-pyrrolidinoamide of 2- (1 H -indazol-3-ii) -1 H-benzimidazole-5-carboxylic acid, (compound designated A91-B63); N- (isobutyl) 2- (1 H -ndazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide, (compound designated A82-B63); N- (cyclohexylmethyl) 2- (1H-indazoI-3-yl) -1H-benzimidazole-5-carboxylic acid amide, (compound designated A83-B63); ? N- (2-furfuryl) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide, (compound designated A84-B63); N-benzyl-N-methylamide of 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid, (compound designated A90-B63); 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 2- (1 H -ndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-methanesulfonyl-benzylidene; (2- (1 H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (naphthalene-1-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1 H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-dimethylamino-benzylamide; 4- ( { [2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carbonyl] -amino} -methyl) -piperidino-1-carboxylic acid tert-butyl ester co; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-nitrobenzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylamide; (2- (1H-indazol-3-yl) -1-hibenzoimidazole-5-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (1,3-dimethyl-1H-pyrazol-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-methyl-thiophen-2-methyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 3- (1 H-ndazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (1-metii-1 H -pyrazl-4-ylmethyl) -amide; 4- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid isopropyl-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethi) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid [3- (3-acetylamino-phenoxy) -propyl] -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [2,2 '] -thiiophenyl-5-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-cyano-benzylamide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; (2- [1 H-indazol-3-yl] -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ymethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyrano-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzo [1,4] dioxin-2-ylmethyl) -amide; 2- (1H-indazoyl-3-yl) -1H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl) -amide; 2- 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid nitrobenzamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazo I-5-carboxylic acid thiophen-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-benzoimidazol-2-ylmethyl) -amide; 3- 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methylbenzylamide; 3- 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid chloro-benzylamide 3-cioro-benzylamide; 4- 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid sulfamoyl-bendlamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -3H-benzoimidazoI-4-carboxylic acid 3-methoxy-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2- (1 H-indazoI-3-yl) -3H-benzoimidazo I-4-carboxylic acid (furan-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid nitro-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid phenylamide; 3- [6- (4-fluoro-phenyl) -1H-benzoxydazol-2-yl] -2H-indazole; 3- [6- (4-methoxy-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-chloro-4-fluoro-phenyl] -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-m-tolyl-1H-benzoimidazol-2-yl) -2H-indazole; 3- (6-o-tolyl-1H-benzoimidazol-2-yl) -2H-indazole; 3- (6-thiophen-3-yl-1 H-benzoimidazol-2-yl) -2H-indazol; 3- [6- (3-chloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-methoxy-phenyl] -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (3,5-dimethyl-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-benzo [1,3] dioxol-5-i [-1 H-benzoimidazol-2-yl) -2 H -ndazole; 3- (6-hex-1-ene-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (3,4-dimethoxy-phenyl) -1H-benzoin-idol-2-yl] -2H-indazole; 3- [2- (2 H -ndazol-3-yl) -3H-benzoimidazol-5-yl] -phenol; 4- [2- (2H-indazoi-3-yl) -3H-benzoimidazol-5-yl] -phenoI; 3- [6- (3,4,5-trimethoxy-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 1-. { 5- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -thiophen-2-yl} -etanone; . { 3- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenyl} -methanol; 3- [6- (2,4-d.fluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-fluoro-2-methyl-phenyl) -1H-benzoimidazol-2-ü] -2H-indazole; . { 4- [2- (2H-indazol-3-yl) -3H-benzoimidazo! -5-yl] -phenyl} -methanol; 3- (6-furan-2-yl-1H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (4-isopropyl-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid tetrahydro-pyrano-4-ylmethyl) -amide; 4- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid acetylamino-benzamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid isopropylamide; [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl] -morpholin-4-yl-methanone; [2- (1 H-indazol-3-yl) -1 H -benzoimidazo! -5-yl] - (4-methyl-piperazin-1-yl) -methanone; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzyl-methyl acid amide; 3- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid nitro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 2,6-difiuoro-benzylamide of 2- (1H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid bromo-2-fluoro-benzylamide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3,4-difluoro-benzylamide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,6-d, fluoro-3-methyl-benzylamide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichioro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-cyclobenzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-fluoro-benzylamide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide; 4- [2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) amide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazo I-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-fiuoro-4-chloro-6-methyl-benzyl) amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide; 2- [5- (benzyloxy) -2H-pyrazol-3-yl] -1 H-benzoimidazole; 2- [5- (3-phenyl-allyloxy) 2 H -pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (3,7-dimethyl-octa-2,6-dienyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (3-bromo-benzyloxy) -2H-pyrazol-3-ii] -1H-benzoimidazole; 2- [5- (3,4-dichloro-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (2-benzenesulfonylmethyl-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (biphenyl-4-ylmethoxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (3-methoxy-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of isonicotinic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of 3-phenyl-propionic acid; 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl ester; 5-methoxy-2- (1 H -indazol-3-yl) -1 H-benzimidazole; 5-bromo 2- (1 H-indazoI-3-yl) -3H-benzimidazole, (compound designated A32-B63); and the corresponding N-oxides, and their prodrugs; and pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. Particularly preferred compounds of formula (Ixb) of the invention for the inhibition of KDR are: 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (cyclohexylmethyl) amide; 2- (1 H-indazoI-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazo I-5-carboxylic acid 4-bromo-benzyamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazo I-5-carboxylic acid 4-methanesulfonyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methylbenzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methylsulfanyl-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 3- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl-benzamide; 3- 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid chloro-benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazo I-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid bromo-2-fluoro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 4-cyclo-benzylamide of 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) acid amide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) acid amide; 2- (1 H -indazol-3-N) -1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-fiuoro-4-chloro-6-methyl-benzyl) amide; 2- (1 H -indazoyl-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide; and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The particular compounds of formula (Ix) of the invention for the inhibition of ITK are: 2- (1H-lndazol-3-yl) -1H-benzoimidazoI- (2-piperidin-1-yl-ethyl) -amide. 5-carboxylic acid, Example 246 (ab); (2- (1 H-lndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide, Example 246 (aq); [3- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide, Example 246 (ad); N- [2- (1 H-lndazol-3-yl) -1 H -benzoimidazol-5-yl] -isobutyramide, Example 246 (ae) N- [3- (5,6-Dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazolo-4-yl] -2-piperidin-1-yl-acetamide, Example 253 (c) and the corresponding N-oxides, and their prodrugs; and the pharmaceutically acceptable salts and solvates (e.g., hydrates) of these compounds and their N-oxides and prodrugs. The compounds of formula (Ix) of the invention exhibit a useful pharmacological activity and, consequently, are incorporated in pharmaceutical compositions and used in the treatment of patients suffering from certain medical disorders. The present invention thus provides, according to a further aspect, compounds of formula (Ix) of the invention and compositions containing compounds of formula (Ix) of the invention for use in therapy. The compounds of formula (Ix) within the scope of the present invention block the kinase catalytic activity according to assays described in the literature and in vitro procedures described below, and the results of the assays are believed to correlate by far-reaching activity. macological in humans and other mammals. Therefore, in a further embodiment, the present invention provides compounds of formula (Ix) of the invention and compositions containing compounds of formula (Ix) of the invention for use in the treatment of a patient suffering from or subject to which can be improved by the administration of protein kinase inhibitors (eg Syk, KDR, tie2 or ITK). For example, the compounds of formula (Ix) of the present invention are useful in the treatment of inflammatory diseases, for example, asthma, atopic dermatitis, inflammatory dermatoses (e.g., psoriasis, dermatitis herpetiformis, eczema, necrotizing and cutaneous vasculitis, bullous disease, acute and chronic urticaria); allergic rhinitis and allergic conjunctivitis; inflammation of the joints that includes arthritis, rheumatoid arthritis and other arthritic conditions such as rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and osteoarthritis. The compounds of formula (Ix) are also useful in the treatment of chronic obstructive pulmonary disease (COPD), respiratory distress syndrome in adults, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, disease peripheral vascular, cardiovascular disease, cutaneous and systemic anaphylaxis, endotexemia, sepsis, septic shock, endotoxic shock, gram-negative sepsis, diabetes, multiple sclerosis, restenoste, myocarditis, B-cell lymphomas, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft-versus-host disease and other rejection events associated with transplantation, reperfusion injury, Crohn's disease and ulcerative colitis, cancers and tumors (such as colo-rectal, prostate, breast, thyroid, colon and lungs), atherosclerosis, degenerative muscle diseases, obesity , congestive heart failure, Parkinson's disease, depression, schizophrenia, stroke, cranial trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, fibrotic diseases of the viscera and intestinal inflammation disease.
The products of the present patent application as SYK inhibitors can be used for the treatment of diseases chosen from the following: asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic lung obstruction disease, respiratory insufficiency syndrome in adults, silicosis, pulmonary sarcoidosis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis, acute and chronic urticaria, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram-negative sepsis negative, diabetes, multiple sclerosis, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft versus host disease, rejection in organ transplantation, reperfusion injury, Crohn's disease and ulcerative colitis. The products of the present patent application as KDR inhibitors can be used especially for the treatment or prevention of diseases chosen from the following group: cancers, especially cancer of the breast, colon, lung and prostate, atherosclerosis, degenerative muscle diseases, obesity, failure congestive heart disease, Parkinson's depression, schizophrenia, stroke, head trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, late-onset amyotrophic sclerosis, cachexia, osteoporosis and fibrotic visceral diseases. A special embodiment of the therapeutic methods of the present invention is the treatment of asthma.
Another special embodiment of the therapeutic methods of the present invention is the treatment of psoriasis. Another special embodiment of the therapeutic methods of the present invention is the treatment of inflammation of the joints. Another special embodiment of the therapeutic methods of the present invention is the treatment of intestinal inflammation disease. Another special embodiment of the therapeutic methods of the present invention is the treatment of cancers and tumors. According to a further feature of the invention, there is provided a method for the treatment of a human or animal patient suffering or being subjected to conditions that can be improved by the administration of a protein kinase inhibitor (eg Syk, KDR, tie2 or ITK) for example, states as described above, comprising administering to the patient an effective amount of a compound of the invention or a composition containing a compound of the invention. "Effective amount" is intended to describe an amount of compound of the present invention effective to inhibit the catalytic activity of a protein kinase such as Syk, KDR, tie2 or ITK and, thus, produce the desired therapeutic effect. References in the present specification to a treatment should be understood to include prophylactic therapy as well as the treatment of established states.
The present invention also includes within its scope pharmaceutical compositions comprising at least one of the compounds of formula (Ix) of the invention, as defined above, or a pharmaceutically acceptable salt or prodrug, in association, where appropriate, with a pharmaceutically acceptable carrier or excipient. The pharmaceutical compositions of the present invention for the treatment of disease states associated with KDR or tie2 may also contain, when appropriate, active ingredients of other antimitotic medicinal products, such as, in particular, those based on taxol, cis-platinum, agents of intercalation of DNA and the like. The compounds of formula (Ix) of the invention can be administered by any suitable means. In practice, the compounds of formula (Ix) of the present invention can generally be administered parenterally, locally by topical application to the skin and membranes., rectally, orally, by inhalation or by intravenous or intramuscular injection, especially by oral route. The compositions according to the invention can be prepared according to the usual methods, using one or more pharmaceutically acceptable adjuvants or excipients. The adjuvants comprise, among others, diluents, sterilized aqueous media and various non-toxic organic solvents. The compositions may be presented in the form of tablets, pills, granules, powders, aqueous solutions or suspensions, injectable solutions, elixirs or syrups, and may contain one or more specific agents. taken between the group comprising sweeteners, flavors, colorants or stabilizers in order to obtain pharmaceutically acceptable preparations. The choice of the vehicle and the content of the active substance in the vehicle are generally determined in accordance with the solubility and chemical properties of the active compound, the particular mode of administration and the provisions that are to be observed in pharmaceutical practice. For example, they can be used in the preparation of excipient tablets such as lactose, sodium citrate, calcium carbonate, dicalcium phosphate and disintegrating agents such as starch, alginic acids and certain complex silicates combined with lubricants such as magnesium stearate, lauryl sulfate sodium and talcum To prepare a capsule, it is advantageous to use high molecular weight lactose and polyethylene glycols. When aqueous suspensions are used, they may contain emulsifying agents or agents that facilitate the suspension. Diluents such as sucrose, ethanol, polyethylene glycol, propylene glycol, glycerol and chloroform or mixtures thereof can also be used. For parenteral administration, emulsions, suspensions or solutions of the products according to the invention are used in vegetable oil, for example, sesame oil, peanut oil or olive oil, in aqueous-organic solutions such as water and propylene glycol, organic esters in -jectable as ethyl oleate as well as sterile aqueous solutions and pharmaceutically acceptable salts. The solutions of the salts of the products according to the invention are especially useful for administration by intramuscular or subcutaneous injection. Aqueous solutions, which they also comprise solutions of the salts in pure distilled water, they can be used for intravenous administration with the condition that their pH is suitably adjusted, that they are suitably buffered and made isotonic with a sufficient amount of glucose or sodium chloride and that they are sterilized by heating, irradiation or microfiltration. For topical administration, gels (based on water or alcohol), creams or ointments containing compounds of formula (Ix) of the invention can be used. The compounds of formula (ix of the invention can be incorporated in a gel or matrix base to be applied in a patch, which would allow controlled release of the compound through the transdermal barrier. For administration by inhalation, the compounds of Formula (Ix) of the invention can be dissolved or suspended in a vehicle suitable for use in a nebulizer and a suspension aerosol or solution, which can be absorbed or adsorbed in a solid carrier suitable for use in a dry powder inhaler Solid compositions for rectal administration include suppositories formulated according to known methods and containing at least one compound of the invention The percentage of active ingredient in the compositions of the invention can be varied, it being necessary that is a proportion such that an adequate dosage is obtained Obviously, they can be administered Various dosage unit forms approximately Same time. The dose employed will be determined by the physician, and depends on the desired therapeutic effect, the route of administration and the duration of the treatment and the condition of the patient. In the adult, the doses are generally from about 0.001 to about 50, preferably from about 0.001 to about 5 mg / kg of body weight per day per inhalation, from about 0.01 to about 100, preferably 0.1 to 70. , more especially 0.5 to 10 mg / kg of body weight per day per oral administration and from about 0.001 to about 10, preferably 0.01 to 1 mg / kg of body weight per day by intravenous administration. In each particular case, the doses will be determined according to the distinguishing factors of the subject that will be treated as age, weight, general state of health and other characteristics that may have an influence on the efficacy of the medicinal product. The compounds of formula (Ix) according to the invention can be administered as frequently as necessary in order to obtain the desired therapeutic effect. Some patients may respond quickly to a higher or lower dose and may find adequate maintenance doses much weaker. For other patients, it may be necessary to have long-term treatments at a ratio of 1 to 4 doses per day, according to the physiological requirements of each particular patient. Generally, the active product can be administered orally one to four times per day. Naturally, for some patients, it will be necessary to prescribe more than one or two doses per day.
The compounds of formula (Ix) of the invention can be prepared by the application or adaptation of known methods, by which are meant methods used hitherto or described in the literature, for example, those described by RCLarock in Comprehensive Organiza- nic Transformations, VCH publishers, 1989. In the reactions described below, it may be necessary to protect reactive functional groups, for example, hydroxy, amino, imino, unclean or carboxy groups, when these are desired in the final product, to avoid their unwanted participation in the reactions. Conventional protecting groups may be used in accordance with standard practice, for example, see the publication of T.W. Greene and PGMWuts in "Protective Groups in Organic Chemistry" John Wiley and Sons, 1991. Compounds of formula (Ix) in which W, X, Y, Z and R are as defined above for compounds of formula ( Ix) and A5 is H, can be prepared by the reaction of compounds of formula (llx): wherein W, X, Y and Z are as defined above for compounds of formula (Ix), with acids of formula (II Ix): R1 - C02H (illx) wherein R1 is as previously defined for the compounds of formula (Ix), at a temperature of about 160 ° C. Alternatively, the reaction can be carried out (i) in the presence of hydrochloric acid at about the reflux temperature, or polyphosphoric acid at a temperature of 160 ° C or (ii) it can be carried out in a microwave oven. The compounds of formula (Ix) wherein W, X, Y, Z and R are as defined above and A5 is H can be prepared by the reaction of compounds of formula (llx) wherein W, X, Y and Z are as defined above for the compounds of formula (Ix), with aldehydes of formula (IVx): R1 - CHO (IVX) wherein R is as defined above for the compounds of formula (Ix) in the presence of an inert solvent such as dimethylformamide or nitrobenzene and at a temperature up to about 145 ° C. Alternatively, the reaction can be carried out (i) in the presence of sodium bisulfite at a temperature of about the reflux temperature or (i) can be carried out in a microwave oven at a temperature of up to about 200 ° C. The compounds of formula (Ix) in which W, X, Y, Z and R are as defined above for the compounds of formula (Ix) and A5 is H, can be prepared by the delation of compounds of formula (Vx) ): wherein W, X, Y, Z and R are as defined above for compounds of formula (Ix). Cyclization can be carried out by heating in the presence of an acid catalyst, such as acetic acid, and at a temperature up to about 120 ° C. The compounds of formula (Ix) in which W, X, Y and Z are as defined above for the compounds of formula (Ix) and R1 is, wherein R9 is as defined above for the compounds of formula (Ix), R7 is hydrogen and R8 is SR4, ie the compounds of formula (Ixaa), can be prepared as shown in Scheme 1.
SCHEME 1 CXIIx) flxa) For example, the diamines of formula (I Ix) in which W, X, Y and Z are as defined above for the compounds of formula (Ix) can be treated, in Step 1, with formic acid in the presence of hydrochloric acid at a temperature of approximately 50 ° C. The group of the resulting compounds of formula (Vlx) in which W, X, Y and Z are as defined above for the compounds of formula (Ix) can then be protected, in Step 2, with a group Suitable protective, for example, when it is a 2- (trimethylsilylanyl) -ethoxymethyl group the protection is conveniently carried out by (i) reaction with sodium hydride in dimethylformamide and then (ii) reaction with 2- (trimethylsilanyl) ethoxymethyl chloride . The resulting compounds of formula (VI Ix) in which W, X, Y and Z are as defined above for the compounds of formula (Ix) and R 1 is a suitable protecting group, such as a 2- (trimethylsilanyl) ethoxymethyl group, can then be treated, in Step 3, with (i) lithium diisopropylamide, in an inert solvent, such as tetrahydrofuran, and at a temperature of about -78 ° C, and subsequently (ii) acetamines of formula R9-C (= 0) -N (CH3) 2 [in that R9 is as defined above for the compounds of formula (Ix)]. The resulting compounds of formula (Xx), wherein W, X, Y, Z, R9 and R11 are as defined above for compounds of formula (Ix) [alternatively prepared by (i) diamine reaction of formula (I Ix) with ß-hydroxy acids of the formula R9CH2CH (OH) C02H [wherein R9 is as defined above for the compounds of the formula (Ix)], wherein Step 1 a, at a temperature of about 70 ° C, (ii) oxidation, in Step 2a, of the resulting compounds of formula (Vlllx) with manganese dioxide in an inert solvent, such as chloroform, and at a temperature of about 60 ° C and (ii) protection of the imino group, in Step 3a, as described in Step 2 above)] can then be treated, in Step 4, with (i) sodium tert-butoxide, in an inert solvent, such as benzene or tetrahydrofuran , at -5 ° C, and then (ii) carbon disulfide and then (iii) compounds of formula R4-X1 [wherein R4 is as defined above for the compounds of formula (lx)] and X1 is halo . The resulting compounds of formula (Xlx) in which W, X, Y, Z, R4, R9 and R11 are as defined above for the compounds of formula (lx) can then be treated, in Step 5, with hydrazine , in an inert solvent, such as ethanol, and at a temperature from about room temperature to about the reflux temperature. The resulting compounds of formula (XI lx) in which W, X, Y, Z, R4, R9 and R11 are as defined above for the compounds of formula (lx) can then be protected. { for example, when R 11 is a 2- (trimethylsilyano) ethoxymethyl group by treatment with hydrochloric acid in an inert solvent, such as ethanol, and at a temperature from about room temperature to about the reflux temperature} , in Step 6, to release the pyrazoles of general formula (Ixaa) wherein W, X, Y, Z, R4 and R9 are as defined above for the compounds of formula (lx). The compounds of formula (Xlx) wherein R 1 is a tetrahydropyran-2-yl protecting group can be deprotected by treatment with an acid, such as p-toluenesulfonic acid, in water at the reflux temperature and subsequently treated with hydrazine, in an inert solvent, such as ethanol, and at a temperature from about room temperature to about the reflux temperature, to provide pyrazoles of general formula (Ixaa), in which W, X, Y, Z, R4 and R9 are as defined above for the compounds of formula (Ix). The compounds of formula (Ix) wherein W, X, Y and Z are as defined above for the compounds of formula (Ix) and A5 is H, and R1 is wherein R9 is as defined above for the compounds of formula (Ix), R7 is hydrogen and R8 is OR4, ie, compounds of formula (Ixab), can be prepared as shown in Scheme 2.
SCHEME 2 (??) Qffllx) For example, the compounds of formula (Ixab) R 1 are as defined above for the compounds of formula (Ix) and R 4 is lower alkyl, they may be treated, in Step 1, with the sodium salt of an alcohol of formula R 4 -OH (in the that R4 is lower alkyl), such as sodium ethoxide, followed by treatment with hydrazine as described above for Scheme 1. The resulting compounds of formula (Xlllx), wherein W, X, Y, Z, R4, R9 and R11 are as defined above for the compounds of formula (Ix) can then be deprotected [eg, when R 1 is a 2- (trimethylsilyl) ethoxymethyl group, by treatment with trifluoroacetic acid at about 50 ° C], in the Stage 2, to release pyrazoles of general formula (Ixab).
The compounds of formula (Ix) wherein W, X, Y, and Z are as defined above for the compounds of formula (Ix) and A5 is H, and R1 is wherein R9 is as defined above for the compounds of formula (Ix), R7 is hydrogen and R8 is -NY1Y2, ie, compounds of formula (Ixac), can be prepared as shown in Scheme 3. SCHEME 3 (Ixac) (XVk) For example, compounds of formula (Xlx), wherein W, X, Y, Z, R9 and R are as defined above for compounds of formula (Ix) and R4 is lower alkyl can be treated, in Step 1, with an amine of formula HNY1Y2 [wherein Y1 and Y2 are as defined above for the compounds of formula (Ix)], for example, morpholine. The resulting compounds of formula (XIVx) in which W, X, Y, Z, R9, T11, Y1 and Y2 are as defined above for the compounds of formula (Ix) and R4 is lower alkyl, can then be treated , in Step 2, with hydrazine as described above for Scheme 1. The resulting compounds of formula (XVx) in which W, X, Y, Z, R9, R11, Y1 and Y2 are as defined above for the compounds of formula (Ix) can then be deprotected as described above, in Stage 3, to release pyrazoles of general formula (Ixac). The compounds of formula (Ix) wherein W, X, Y and Z are as defined above for the compounds of formula (Ix) and A5 is H, and that is, the compounds of formula (Ixad) can be prepared as shown in Scheme 4.
ESQUE A 4 (Ixad) For example, compounds of formula (Xlx) wherein W, X, Y, Z, R9 and R11 are as defined above for the compounds of formula (Ix) and R4 is lower alkyl can be treated, in the Step 1, with hydroxylamine in the presence of sodium methoxide and in methanol at the reflux temperature. The resulting compounds of formula (XVlx) in which W, X, Y, Z, R4, R9 and R11 are as defined above for the compounds of formula (Ix) can then be deprotected as described above, in the Step 2, to release isoxazoles of general formula (Ixad).
The compounds of the invention of formula (lx) can also be prepared by the interconversion of other compounds of the invention. Thus, for example, compounds of formula (Ix) which contain a carboxy group can be prepared by hydrolysis of the corresponding esters. The hydrolysis can be conveniently carried out by alkaline hydrolysis using a base, such as an alkali metal hydroxide, for example, sodium hydroxide, or an alkali metal carbonate, eg, potassium carbonate, in the presence of a mixture of aqueous / organic solvents, using organic solvents such as dioxane, tetrahydrofuran or methanol, at a temperature from about ambient to about the reflux temperature. The hydrolysis of the esters can also be carried out by acid hydrolysis using an inorganic acid, such as hydrochloric acid, in the presence of a mixture of aqueous / inert solvents, using organic solvents such as dioxane or tetrahydrofuran, at a temperature of about 50 °. C up to about 80 ° C. As another example, compounds of formula (lx) containing a carboxy group can be prepared by acid-catalyzed suppression of the tere-butyl group of the corresponding tert-butyl esters using standard reaction conditions, for example, reaction with trifluoroacetic acid at a temperature of about room temperature.
As another example, compounds of formula (Ix) containing a carboxy group can be prepared by hydrogenation of the corresponding benzylic esters. The reaction can be carried out in the presence of ammonium formate and a suitable metal catalyst, for example, palladium on a support of an inert material such as carbon, preferably in a solvent such as methanol or ethanol and at a temperature of about the reflux temperature. . The reaction may alternatively be carried out in the presence of a suitable metal catalyst, for example, platinum or palladium optionally on a support of an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. As another example, compounds of formula (Ix) containing a carboxy group can be prepared by treatment of compounds of formula (Ix) containing a cyano group with hydrochloric acid in acetic acid at a temperature of about 100 ° C. As another example of the interconversion process, compounds of formula (Ix) containing a group C (= 0) -NY1 Y2 can be prepared by reacting the compounds of formula (Ix) containing a carboxy group with an amine of HNY1Y2 formula for providing an amide bond using standard peptide coupling methods, for example, by coupling in the presence of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, hydroxybenzotriazole and bi-isopropylethylamine in an inert solvent, such as dimethylformamide and at a temperature of approximately 80 ° C. The reaction can be carried out alternatively in the presence of 0- (7-azabenzotriazol-1-yl) -1, 1, 3,3-tetramethyluronium hexafluorophosphate and triethylamine (or diisopropylethylamine) in tetrahydrofuran (or dimethylformamide) at room temperature. As another example of the interconversion procedure, compounds of formula (Ix) containing a group -NH-C (= 0) -R4 can be prepared by: (i) coupling compounds of formula (Ix) containing an amino group with acids of formula R4-C02H using standard coupling conditions as described above, or (ii) by reaction of compounds of formula (Ix) containing an amino group with acid chlorides of formula R4-C (= 0) -Cl in the presence of a tertiary base, as di-isopropylethylamine, in an inert solvent, such as dichloromethane, and at a temperature of about room temperature. In some cases a bis-acylated derivative is obtained by the reaction of compounds of formula (Ix) which contain an amino group and in which A5 is H, with chlorides of acids of formula R4-C (=) 0-Cl . These bis-acylated derivatives can be converted into compounds of formula (Ix) containing a group -NH-C (= 0) -R4 and wherein A5 is H, by treatment with potassium hydroxide in aqueous methanol at a temperature of approximately 60 ° C. As another example of the interconversion process, compounds of formula (Ix) wherein R is a pyrazolyl moiety wherein R8 and R9 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is -C (= 0) R4) can be prepared by the reaction of compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is hydrogen) with acid chlorides of formula R4-C (= 0) -CI in the presence of a tertiary base, such as di-isopropylethylamine, in an inert solvent, such as dichloromethane, and at a temperature of about room temperature. As another example of the interconversion process, the compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9 together with the carbon atoms to which they are attached form a 5- or 6-membered heterocyclic ring containing a group po NY5 (where Y5 is -C (= 0) NY1Y2) can be prepared by the reaction of compounds of formula (Ix) wherein R1 is a pyrazolyl moiety wherein R8 and R9, together with the carbon atoms to which they are attached, form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is hydrogen) with carbamoyl chlorides of formula Y Y2N- C (= 0) -Cl in the presence of a tertiary base, such as diisopropylethylamine, in an inert solvent, such as dichloromethane, and at a temperature of about room temperature. As another example of the interconversion process, the compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9, together with the carbon atoms to which they are attached, form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is -C (= 0) OR4) can be prepared by the reaction of compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9, together with the carbon atoms to which they are attached, form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is hydrogen) with chloroformates of formula R40-C (= 0) -Cl in the presence of a tertiary base, such as diisopropylethylamine, in an inert solvent, such as dichloromethane, and at a temperature of about room temperature. As another example of the interconversion process, the compounds of formula (Ix) wherein R 1 is a pyrazolyl moiety wherein R8 and R9, together with the carbon atoms to which they are attached, form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is -S02R4) can be prepared by the reaction of compounds of formula (Ix) wherein R1 is a pyrazolyl moiety wherein R and R, together with the carbon atoms to which they are attached, form a 5- or 6-membered heterocyclic ring containing a group NY5 (where Y5 is hydrogen) with sulfonyl chlorides of the formula R4S02-CI in the presence of a tertiary base, such as diisopropylethylamine, in a solvent inert, such as dichloromethane, and at a temperature of about room temperature. As another example of the interconversion process, compounds of formula (Ix) containing a -NH-C (= 0) -R4 group, wherein R4 is alkyl substituted with NY Y2, can be prepared by (i) coupling of compounds of formula (Ix) containing an amino group with the appropriate chloroalkyl acid chloride, in the presence of a tertiary base, such as di-isopropylethylamine, in an inert solvent, such as dichloromethane, and at a temperature of about room temperature, followed by (ii) reaction with an amine of formula HNY1Y2. As another example of the interconversion process, the compounds of formula (Ix) which contain a group -NH-C (= 0) -R4 [wherein R6 is hydrogen, Y1 is hydrogen and Y2 is alkenyl, aryl, cycloalkyl, hetero optionally substituted alkyl or alkyl] can be prepared by the reaction of compounds of formula (Ix) containing an amino group with isocyanates of the formula Y 2 N = C = 0 (wherein Y 2 is alkenyl, aryl, cycloalkyl, heteroaryl or optionally substituted alkyl] in an inert solvent, such as tetrahydrofuran, and at a temperature of about room temperature. As another example of the interconversion process, compounds of formula (Ix) containing a group -N (R6) C (= 0) NY1Y2 [wherein R6 is hydrogen] can be prepared by the reaction of compounds of formula (Ix) ) containing an amino group with 1, 1- carbonyldiimidazole in an inert solvent such as tetrahydrofuran and at a temperature of about 60 ° C followed by reaction with an amine of formula HNY1Y2. As another example of the interconversion process, compounds of formula (Ix) containing an amino group can be prepared by reducing the corresponding compounds of formula (Ix) containing a nitro group. For example, the reduction can be conveniently carried out by hydrogenation in the presence of a suitable metal catalyst, for example, platinum or palladium optionally on a support of an inert carrier such as carbon, preferably in a solvent such as methanol or ethanol. The reduction can also be conveniently carried out by means of a reaction with tin chloride, in an inert solvent, such as methanol or ethanol, and at a temperature of about the reflux temperature. Alternatively, the reaction with tin chloride can be carried out in a microwave oven at a temperature of about 140 ° C. As another example of the interconversion process, the compounds of formula (Ix) containing a -CH2OH group can be prepared by reducing the corresponding compounds of formula (Ix) which contain a -CHO or -C02-alkyl group. the inferior. For example, the reduction can be conveniently carried out by means of a reduction with lithium-aluminum hydride, in an inert solvent, such as tetrahydrofura- no, and at a temperature from about room temperature to about the reflux temperature. As another example of the interconversion process, compounds of formula (Ix) containing a group -CH (OH) R4 can be prepared by treating compounds of formula (Ix) containing a -C (= 0) R4 group with diisobutylaluminum hydride , in an inert solvent, such as tetrahydrofuran, and at a temperature from about -78 ° C to about room temperature. As another example of the interconversion process, the compounds of formula (Ix) wherein R 1 is aryl or heteroaryl substituted with hydroxy can be prepared by the reaction of the corresponding compounds of formula (Ix) wherein R 1 is aryl or substituted heteroaryl with methoxy with a Lewis acid, such as boron tribromide, in an inert solvent, such as dichloromethane, and at a temperature of from about-0 ° C to about room temperature. As another example of the interconversion process, compounds of formula (Ix) containing sulfoxide bonds can be prepared by the oxidation of the corresponding compounds containing -S- bonds. For example, the oxidation can be conveniently carried out by means of a reaction with a peroxyacid, for example, 3-cycloperbenzoic acid, preferably in an inert solvent, for example, dichloromethane, preferably at room temperature or in its vicinity or , alternatively, by means of hydrogen-peroxomonosulfate of potassium in a medium such as aqueous methanol, buffered at about pH 5, at temperatures between about 0 ° C and room temperature. The latter method is preferred for compounds containing a labile acid group. As another example of the interconversion process, compounds of formula (Ix) containing sulfone bonds can be prepared by oxidation of the corresponding compounds containing -S- or sulfoxide bonds. For example, the oxidation can be conveniently carried out by means of a reaction with a peroxyacid, for example, 3-chloroperbenzoic acid, preferably in an inert solvent, for example, dichloromethane, preferably at room temperature or in its vicinity. As another example of the interconversion process, compounds of formula (Ix) containing a cyano group can be prepared by reacting the corresponding compounds of formula (Ix) which contain a group -C (= 0) -NH2 with phosphorus pentachloride in the presence of triethylamine. The reaction can be conveniently carried out in an inert solvent, such as tetrahydrofuran, at a temperature of about the reflux temperature. As another example of the interconversion process, compounds of formula (Ix) containing a -C (= 0) -NH2 group can be prepared by reacting the corresponding compounds of formula (Ix) which contain a cyano group with peroxide of hydrogen in sodium hydroxide. The reaction can be conveniently carried out in methanol at a temperature of about room temperature. Alternatively, compounds of formula (Ix) containing a group -C (= 0) -NH2 can be prepared by reacting the corresponding compounds of formula (Ix) containing a cyano group with hydrochloric acid in acetic acid a a temperature of about 80 ° C to about 100 ° C. As another example of the interconversion process, the compounds of formula (Ix) which contain a tetrazolyl group can be prepared by the reaction of the corresponding compounds of formula (Ix) which contain a cyano group with azidotributyl tin. Conveniently carry out in an inert solvent, such as toluene, at a temperature of about the reflux temperature According to a further feature of the invention, salts can be prepared by acid addition of the compounds of this invention by a base reaction. free with the appropriate acid, by the application or adaptation of known methods, For example, the acid addition salts of the compounds of this invention can be prepared by dissolving the free base in water or an aqueous solution of alcohol or other suitable solvents which contain the appropriate acid and adding the salt by evaporating the solution n, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by concentration of the solution.
The compounds of this invention can be regenerated from their salts by the addition of acids by the application or adaptation of known methods. For example, the parent compounds of the invention can be regenerated from their salts by addition of acids by treatment with an alkali, for example, aqueous solution of sodium bicarbonate or aqueous solution of ammonia. According to a further feature of the invention, the base addition salts of the compounds of this invention can be prepared by the reaction of the free acid with the appropriate base, by the application or adaptation of known methods. For example, the base addition salts of the compounds of this invention can be prepared by dissolving the free acid in water or an aqueous solution of alcohol or other suitable solvents containing the appropriate base and isolating the salt by evaporating the solution, or by reacting the free acid and the base in an organic solvent, in which the salt is separated directly or can be obtained by concentrating the solution. The compounds of this invention can be regenerated from their salts by addition of bases or by the application or adaptation of known methods. For example, the parent compounds of the invention can be regenerated from their salts by addition of bases by treatment with an acid, for example, hydrochloric acid. The compounds of the present invention can be conveniently prepared or formed during the process of the invention in form of solvates (for example, hydrates). The hydrates of the compounds of the present invention can be conveniently prepared by recrystallization from a mixture of aqueous / organic solvents, using organic solvents such as dioxane, tetrahydrofuran or methanol. The starting materials and intermediates can be prepared by the application or adaptation of known methods, for example, as described in the Reference Examples or their obvious chemical equivalents. The intermediates of formula (llx), in which W, X, Y and Z are as. previously defined for the compounds of formula (Ix) can be prepared by reducing the corresponding nitro compounds of formula (1): wherein W, X, Y and Z are as defined above for compounds of formula (Ix). For example, the reduction can be conveniently carried out by means of a reduction with tin chloride, in an inert solvent, such as "methanol or ethanol, and at a temperature of about the reflux temperature." Alternatively, the reaction can be carried in a microwave oven at a temperature of approximately 140 ° C.
Intermediates of formula (Ilx) in which W, X, Y and Z are as defined above for the compounds of formula (Ix) can also be prepared by reducing the corresponding dinitro compounds of formula (2): wherein W, X, Y and Z are as defined above for compounds of formula (Ix) with tin chloride as above. The nitro compounds of formula (1) wherein W is CH, X is C-R2, Y is C-R3 and Z is CH [wherein R3 is as defined above for the compounds of formula (Ix)], can be prepared from the corresponding anilines of formula (3) wherein X is C-R2 and Y is C-R3 [wherein R3 is as defined above for the compounds of formula (Ix)], by (i) reaction with acetic anhydride in the presence of triethiamine, in an inert solvent, such as dichloromethane, and at a temperature of from about 0 ° C to about room temperature, (ii) reduction with nitric acid in the presence of acetic acid and acetic anhydride at a temperature of approx.
At -5 ° C and (ü) reaction with an alkali metal alkoxide, such as sodium metoxide, in methanol and at room temperature. The nitro compounds of formula (1) wherein W is CH, X is C-R2 (wherein R2 is alkyl), Y is C-R3 (wherein R3 is an aryl or heteroaryl group) and Z is CH they can be prepared by the reaction of compounds of formula (4): wherein X is C-R2 (where R2 is alkyl) and X2 is bromine or iodine, with an aryl- (or heteroaryl-) boronic acid in the presence of a suitable catalyst, such as tetrakis (trphenylphosphine) palladium, in an inert solvent, such as tetrahydrofuran, and at a temperature of about 85 ° C. The intermediates of formula (lllx), in which R1 is wherein R7 is hydrogen, R8 is alkyl and R9 is hydrogen or alkyl can be prepared by the. reaction of compounds of formula (5): wherein R8 is alkyl and R9 is hydrogen, with hydrazine in the presence of acetic acid at the reflux temperature, followed by hydrolysis.
The intermediates of formula (lllx) in which R is wherein R7 is hydrogen and R8 and R9 together with the carbon atoms to which they are attached form a carbocyclic ring of 5, 6 or 7 members can be analogously prepared by reaction of the compounds of formula (5) in which R8 and R9 together with the carbon atoms to which they are attached form a carbocyclic ring of 5, 6 or 7 members, with hydrazine, followed by hydrolysis. The intermediates of formula (lllx) in which R is wherein R7 is hydrogen, R13 is alkyl and X1 is O, s, S02 or NY5 (wherein Y5 is R4, -C (= 0) R4 -C (= 0) NY1Y2, -C (= 0) OR4 O- S02R4) can be analogously prepared by the reaction of compounds of formula (6): (6) wherein R13 is alkyl and X1 is O, S, SO2, or Y ^ (where d is R 4 -C (= 0) R 4, -0 (= 0) 2, -C (= 0) OR 4 or -S0 2 R 4), with hydrazine, followed by hydrolysis. The compounds of formula (5) in which R8 is alkyl and R9 is hydrogen, can be prepared by the reaction of compounds of formula (7): wherein R is alkyl, with diethyl oxalate, in the presence of an alkali metal alkoxide, such as sodium ethoxide, in an inert solvent, such as ethanol, and at a temperature of about 60 ° C. The compounds of formula (5), in which R8 and R9 together with the carbon atoms to which they are attached form a carbocyclic ring of 5, 6 or 7 members, can be analogously prepared by the reaction of cyclopentanone or cyclohexanone. with diethyl oxalate. The compounds of formula (6), wherein R13 is alkyl and X1 is O, S, S02, or NY5 (where Y5 is R4, -C (= 0) R4, -0 (=?) ???? 2, -C (= 0) OR or -S02R) can be analogously prepared by the reaction of compounds of formula (8): wherein R13 is alkyl and X1 is O, S, S02, or NY5 (wherein Y5 is R 4 -C (= 0) R 4, -C (= 0) NY 1 Y 2, -C (= 0) OR 4 or -SO 2 R 4), with diethyl oxalate. The intermediates of formula (IVx) in which R1 is as defined above for the compounds of formula (Ix), can be prepared by the oxidation of compounds of formula (9) R1-CH2OH (9) wherein R is as defined above for the compounds of formula (ix). The oxidation can be conveniently carried out with manganese dioxide, or pyridinium chlorochromate, in an inert solvent, such as chloroform or dichloromethane, and at a temperature of about 60 ° C. This process is particularly suitable for intermediates of formula (IVx) in which R1 is (where R 0 and p are as previously defined). The compounds of formula (9) in which R1 is as defined above for the compounds of formula (Ix) can be prepared by reducing acids of formula (10): R1-C02H (10) wherein R1 is as defined above for the compounds of formula (Ix). The reduction can be conveniently carried out with lithium aluminum hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature of about room temperature. The compounds of formula (9) in which R1 is as defined above for the compounds of formula (Ix), can be prepared by the reduction of alkyl esters of formula (10a): R -C02-alkyl (10a) wherein R1 is as defined above for the compounds of formula (Ix). The reduction can be conveniently carried out with lithium aluminum hydride, in an inert solvent, such as tetrahydrofuran, and at a temperature of about room temperature. The acids of formula (10), wherein R 1 is (wherein R10 and p are as defined above) can be prepared by the reaction of indole diones of formula (11): wherein R and p are as defined above, with (i) sodium hydroxide at 50 ° C, (ii) sodium nitrite and then sulfuric acid at 5 ° C and (iii) tin (II) chloride. The indole diones of formula (11), in which R10 is as defined above and p is one, can be prepared by the reaction of compounds of formula (12): wherein R10 is as defined above, with polyphosphoric acid at a temperature of about 80 ° C. The compounds of formula (12), in which R 10 is as defined above, can be prepared by the reaction of anilines of formula (13): wherein R10 is as defined above, with doral hydrate and hydroxylamine in the presence of hydrochloric acid at a temperature of about 80 ° C. The intermediates of formula (Vx) in which W, X, Y, Z and R1 are as defined above for the compounds of formula (Ix), can be prepared by the reaction of compounds of formula (1) with chlorides of acids of formula R1-C (= 0) -Cl, optionally in the presence of a tertiary base, such as pyridine, and in an inert solvent, such as dichloromethane, at a temperature of about room temperature. The following references are also cited, which can be used for the preparation of benzimidazoles, pyrazoles or indazoles in the context of the present invention: - G. R. Newkome, W.W. Paudler, Comtemporary Heterocyclic Chemistry, Syntheses, Reactions and Applications, J. Wiley, 1982 - Preston, Heterocyclic Compounds, Benzimidazols and congeneric tricyclic compounds, J. Wiley, 1981 - Behr, Fusco, Jarboe, Heterocyclic Compounds, Pirazols, Pyrazolines, Pirazolidines, indazols and condensed rings, J. Wiley, 1967. The following schemes, schemes 5 to 13, illustrate the synthesis of specific examples within the specification, using the procedures described herein and by the use of suitable protecting groups when appropriate. necessary.
SCHEME 5 Example 15 SCHEME 6 PlCHjNHNH, Ac £ 3H 'reflux'? n'rtrobp.nceno, 5 ° C NaHSOj.DUF. ret 0 EtOOC-? - CQ ^ t 3 H ,, Pd DEt SCHEME 8 SCHEME 9 SCHEME 10 . SCHEME 11 SCHEME 12 twenty SCHEME 14 The present invention is set forth with additional examples but is not limited by the following illustrative examples and reference examples. Nuclear magnetic resonance spectra were recorded.
(NMR) 400 MHz H1 in a Varian Unity INOVA device. In the nuclear magnetic resonance (NMR) spectra the displacements (d) are expressed in ppm relative to tetramethylsilane. The abbreviations have the following meanings: s = singlet; d = doublet; t = triplet; m = multiplet; q = quartet; dd = doublet of doublets; ddd = double doublet doublet. The RF values of thin layer chromatography (TLC) were determined using Merck silica plates. The conditions of high pressure liquid chromatography mass spectroscopy (LC-MS) for the determination of the retention times (RT) and the associated mass ions were as follows: METHOD A: Mass Spectrometer (MS) - LCT Time-of-FIig (Micromass UK Ltd) serial no. KA014 [ionization mode: electrospray (positive ion); Scan: Tof MS (full scan m / z 100-1200, sum for 0.4 s at 50 ps / scan) centroid mode]. Liquid chromatography (LC): binary pump of the HP1 100 series (serial no. US80301343) Degasser (serial no. JP73008973). Hypersil BDS C-18, 3μ (4.6 mm x 50 mm), reverse phase column operating under gradient elution conditions using (A) water containing 0.05% trifluoroacetic acid and (B) acetonitrile containing 0 , 05% trifluoroacetic acid as the mobile phase (gradient: 0.00 minutes, 00% A, linear gradient up to 100% B in 2 minutes, then maintained until 1.5 minutes); flow rate 1 ml / minute for the column and to the UV detector, division of the flow after the UV detector so that they are 0.75 ml / minute for the ELS detector and 0.25 ml / minute for the mass spectrometer; injection volume 10 μ ?; Auxiliary detectors: (i) UV detector of the HP 100 series (serial no. JP73704703) wavelength = 220 nm; (ii) Evaporative light scattering detector (ELS) Sedere (France) Model SEDEX 75 (serial no. 9970002A); temperature = 46 ° C, nitrogen pressure = 4 bar; injector: Gilson Model 215 Liquid Handler with 819 model injection valve (serial no. 259E8280). METHOD B: Waters Symmetry C8 3.5 pms HPLC column operating under gradient conditions with mixtures of (A) water containing 0.1% formic acid and (B) acetonitiril containing 0.1% formic acid as the mobile phase (gradient: 0.00 minutes, 9 %% A: 5% B, 0.75 minutes, 95% A: 5% B; 3.00 minutes 100% B, 4.00 minutes 100% B, 4.25 minutes 95% A: 5% B); flow rate 1.5 mi / minute with division of approximately 200 μ? / minute to the mass spectrometer; injection volume 20 μ ?; row of diodes in line (210-300 nm), ELS detection by evaporative light scattering (ELS) in line - temperature 40 ° C, gain 7-1, 5 ml / minute; temperature of the source 150 ° C. METHOD C: Waters Symmetry C8 3.5 pM HPLC column operating under gradient conditions with mixtures of (A) water containing 10 mM ammonium acetate and (B) methanol containing 10 mM ammonium acetate as the mobile phase (gradient: 0.00 minutes, 95% A: 5% B, 0.75 minutes, 95% A: 5% B, 3.00 minutes 100% B, 4.00 minutes 100% B, 4.25 minutes 95 % A: 5% B); flow rate 1.5 ml / minute with division of approximately 200 μ? / minute to the mass spectrometer; injection volume 20 μ ?; line of diodes in line (210-300 nm), ELS detection by evaporative light scattering (ELS) in line - temperature 40 ° C, gain 7-1, 5 ml / minute; temperature of the source 150 ° C. METHOD D: Fenomenex Luna C8 HPLC Column (250 x 4.6 mm) operating under gradient conditions with mixtures of (A) methanol containing 10 mM ammonium acetate and (B) water containing ammonium acetate 10 mM as the mobile phase (gradient: 0 to 2 minutes 10% A: 90% B, 2 to 23 minutes climbing to 100% A, 23 to 30 minutes 100% A, 30 to 37 minutes 10% A: 90% B); flow rate 1 ml / minute. . METHOD E: Mass Spectrometer (MS) - LCT Time-of-Flight (Micromass UK Ltd) serial no. KA014 [ionization mode: electrospray (positive ion); scan: Tof MS (Full Sean m / z 100 - 1200, sum for 0.4 s at 50 ps / scan) centroid mode]. Liquid chromatography (LC): Hewlett Packard binary pump of the HP1 100 series (serial no. US80301343) and Degasser (serial no. JP73008973). Reverse Phase Column 20X4 Synergi 2U Hydra. Solvent 0.1% trifluoroacetic acid in water; solvent B 0.1% trifluoroacetic acid in acetonitrile. Gradient 5% B for time 0 to 90% B in a time of 2 minutes to 100% B in 5 minutes; flow rate 1 ml / minute for the column and for the UV detector, division of the flow rate after the UV detector so that they are 0.75 ml / minute for the ELS detector and 0.25 ml / minute for the mass spectrometer; injection volume 10 μ ?; Auxiliary detectors: (i) UV detector of the Hewlett Packard Model HP1100 series (series No. JP73704703) wavelength = 220 nm; (ii) Evaporative light scattering detector (ELS) Sedere (France) Model SEDEX 75 (serial no. 9970002A); temperature = 46 ° C, nitrogen pressure = 4 bar; auto-matic sampling / injector: Gilson Model 215 Liquid Handler with injection valve Model 819 (serial no. 259E8280).
METHOD F: HPLC Agilent 1100 series with a 4.6 mm by 33 mm reversed phase column YMC CombiScreen Pro C 8 of 5.5 μp? using a gradient elution with a mixture of (A) acetonitrile / 0.1% trifiuoroacetic acid and (B) water / 0.1% trifiuoroacetic acid (5% A: 95% B at 95% A: 5% B during 5.1 minutes) with a flow rate of 1.2 mi / minute; Agilent 1100 Series automatic well plate sampling device with 2 μ? injection; Agilent 1100 Series diode array detector with wavelength detection: 215, 254 and 300 nM; Mass spectrometer series Hewlett Packard 1100 Series with electrospray and positive ionization. METHOD G: HPLCL Rainin HPXL Dual Pump System with a Rai-nin Dynamax UV-D II detector for wavelength of 254 nM, C18 Metachrom Monochrom 10μ column? (100 x 4.6 mm) using gradient elution with a mixture of (A) water with 0.1% trifiuoroacetic acid and (B) acetonitrile as the mobile phase (90% A: 10% B at 0% A in 12 minutes) with a flow rate of 1.0 ml / minute, column C18 Metachem Monochrom 10 μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) methanol and (B) water with 10 mM ammonium acetate as the mobile phase (0-2 minutes, 10% A: 90% B; 25 minutes rise to 100% A, 25-32 minutes 100% A, 32-33 minutes 10% A: 90% B) with a flow rate of 1.0 ml / minute.
METHOD H: Waters Symmetry C8 column 3.5 μ? (50 x 4.6 mm) using gradient elution with a mixture of (A) water / 0.1% formic acid and (B) acetonitrile / 0.1% formic acid (5% B: 95% A to 100 % B in 3.5 minutes, 100% B for 1 minute, 100% B to 5% B: 95% A in 0.1 minute, balanced to 5% B: 95% A 0.49 minutes, total time of the experiment 5 minutes) with a flow rate of 1.5 ml / minute; detection 210-300 nM, interval 2 nM; column temperature 30 ° C; Quadrupole mass spectrum, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 140 to 850 Da, ex-ploration 0.6 seconds, delay between scans 0.4 seconds. METHOD J: Waters Symmetry C8 column 3.5 μ? (50 x 4.6 mm) using gradient elution with a mixture of (A) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile (5% B: 95% A 0, 75 minutes at 100% B in 4 minutes, 100% B for 0.5 minutes, 100% B at 5% B: 95% A at 1 minute, total experiment time 5 minutes at a flow rate of 1.5 ml / minute; 210-300 nM detection, 2 nM interval, 30 ° C column temperature, Quadrupole mass spectrum, electrospray, 25 V conical voltage, +/- ion switching, centroid data, 140 to 850 Da, 0.6 scan seconds, re-trapping between scans 0.4 seconds METHOD K: Waters Symmetry C8 column 3.5 μ (50 x 4.6 mm) using gradient elution with a mixture of (A) 0 mM ammonium acetate in water and ( B) 10 mM ammonium acetate in methanol (5% B: 95% At 0.75 minutes at 100% B in 4 minutes, 100% B for 0.5 minutes, 00% B at 5% B: 95% A at 1 minute , total time of the experiment 5 minutes) with a flow rate of 1.5 ml / minute; 210-300 nM detection, 2 nM range; column temperature 30 ° C; Quadrupole mass spectrum, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 140 to 850 Da, scan of 0.6 seconds, delay between scans 0.4 seconds. METHOD L: Column Fenomenex Luna C18 (2) 3 μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) 0.1% formic acid in water and (B) 0.1% formic acid in acetonitrile (20% B: 80% A to 100 % B in 10 minutes, 100% B for 2 minutes, 100% B to 20% B: 80% A in 0.5 minutes, 20% B: 80% A for 3.5 minutes, total experiment time 16 minutes with a flow rate of 1.0 ml / minute, 210-300 nM, 220 and 254 nM extracted and ELSD, column temperature 30 ° C, Quadrupole mass spectrum, electrospray, 25 V conical voltage, ion switching +/- , data inside, 100 to 900 Da, scan of 0.6 seconds, delay between scans 0.4 seconds METHOD M: Column Fenomenex Luna C18 (2) 3 μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) 0.1% 0 formic acid in water and (B) 0.1%) formic acid in acetonitrile (5% B: 95% A to 60% B: 40% A in 10 minutes, 60 %) B: 40% A for 2 minutes, 60% B: 40% A to 5% B: 95% A in 0.5 minutes, 5% B: 95% A for 3.5 minutes, total time of expe rimento 16 minutes with a flow rate of 1.0 ml / minute; 210-300 nM, 220 and 254 nM extracted and ELSD; column temperature 30 ° C; mass spectrum Quadrupole, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 100 to 900 Da, scan of 0.6 seconds, delay between explorations 0.4 seconds. METHOD N: Waters Symmetry C8 column 3.5 μ? (50 x 4.6 mm) using gradient elution with a mixture of (A) 10 mM ammonium acetate in water and 10 mM ammonium acetate in methanol (5% B: 95% A to 100% B in 3.5 minutes, 100% B for 1 minute, 100% B to 5% B: 95% A in 0.1 minute, balanced 5% B: 95% A in 0.49 minutes, total experiment time 5 minutes) with a flow rate of 1.5 ml / minute; detection 210-300 nM, interval 2 nM; column temperature 30 ° C; Quadrupole mass spectrum, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 140 to 850 Da, scan of 0.6 seconds, delay between scans 0.4 seconds. METHOD P: Fenomenex Luna C18 column (2) 3 μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) 10 mM ammonium acetate in water and (B) 10 mM ammonium acetate in methanol (5% B: 95% A to 60% B: 40 % A in 10 minutes, 60% B: 40% A for 2 minutes, 60% B: 40% A to 5% B: 95% A in 0.5 minutes, 5% B: 95% A for 3.5 minutes , total time of the experiment 16 minutes with a flow rate of 1.0 ml / minute, 210-300 nM, 200 and 254 nM extracted and ELSD, column temperature 30 ° C; pole, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 100 to 900 Da, scan of 0.6 seconds, delay between scans 0.4 seconds. METHOD Q: Fenomenex Luna C18 column (2) 3 μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) 10 mM ammonium acetate in water and (B) 10 mM ammonium acetate in methanol (20% B: 80% A to 100% B in 10). minutes, 100% B for 2 minutes, 100% B to 20% B: 80% A in 0.5 minutes, 20% B: 80% A for 3.5 minutes, total experiment time 16 minutes with a flow rate of 1 , 0 ml / minute, 210-300 nM, 200 and 254 nM extracted and ELSD, column temperature 30 ° C, Quadrupole mass spectrum, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 100 a 900 Da, scan of 0.6 seconds, delay between scans 0.4 seconds METHOD R: Column Fenomenex Luna C18 (2) 5 μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) acetate ammonium 10 mM in water and (B) 10 mM ammonium acetate in methanol (40% B: 60% A to 100% B in 10 minutes, 100% B for 2 minutes, 100% B to 40% B: 60% A in 0.5 minutes, 40% B: 60% A for 3.5 minutes, total experiment time 16 minutes with a flow of 1.0 ml / minute; 210-300 nM, 200 and 254 nM extracted and ELSD, column temperature 30 ° C; Quadrupole mass spectrum, electrospray, 25 V conical voltage, ion switching +/-, centroid data, 100 at 900 Da, scan of 0.6 seconds, delay between scans 0.4 seconds. The conditions of high pressure liquid chromatography for the determination of the retention times (Rj) were as follows: METHOD A1: YMC ODS-AQ column (2 x 50mm) using gradient elution conditions with mixtures of acetonitrile, water and formic acid as the mobile phase [95/5 / 0.1% at 5/95 / 0.1%] and a flow rate of 0.4 ml / minute. METHOD B1: Column C18 Fenomenex Luna 5μ? (150 x 4.6 mm) using gradient elution with mixtures of (A) acetonitrile containing 0.1% formic acid and (B) water containing 0.1% formic acid as the mobile phase (gradient: 0- 2 minutes 10% A: 90% B, 2-25 minutes ascension up to 10% A, 25-32 minutes 100% A, 32-33 minutes 10% A: 90% B) with a flow rate of 1.0 ml / minute . METHOD C1: Column C18 Fenomenex Luna 5μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) methanol and (B) water with 10 mM ammonium acetate as the mobile phase (0-2 minutes 10% A: 90% B; 2-25 minutes ascension up to 100% A; 25-32 minutes 100% A; 32-33 minutes 10% A: 90% B) with a flow rate of 1.0 ml / minute.
METHOD D1: Column C18 Fenomenex Luna 3μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) acetonitrile containing 0.1% formic acid and (B) water containing 0.1% formic acid with a flow rate of 1.0 ml /minute. METHOD E1: Column C18 Fenomenex Luna 3μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) methanol and (B) water with 10 mM ammonium acetate as the mobile phase (29% A: 80% B to 100% A in 10 minutes; 100% A for 2 minutes, 100% A at 20% A: 80% B in 0.5 minutes, 20% A: 80% B for 3.5 minutes) with a flow rate of 1.0 ml / minute. METHOD F1: Column C18 Fenomenex Luna 3μ? (150 x 4.6 mm) using gradient elution with a mixture of acetonitrile and water with 0.1% formic acid. METHOD G1: Column C18 Fenomenex Luna 3μ? (150 x 4.6 mm) using gradient elution with a mixture of (A) methanol and (B) water with 10 mM ammonium acetate as the mobile phase (5% A, 95% B to 60% A: 40% B in 10 minutes, 60% A: 40% B for 2 minutes, 60% A: 40% B to 5% A: 95% B in 0.5 minutes, 5% A: 95% B for 3.5 minutes ) with a flow rate of 1.5 ml / minute.
The conditions of gas chromatography-mass spectrometry (GC-MS) for the determination of the retention times (RT) and associated mass ions were as follows: Gas chromatograph They vary 3800 with 30 m column of fused silica of 0 , 25 mm diameter Chrompack using a 20 minute elution with gradient of 25 ° C / minute from 50 to 300 ° C for the time of 1 to 1 1 minutes; helium mobile phase with a flow rate of 1.2 ml / minute; injection volume 3-8 μ? with 50:50 injection division ratio; Mass spectrometer Varies 2000R with electronic impact detection for ions 40 to 650 m / z. General method of purification by LC / MS of Examples 1 to 229: a Waters Fraction Lynx system is used, and the separations were carried out on a Waters Symmetry column (C18, 5 μ ?, 19x50 mm, catalog No. 186000210) , eluting with a linear gradient of acetonitrile containing 0.07% trifluoroacetic acid (v / v) in water containing 0.07% trifluoroacetic acid (v / v), gradient rising from 5% to 95% (v / v) acetonitrile / trifluoroacetic acid for 8 minutes, followed by 2 minutes at 95% acetonitrile / trifluoroacetic acid at a flow rate of 10 ml / minute. The products are injected in solution in dimethyl sulfoxide and collected according to the detection of their molecular weight. The names of the compounds were generated using a self-denotation system for ISIS 2.3 or ISIS 2.4.
PLO AXLE 2- (1 H-indazol-3-n-1 H-benzamidazole-5-carboxylic acid benzylamide The benzylamide of 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid can be prepared in the following manner. A solution of 27.3 mg of HDPU in 0.2 ml of dimethylformamide is added, at a temperature around 20 ° C, to a solution of 20 mg of 2- (1 H-indazol-3) acid. il) -1 H-benzimidazole-5-carboxylic acid in 0.42 ml of anhydrous dimethylformamide. After stirring at a temperature in the vicinity of 20 ° C for one hour, 5.7 ml of benzylamide are added followed by the addition of 12.4 ml of α, β-diisopropylethylamine dissolved in 0.32 ml of dimethylformamide. After 20 hours, at a temperature in the vicinity of 20 ° C, the reaction medium is concentrated under reduced pressure, at a temperature in the vicinity of 40 ° C. The obtained crude residue is dissolved in DMSO and purified by preparative LC / MS. The fractions containing the desired product are combined and concentrated under reduced pressure. ducida at a temperature around 40 ° C. This gives 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid benzylamide in the form of a cream-colored powder, the characteristics of which are the following: Retention time LC / MS = 2.86 minutes. 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid can be prepared in the following manner: 1.3 g of sodium metabisulfite and 1.04 g of 3,4-acid are added. -diaminobenzoic acid, at a temperature in the vicinity of 20 ° C, to a solution of 1 g of H-indazole-3-carboxaldehyde in 10 ml of dimethylformamide. The reaction mixture is refluxed for one hour and then cooled to a temperature in the vicinity of 20 ° C and diluted with dichloromethane and the mixture is filtered. The collected filtrate is concentrated under reduced pressure. The brown liquid obtained (340 mg) is purified by preparative LC / MS. 138.8 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazoi-5-carboxylic acid are thus obtained in the form of a beige powder. 1 H-indazoI-3-carboxaldehyde can be prepared as follows: A solution of 2.27 g of (1H-indazol-3-yl) methanol in 220 ml of 1,2-dimethoxyethane is added to 13.32 g of manganese dioxide. After one hour at a temperature around 20 ° C, the reaction mixture is refluxed for 15 minutes. After cooling to a temperature of about 20 ° C, the reaction medium is filtered through a sinter funnel filled with Celite. The collected filtrate is concentrated under reduced pressure at a temperature of approximately 40 ° C. Thus 2.02 g of 1 H-indazole-3-carboxaldehyde are obtained in the form of a yellow powder, whose characteristics are the following: H NMR (DMSO d6, 400 MHz): 7.40 ppm (triplet, 1 H); 7.55 ppm (triplet, 1 H); 7.75 ppm (doublet, 1 H); 8.18 ppm (doublet, 1 H); 10.23 ppm (sin-glete, H); 14.2 ppm (multiplet, 1 H). The (1 H-indazol-3-yl) methanol can be prepared in the following manner: 3.2 g of lithium aluminum hydride are added dropwise to a solution of 7.08 g of methyl 3-indazolecarboxylate in 80 ml of tetrahydrofuran is cooled to a temperature of about 0 ° C by means of a bath with ice. After 4 hours at a temperature of about 0 ° C, 1.6 g of lithium aluminum hydride are added. After 2 hours at a temperature of about 0 ° C, the reaction medium is treated successively with 6 ml of water and then 6 ml of 1 N aqueous sodium hydroxide solution and finally 18 ml of water. The reaction mixture is filtered through paper and the aqueous filtrate is then extracted with diclo-romethane. The collected organic fractions are combined, dried over magnesium sulfate and concentrated under reduced pressure at a temperature of about 40 ° C. 3.15 g of (1 H-indazol-3-yl) methanol are obtained in the form of an off-white powder, the characteristics of which are the following: 1 H NMR (D SO d 6, 400 MHz): 4.80 ppm (doublet, 2H); 5.25 ppm (triplet, 1H); 7.15 ppm (triplet, 1H); 7.35 ppm (triplet, 1 H); 7.51 ppm (doublet, 1 H); 7.87 ppm (doublet, 1 H); 12.81 ppm (multiplet, 1 H). The methyl 3-indazolecarboxylate can be prepared in the following manner: 0.5 ml of concentrated sulfuric acid (95%), at a temperature of about 20 ° C, is added dropwise to a solution of 9.13. g of 3-indazolecarboxylic acid in 100 ml of methanol. After refluxing for 20 hours, the reaction medium is concentrated under reduced pressure at a temperature of about 40 ° C. The aqueous residue obtained is extracted with dichloromethane. The organic phases are combined, washed with water until neutral, dried over magnesium sulfate and then concentrated under reduced pressure at a temperature of about 40 ° C. The yellow powder obtained is washed with ethyl ether. You get a white powder. The filtrate is concentrated under reduced pressure until a yellow powder is obtained. The yellow powder is washed again with ethyl ether until a white powder is obtained. The yellow filtrate is concentrated a third time under reduced pressure and the yellow powder collected is also washed with ethyl ether. All white powder fractions are combined. 7,08 g of methyl 3-indazolecarboxylate are thus obtained in the form of a white powder. EXAMPLE 2 2- (1H-Indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-methylamide 2- (1 H-indazoI-3-yl) -1 H -benzimidazo I-5-carboxylic acid N-methylamide can be prepared following the procedure for the preparation of 2- (1 H-indazole-3-N-benzylamide -yl) -1H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and 71.8 μ? from a solution of methylamine (2 M in tetrahydrofuran), 14.8 mg of expected product are obtained. EXAMPLE 3 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide can be prepared following the procedure for the preparation of 2- (1 H-indazol-3) N-benzylamide -yl) -1H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazo! -3-ii) -1 H-benzimidazole-5-carboxylic acid and 19.4 ml of an ethylamine solution (33% in water), 14.8 are obtained. mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide. EXAMPLE 4 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide N-isopropylamide of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid can be prepared following the procedure for the preparation of 2- (1 H-indazole-3-N-benzylamide -yl) -1H-benzimidazole-5-carboxylic acid (Example): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and, 3 ml of isopropylamine, 16.5 mg of 2- (1 H-indazoI-3-yl) -1 H-benzimidazo I-5-carboxylic acid N-isopropylamide are obtained. EXAMPLE 5 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide 2- (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide can be prepared following the procedure for the preparation of 2- (1 H-indazol-3-) N-benzylamide il) -1H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and 13.1 ml of aniline , 14.1 mg of 2- (1 H-indazoI-3-yl) -1H-benzimidazole-5-carboxylic acid N-phenylamide are obtained in the form of a white powder. EJEÍVÍPLO 6 N-phenethylamide 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid The 2- (1 H-indazol-3-yl) -1 H -benzimidazo I-5-carboxylic acid N-phenethylamide can be prepared following the procedure for the preparation of 2- (1 H-indazole-) N-benzylamide. 3-l) -1 H-benzimidazo I-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and 18 ml of phenethylamine, 17.7 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide are obtained in the form of a white powder.
EXAMPLE 7 2- (1 H-indazol-3-yl) - H-benzimidazole-5-carboxylic acid N-morpholinoamide The 2- (1 H-indazol-3-yl) -H-benzimidazole-5-carboxylic acid N-morpholinoamide can be prepared following the procedure for the preparation of 2- (1 H-indazole-) N-benzylamide. 3-yl) -H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and 12.5 ml of morpholine, 18.6 mg of 2- (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-morpholinoamide are obtained in the form of a pale yellow powder. EXAMPLE 8 N- (N'-methyl-piperazinp) 2- (1 H-indazol-3-iQ-1 H-benzimidazole-5-carboxylic acid) amide N- (N'-methyl-piperazino) 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide can be prepared following the procedure for the Preparation of 2- (1H-indazoI-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzylamide (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) acid -1 H-benzimidazole-5-carboxylic acid and 15.9 ml of N-methylpiperazine, 16.1 mg of N- (N'-methyl-piperazino) 2- (1 H-indazol-3-yl) amide are obtained ) -1 H-benzimidazole-5-carboxylic acid in the form of a yellow oil. EXAMPLE 9 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide It is possible to prepare 2- (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide following the procedure for the preparation of 2- (1H-indazoI-3-) N-benzylamide il) -1H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and 12 ml of pyrrolidine, they obtain 17.7 mg of 2- (1 H-indazoI-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide in the form of a pale yellow powder. EXAMPLE 10 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (isobutyl) amide N- (isobutyl) amide of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid can be prepared following the procedure for the preparation of 2- (1H-indazole-) N-benzylamide. 3-yl) -1H-benzimidazo I-5-carboxylic acid (Example 1): Starting with 20 'mg of 2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 14.6 ml of isobutylamine, 7.6 mg of 2- (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (isobutyl) amide is obtained in the form of a pale yellow powder. EXAMPLE 11 N- (2- (1H-indazol-3-ylHl-benzimidazole-5-carboxylic acid cyclohexylmetinamide.
N- (cyclohexylmethyl) amide of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid can be prepared following the procedure for the preparation of 2- (1H-indazole) N-benzylamide -3-l) -1 H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid and 18.7 ml of cyclohexylmethylamine, 16.1 mg of N ~ (cyclohexylmethyl) amide 2- are obtained (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid in the form of a white powder. EXAMPLE 12 2- (1 H -ndazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide N- (2-furfuryl) amide of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid can be prepared by the following procedure for the preparation of N-benzylamide of 2- ( 1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1H-indazoI-3-yl) -1H-benzimidazole-5-carboxylic acid and 13.3 ml of 2-furfurylamine, 14.8 mg of 2- (1 H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide in the form of a white powder. EXAMPLE 13 '2- (1H-indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide N-benzyl-N-methylamide of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid can be prepared by the following procedure for the preparation of 2- (1-N-benzylamide. H-indazol-3-yl) -1 H-benzimidazo-5-carboxylic acid (Example 1): Starting with 20 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid and 18.6 ml of N-methylbenzylamine, 7.3 mg of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide are obtained in the form of a pale yellow powder. EXAMPLE 14 2- (1 H -ndazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl ester Methyl 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylate can be prepared as follows: A mixture of 0.1 g of 1 H-indazole-3-carboxaldehyde and 13.7 mg of methyl 3,4-diaminobenzoate in 10 ml of nitrobenzene is maintained at a temperature of about 145 ° C for 3 hours and 45 minutes.
After cooling to a temperature of about 20 ° C, the reaction mixture is purified in SPE (5 g of SCX phase, treatment and washing with methanol, extraction with a 2 N ammoniacal methanol solution). The ammoniacal solution collected during the separation is then concentrated under reduced pressure at a temperature of about 40 ° C. 198.3 mg of an orange liquid is obtained which is purified by preparative LC / MS. Thus, 42.7 mg of methyl 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylate are obtained in the form of a beige powder, whose characteristics are the following: H NMR (D SO d6, 400 MHz): 3.95 ppm (singlet, 3H); 7.40 ppm (triplet, 1 H); 7.55 ppm (triplet, 1 H); 7.75 ppm (doublet, 1 H); 7.77 ppm (doublet, 1 H); 7.95 ppm (doublet, 1 H); 8.57 ppm (doublet, 1 H); 13.85 ppm (multiplet, 1 H). EXAMPLE 15 5,6-dimethyl-2- (1 H-indazol-3-yl) -1 H-benzimidazole 5,6-Dimethyl-2- (H-indazol-3-yl) -1H-benzimidazole can be prepared by the following procedure for the preparation of 2- (1 H-indazol-3-yl) -3H-benzimidazole- Methyl 5-carboxylate (Example 14): Starting with 200 mg of 1 H-indazole-3-carboxaldehyde and 177 mg of 4,5-dimethyl-1,2-phenylethylenediamine in 10 ml of nitrobenzene, 15.9 mg are obtained of 5,6-dimethyl-2- (1 H -ndazol-3-yl) -1 H -benzimidazole in the form of a dark red powder, whose characteristics are the following: 1 H NMR (DMSO d6, 400 MHz) : 2.60 ppm (singlet, 6H); 7.42 ppm (triplet, 1 H); 7.53 ppm (singlet, 2H); 7.58 ppm (triplet, H); 7.78 ppm (doublet, 1 H); 8.52 ppm (doublet, 1 H); 14.05 ppm (multiplet, 1 H). 5,6-Dimethyl-2- (1 H-indazol-3-yl) -1 H-benzimidazole can also be prepared according to the following procedure: 389 mg of sodium metabisulfite is added at a temperature of about 20 ° C. to a solution of 300 mg of 1 H-indazoI-3-carboxaldehyde and 279 mg of 4,5-dimethyl-1,2-phenylenediamine in 3 ml of dimethylformamide. The reaction mixture is refluxed for 4 hours and then cooled to a temperature of about 20 ° C and filtered through paper. The collected filtrate is concentrated under reduced pressure. The brown liquid obtained (340 mg) is purified by preparative LC / MS. 138.8 mg of 5,6-dimethyI-2- (1 H-indazol-3-yl) -1 H-benzimidazole were obtained in the form of a beige powder. EXAMPLE 16 5-methoxy-2- (1 H -indazol-3-yl) -1 H-benzimidazole 5-Methoxy-2- (1 H -ndazol-3-yl) -1H-benzimidazole can be prepared following the procedure for the preparation of 2- (1H-indazol-3-yl) -3H-benzimidazole-5-carboxylate of methyl (Example 14): Starting with 200 mg of 1 H-indazole-3-carboxaldehyde and 274.4 mg of 4-methoxy-1,2-phenylenediamine dihydrochloride in 10 ml of nitrobenzene, 45.6 mg of 5-methoxy-2- (H-indazol-3-yl) -1 H-benzimidazole in the form of a light brown powder, whose characteristics are the following: 1 H NMR (DMSO d6, 400 MHz): 3.90 ppm (singlet, 3H); 7.00 ppm (doublet, 1H); 7.18 ppm (doublet, 1 H); 7.40 ppm (triplet, 1H); 7.55 ppm (triplet, 1H); 7.64 ppm (doublet, 1H); 7.73 ppm (doublet, H); 8.52 ppm (doublet, 1 H); 13.91 ppm (multiplet, 1H). EXAMPLE 17 2- (1 H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid 2- (1 H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid can be prepared by following the procedure for the preparation of 2- (1 H-indazol-3-y!) - 3 H -benzimidazole Methyl carboxylate (Example 14): Starting with 237 mg of 1H-indazole-3-carboxaldehyde and 305.5 mg of 2,3-diaminobenzoic acid hydrochloride in 10 ml of nitrobenzene, 20.5 mg of nitrobenzene are obtained. 2- (1H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid in the form of a beige powder, whose characteristics are the following: 1 H NMR, DMSO d 6, 400 MHz: 7,40 ppm (triplet , 1 HOUR); 7.42 ppm (triplet, H); 7.55 ppm (triplet, 1H); 7.72 ppm (doublet, 1 H); 7.90 ppm (doublet, 1 H); 8.02 ppm (doublet, 1H); 8.52 ppm (doublet, 1H); 13.68 ppm (multiple-te, H). EXAMPLE 18 5-Bromo-2- (1H-indazol-3-yl) -3H-benzimidazole 5-Bromo-2- (1 H-indazol-3-yl) -3H-benzimidazole can be prepared following the procedure for the preparation of 5,6-dimethyl-2- (1 H-indazol-3-yl) -1 H-benzimidazole (Example 15): Starting from 643 mg of 1 H-indazole-3-carboxaldehyde, 816 mg of 4-bromo-1,2-phenylenediamine and 836.5 mg of sodium metabisulfite in 15 ml of dimethylformamide , and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by chromatography under pressure on silica, 939 mg of 5-bromo-2- (1 H-indazol-3-yl) are obtained. ) -3H-benzimidazole in the form of a brick-red powder. EXAMPLE 19 2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid 2- (5-Ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid can be obtained from 2- (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) acid ) -1 H-benzimidazole-4-carboxylic acid by deprotection of the benzyl group in the presence of hydrogen and a catalyst such as palladium. 2- (2-Benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid can be prepared following the procedure for the preparation of 5,6-dimethyl-2- (1H -indazo! -3-yl) -1 H-benzimidazole (Example 15): Starting from 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde and 17.7 mg of 3,4-diaminobenzoic acid hydrochloride in 1 ml of nitrobenzene, and after purification by SPE ( SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) gave 50.9 mg of 2- (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid in the form of a yellow liquid. 2-Benzyl-5-ethoxy-2H-pyrazole-3-carboxaIdehyde can be prepared in the following manner: 4A molecular sieves are added to a solution of 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazole) -3-yl) methanol in 0.5 ml of dichloromethane, followed by the addition of 43.1 mg of pyridinium chlorochromate. After 20 hours at a temperature of about 20 ° C, the reaction mixture is filtered through Celite. The insoluble material formed is rinsed with ethyl acetate and then with dichloromethane. The filtrate is washed with water. After separating the phases by decantation, the aqueous phase is extracted again with dichloromethane. The organic phases are combined, dried over magnesium sulfate, filtered and then concentrated under reduced pressure. Thus, 21.6 mg of 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxaldehyde are obtained in the form of a brown liquid, whose characteristics are the following: 1 H NMR (DMSO d6, 400 MHz): 1, 35 ppm (triplet, 3H); 4.25 ppm (quartet, 2H); 5.30 ppm (singlet, 2H); 6.30 ppm (singlet, 1H); 7.25-7.40 ppm (multiplet, 5H); 9.72 ppm (singlet, 1 H). (2-Benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol can be prepared in the following manner: 11.1 mg of lithium aluminum hydride are added to a solution of 76 mg of 2-benzyl- Methyl 5-ethoxy-2H-pyrazoyl-3-carboxylate in 0.75 ml of tetrahydrofuran, cooled to a temperature of about 0 ° C by means of an ice bath. After 3 hours at a temperature of about 0 ° C, 22.2 mg of lithium aluminum hydride is added and the reaction medium is allowed to warm to a temperature of about 20 ° C. After 30 minutes at a temperature of approximately 20 ° C10 ml of ice cold water are added and the reaction mixture is then filtered through Celite. After separating the phases by sedimentation, the aqueous phase is extracted with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated under reduced pressure. 45.7 mg of (2-benzyl-5-ethoxy-2H-pyrazol-3-yl) methanol are thus obtained in the form of a brown liquid, whose characteristics are the following: "? NMR (DMSO d6, 400 MHz) : 1.35 ppm (triplet, 3H); 4.15 ppm (quatrain, 2H); 4.30 ppm (doublet, 2H); 5.00 ppm (triplet, 1H); 5.08 ppm (sin-glete, 2H); 5.70 ppm (singlet, 1 H); 7.20-7.40 ppm (multiplet, 5H). Methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylate can be prepared in the following manner: 5 mg of sodium iodide, 36 μ? of bromoethane and 70 mg of potassium carbonate, at a temperature of about 20 ° C, to a solution of 100 mg of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate. it in 1 ml of acetone. The reaction mixture is refluxed for 9 hours, cooled to a temperature of about 20 ° C and filtered. The filtrate is concentrated under reduced pressure. Thus 76 mg of methyl 2-benzyl-5-ethoxy-2H-pyrazole-3-carboxylic acid are obtained in the form of a solid, the characteristics of which are as follows: 1 H NMR (DMSO d6, 400 MHz) : 1, 35 ppm (triplet, 3H); 3.50 ppm (singlet, 3H); 4.22 ppm (quatrain, 2H); 5.22 ppm (singlet, 2H); 6.28 ppm (singlet, 1 H); 7.20-7.40 ppm (multiplet, 5H). Methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate can be prepared in the following manner: 1.72 ml of dimethylacetylene dicarboxylate is added, at a temperature of about 20 ° C, to a solution of 2 g. , 73 g of benzylhydrazine dihydrochloride in 45 ml of glacial acetic acid. The reaction mixture is refluxed for 3 'hours, cooled to a temperature of about 20 ° C and then concentrated under reduced pressure. After separating the insoluble material formed by filtration, 252 mg of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate are collected in the form of a white powder, the characteristics of which are the following: H NMR (DMSO) d6, 400 MHz): 3.76 ppm (singlet, 3H); 5.19 ppm (singlet, 2H); 5.85 ppm (singlet, 1 H); 7.25-7.45 ppm (multiplet, 5H); 11, 69 ppm (multiplet, 1 H). The filtrate can be purified by flash chromatography on 400 g of silica from 20-45 pm (applied in a 25/75 mixture of ethyl acetate). ethyl / cyclohexane; eluent: 25/85 and then 40/60 ethyl acetate / cyclohexane) to give an additional batch of methyl 2-benzyl-5-hydroxy-2H-pyrazole-3-carboxylate in the form of a white powder . EXAMPLE 20 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole 5,6-Dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimethyl-2- (1 H-indazole- 3-yl) -1H-benzimidazole (Example 15): Starting with 53.3 mg of 5-methyl-2H-pyrazole-3-carboxaldehyde, 65.9 mg of 4,5-dimethyl-1,2-phenylenediamine and mg of sodium metabisulfite, in 0.5 ml of ethanol and 1.5 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by chromatography under silica pressure , 20.8 mg of 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1H-benzimidazole are obtained in the form of a white powder. 5-Methyl-2H-pyrazole-3-carboxaldehyde can be prepared from ethyl 5-methyl-2H-pyrazole-3-carboxylate following the procedure described for the preparation of 1H-indazole-3-carboxaldehyde, starting from methyl indazolcarboxylate.
EXAMPLE 21 5,6-Dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1 H-benzimidazole 5,6-DimetiI-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimethyl-2- (1 H-indazol-3-yl) -1H-benzimidazole (Example 15): Starting from 16.2 mg of 5-thiophen-2-yl-2H-pyrazole-3-carboxaldehyde, 12.4 mg of 4.5- dimethyl-1, 2-phenylenediamine and 17.3 mg of sodium me-tabisulfite, in 0.2 ml of ethanol and 0.6 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by chromatography under pressure on silica and purification by LC / MS, gives 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1 H-benzimidazole in the form of a white powder. 5-Thiophen-2-yl-2H-pyrazole-3-carboxaldehyde can be prepared from commercial ethyl 5-thiophen-2-yl-2H-pyrazole-3-carboxylate following the procedure described in the preparation of H-indazole -3-carboxaldehyde couple of methyl 3-indazolecarboxylate. EXAMPLE 22 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzimidazole 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimetii-1 H-benzimidazole can be prepared by the following procedure described for the preparation of 5,6-dimethyl-2- (1 H- indazol-3-yl) -1 H-benzimidazole (Example 15): Starting from 100 mg of commercial 4-bromo-2H-pyrazole-3-carboxaldehyde77.8 mg of 4,5-dimethyl-1,2-phenylenediamine and 108.6 mg of sodium metabisulfite in 1 ml of ethanol and 2 ml of dimethylformamide and after purification by SPE (phase SCX, washing with methanol, extraction with 2N ammoniacal methanol) followed by chromatography under pressure on silica, gave 143.2 mg of 2- (4-bromo-2H-pyrazol-3-yl) -5,6-dimethyl- 1H-benzimidazole in the form of a yellow foam. EXAMPLE 23 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimethyl-2- (1 H-indazo! -3-yl) -1H-benzimidazole (Example 15): Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 110 mg of 4,5-dimetii-1,2-phenylenediamine and 153 mg of metabisulfite of sodium, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (C18 phase of 5 mm, dimensions 100 x 25 mm, flow rate 20 ml / minute, elution gradient acetonitrile / 0.07% TFA-water / 0.07% TFA from 5-95 to 95-5 (v / v)) and desalification by SPE (SCX phase, washing with methanol , extraction with 2N ammoniacal methanol), 82 mg of 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1H-benzimidazole are obtained in the form of a beige powder, whose characteristics are as follows: 1 H NMR (DMSO d6, 300 MHz): 1, 26 (t, J = 7 Hz: 3H); 2.31 (s: 6H); 2.70 (broad q, J = 7 Hz: 2H); 6.60 (broad s: 1 H); 7.22 (mu! T: 1H); 7.36 (mult: 1 H); 12.37 (mult: 1 H); 12.92 (mult: 1 H). 5-Ethyl-2H-pyrazole-3-carboxaldehyde can be prepared from Ethyl 5-ethyl-2H-pyrazoyl-3-carboxylate following the procedure described the preparation of 1H-indazole-3-carboxaldehyde starting from methyl indazolecarboxylate. Ethyl 5-ethyl-2H-pyrazole-3-carboxylate can be prepared according to the general procedure of the following reference: Kunio Seki et al., Chem. Pharm. Bull., 32 (4), 1568-1577 (1984). EXAMPLE 24 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1 H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimethyl-2- (1H -indazol-3-yl) -1H-benzimidazole (Example 15): Starting with 100 mg of 5-ethyl-2H-pyrazoI-3-carboxaldehyde, 134 mg of 3,4-ethylenedioxy-1,2-phenylenediamine and 153 mg of sodium metabisulfite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (5 mm, C18 phase, dimensions 100 x 25 mm, flow rate 20 ml / minute, elution gradient acetonitrile / 0.07% TFA -water / 0.07% TFA from 5-95 to 95-5 (v / v)) and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol), 60 mg of 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1H-benzimidazole are obtained in the form of a brown liquid, whose characteristics are the following: 1 H NMR (DMSO d 6, 300 MHz): 1.27 (t, J = 7 Hz: 3 H); 2.70 (broad q, J = 7 Hz: 2H); from 4.20 to 4.45 (mt 4H); 6.61 (broad s: 1 H); 6.72 (d, J = 8 Hz: 1H); 6.88 (broad d, J = 8 Hz: 1H); 12.50 (mult: 1H); 12.94 (mult: 1 H). EXAMPLE 25 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1 H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimetii-2- (1 H-indazol-3 -yl) -1H-benzimidazole (Example 15): Starting from 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 138 mg of 4-methoxy-1,2-phenylenediamine and 153 mg of sodium metabisulfite, in 1 mL of ethanol and 3 mL of dimethylformamide, and after purification by SPE (SCX phase, methanol washing, 2 N ammoniacal methanol extraction) followed by reverse phase HPLC (5 mm C18 phase, dimensions 100 x 25 mm) , flow rate 20 ml / minute, elution gradient: acetonitrile / 0.07% TFA - water / 0.07% TFA from 5-95 to 95-5 (v / v)) and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) affords 61 mg of 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1H-benzimidazole in the form of a brown liquid, whose characteristics are the following: "• H NMR (DMSO d6 with the addition of a few drops of CD3COOD, 300 MH z): 1, 26 (t, J = 7 Hz: 3H); 2.70 (q, J = 7 Hz: 2H); 3.79 (s: 3H); 6.61 (s: 1 H); 6.81 (dd, J = 8.5 and 2.5 Hz: 1 H); 7.03 (broad s: 1 H); 7.42 (d, J = 8.5 Hz: 1 H) EXAMPLE 26 2- (5-etl-2H-pyrazol-3-yl) -4-hydroxy-1 H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -4-hydroxy-H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimethyl-2- (1H-indazol-3-yl) ) -1 H-benzimidazole (Example 15): Starting with 100 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 100 mg of 2,3-diaminophenol and 153 mg of sodium metabisulfite, in 1 ml of ethanol and 3 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (5 mm, phase C18, dimensions: 100 x 25 mm, flow rate 20 ml / minute, elution gradient: acetonitrile / 0.07% TFA - water / 0.07% TFA from 5-95 to 95-5 (v / v)) and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) 6 mg of 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1H-benzimidazole are obtained in the form of a brown liquid, the characteristics of which are the following: 1 H NMR (DIVISO d6 with the addition of a few drops of CD3COOD, 300 MHz): 1.26 (t, J = 7 Hz: 3H); 2.70 (q, J = 7 Hz: 2H); 6.55 (t, J = 4.5 Hz: 1 H); 6.66 (s: 1 H); 6.96 (broad d, J = 4.5 Hz: 2H). EXAMPLE 27 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1H-benzimidazole 2- (5-Ethyl-2H-pyrazol-3-yl) -5-bromo-1 H-benzimidazole can be prepared following the procedure described for the preparation of 5,6-dimethyl-2- (1 H-indazol-3 -yl) -1H-benzimidazole (Example 15): Starting with 20 mg of 5-ethyl-2H-pyrazole-3-carboxaldehyde, 30 mg of 4-bromo-1,2-phenylenediamine and 30 mg of sodium metabisulfite, in 1 ml of ethanol and 2 ml of dimethylformamide, and after purification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) followed by reverse phase HPLC (phase C18 of 5 mm, dimensions: 100 x 25 mm , flow ml / minute, elution gradient: acetonitrile / 0.07% TFA - water / 0.07% TFA from 5-95 to 95-5 (v / v)) and desalification by SPE (SCX phase, washing with methanol, extraction with 2N ammoniacal methanol) 21 mg of 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1 H-benzimidazole are obtained in the form of a yellow powder, whose characteristics are the following: 1 H NMR (DMSO d6, 300 MHz): 1.28 (t, J = 7 Hz: 3H); 2.71 (q, J = 7 Hz: 2H); 6.67 (s: 1 H); 7.30 (dd, J = 8.5 and 2.5 Hz: 1 H); 7.49 (mt: 1H); 7,712 (broad s: H); from 12.5 to 13.5 (mult wide: 2H). The products of formula (I) of the present invention can also be prepared according to the following procedure: The products of Examples 97 to 145 of the present application represented in the following TABLE 3 can be prepared according to the schemes indicated above and, in particular, according to the procedures indicated below. EXAMPLE 97 3- (6-Phenylt-1 H-benzimidazol-2-yl) -2H-indazole Step 1: Synthesis of 3- (6-bromo-1 H-benzimidazol-2-yl) -2H-indazole ( Another preparation of Example 18 4.25 g of 1-hydroxybenzotriazole and 4.3 g of calcium sulfate are added at room temperature to a solution of 4.6 g of indazole-3-carboxylic acid in 50 ml of dimethylformamide. The reaction mixture is cooled to approximately 0 ° C and then 4.9 ml of β, ε-diisopropylcarbodiimide are added slowly after stirring for 2 hours at room temperature.
At room temperature, 5.9 g of 4-bromo-O-phenylenediamine are added. After stirring for 60 hours at room temperature, the reaction mixture is concentrated to dryness under reduced pressure. The brown oil obtained is taken up in 50 ml of water and extracted 3 times with 50 ml of ethyl acetate. The organic phases are combined, dried over magnesium sulfate and then concentrated to dryness under reduced pressure. This gives 18 g of a brown oil, which is taken up in 100 ml of a 20% solution of hydrochloric acid in ethanol. The mixture is refluxed for 4 hours and then concentrated to dryness, the brown oil obtained is taken up in 20 ml of water, a solution of aqueous ammonia is added until a pH of the mixture of about 8-9 is obtained. . The aqueous phase is then extracted 3 times with 30 ml of ethyl acetate and the organic phases are combined, they are dried over magnesium sulfate and concentrated to dryness under reduced pressure. After purification by chromatography under pressure on silica (eluent water / acetonitrile), there is thus obtained 5 g of 3- (6-bromo-1 H-benzimidazol-2-yl) -2H-indazole. IR spectrum (KBr): characteristic bands in 1621, 1570, 1441, 1344, 1324, 1273, 1239, 1135, 1042, 914, 804, 774 and 746 crrf1 Stage 2: Synthesis of 1- [2- (1-acetyl- 1 H-indazol-3-yl) -5-bromobenzimidazol-1-yl] ethanone 5 g of 3- (6-bromo-1 H-benzimidazol-2-yl) -2H-indazole are introduced into a 40 ml solution. of acetic anhydride and 40 ml of pyridine. The mixture is refluxed for 4 hours and then concentrated until dryness after returning to room temperature. The brown solid obtained is taken up in 50 ml of ethyl acetate and washed with 50 ml of a saturated solution of sodium hydrogencarbonate until a pH of 7-8 is obtained. The organic phase is dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure. The light brown solid obtained is triturated in 20 ml of ethyl acetate and then filtered off in a sintered glass funnel. Thus, 1.5 g of the compound 1 - [2- (1-acetyl-H-indazol-3-yl) -5-bromobenzimidazol-1-yl] ethanone is obtained. A second crop is obtained by chromatography over the filtrate under pressure on silica (eluent cyclohexane / ethyl acetate), ie 1.3 g of the same compound. Characteristics of the compound: 1 H NMR spectrum (300 MHz, (CD3) 2 SO d6, d in ppm), The mixture of two positional isomers is observed in the 50/50 portions. 2.61 and 2.62 (2 s, 3H in all); 2.80 (s, 3H); 7.62 (broad t, J = 7.5 Hz, 1 H); 7.68 and 7.71 (2 dd, J = 9 and 2 Hz, 1 H in all); 7.80 (ddd, J = 8.5, 7.5 and 0.5 Hz, 1 H); 7.91 and 8.01 (2 d, J = 9 Hz, 1 H); 8.18 and 8.20 (2 d, J = 2 Hz, H in all); 8.27 and 8.30 (2 d, J = 7.5 Hz, 1 H in tdoos); 8.46 (d, J = 8.5 Hz, 1 H). IR spectrum (KBr): characteristic bands in 1727, 1610, 1450, 1405, 1374, 1326, 1290, 1198, 1176, 964 and 760 crrf1. Stage 3: Synthesis of 3- (6-phenyl-1 H-benzimidazol-2-yl) -2H-indazole 40 mg of sodium carbonate, 7 mg of dihydrogenodichlorobis (di-tert-butylphosphonite-KP) paladate (2-) (POPd [0]) and 46 mg of phenylboronic acid are added to a 50 mg solution under argon atmosphere. of 1- [2- (1-acetyl-1 H-indazol-3-yl) -5-bromobenzimidazoI-1-yl] ethanone in 800 μ? of anhydrous te-trahydrofuran. The reaction mixture is refluxed for 3 hours and then cooled to room temperature. The mixture is then diluted with 3 m! of ethyl acetate and then washed twice with 2 ml of water. The organic phase is dried over magnesium sulfate and then concentrated to dryness under reduced pressure. 48 mg of brown solid are obtained, which solid dissolves in 500 μ? of tetrahydrofuran, to which 500 μ? of diethylamine. The reaction mixture is heated at 60 ° C for 4 hours and then allowed to return to room temperature. The mixture is then concentrated to dryness and the solid obtained is then purified by LC / MS to yield 12.5 mg of 3- (6-phenyl-1 H-benzimidazol-2-yl) -2H-indazole (6); analytical retention time 3.10, MS 311 [M + H] +. The products of formula (I) of the present application and, in particular, Examples 98 to 145, can be prepared according to the following procedure: The synthesis of Examples 98 to 145 is carried out in a manner similar to the synthesis of 3- (6-phenyl-1H-benzimidazol-2-yl) -2H-indazole (Example 97) but substituting phenylboronic acid with acids boronic acids of formula RB (OH) 2. The products of formula (I) of the present application which constitute Examples 28 to 96 and 146 to 180 of the present application are shown in Table 3: these products can be prepared according to the schemes indicated above and, in particular, as indicated above for the product of Example 1. -474- TABLE 3 5 10 fifteen -475- -476- -477- -478- fifteen -479- -480- -481- -482- -483- fifteen -484- 5 10 fifteen -48.5- -486- 5 10 fifteen -487- -489- 5 fifteen 490- -491- -492- 10 fifteen -493- -494- -495- -496- -497- -498- -499- -500- -501- -502- -503- -504- -505- -506- -507- -508- -509- 10 fifteen -510- eleven -511- -512- 10 -514- -515- -517- -518- -519- 5 10 fifteen -520- -521- fifteen -522- -523- 2- (1 H-ndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide -524- -525- The products of formula (I) of the present application can also be prepared according to the following procedure: In the previous scheme, the values of Z3 and Z4 are chosen between the values of R2 and R3 as defined above and the values of Z1 and -OZ2 are chosen between the values of X1, X2 or X3 and R1 represents a pyrazole radical, When Z1, Z3 and Z4 represent a hydrogen atom, it is possible, in particular, to prepare products of formula (I) of the present application according to the following synthesis scheme: The products of formula (I) of the present application which constitute Examples 181 to 228 of the present application are represented in Table 4 below: these products can be prepared according to the schemes indicated above and, in particular, the product of Example 181 It can be prepared according to the procedure indicated later. The products of Examples 182 to 228 can be prepared as the product of Example 181. EXAMPLE 181 2-r5- (benzyloxy) -2H-pyrazol-3-yn-1 H-benzoimidazole Step 1: The delation is performed as in the publication Chem. Pharm. Bull., 31 (4), 1228-1234 (1983); J. Org. Chem., 47 (2), 214-221 (1982). Step 2: To 1.015 g of the crude ester in 50 ml of MeOH was added 5.5 ml of 6 N NaOH and the mixture was refluxed for 2 h. After evaporating most of the methanol, the medium is cooled and concentrated HCl is added until pH = 2. After further evaporation to dryness, the solid is triturated three times with 30 ml of MeOH / AcOEt 1/1 and the The filtrate is evaporated to give 0.875 g of a light brown solid after drying. LC-MS: [gradient acetonitrile / water 0.1% HCOOH; Xterra RP18 2.1 x 50 mm] retention time 0.53 minutes, NH + = 129.95% pure. Step 3: To 3.5 g of PPA (polyphosphoric acid, 0.701 g of 1,2-phenyldiamine and 0.87 g of the acid from Step 2 were added. The mixture is heated at 150 ° C for 1.5 h. After cooling, concentrated NH4OH was added until pH = 3. The green precipitate was filtered, washed with water and then with acetone, After drying overnight under vacuum at 50 ° C, 2.1 g of solid containing about 50 remained. % of mineral salts MS: M + = 200. Stage 4: Ex 181: to 80 mg of the solid of Step 3 in 4 ml of NMP were added 137 mg of cesium carbonate and 72 mg of benzyl bromide. After 2 h the mixture is hydrolyzed with saturated KH2PO4 and extracted with AcOEt After evaporation, the crude mixture is subjected to preparative LC-MS to give 8 mg of pure compound LC-MS [acetonitrile / water gradient] 0.1% HCOOH; Xterra RP18 2.1 x 50 mm] retention time 3.17 minutes, MH + = 291. 97% pure.Similarly, Stage 4 is carried out with ben bromides cyl or allyl, ot-bromocarbonyl-15 compounds and acyl chlorides in DMF or NMP to provide the expected compounds of TABLE 4. Examples 181 to 228 of the present application are depicted in TABLE 4.
TABLE 4 CHEMISTRY 2- [5- (benzoyloxy) -2H 181 pyrazol-3-yl] -IH-benzoimidazole 2- [5- (3-Phenyl-allyloxy) - 182 2H-pyrazol-3-yl] -IH- H H benzoimidazole 2- [5- (2-Methyl-allyloxy) - 183 2H-pyrazol-3-yl] -1H-H H benzoimidazole 2- [5- (3,7-Dimethyl-octa-2,6-dienyloxy) -2H-184 pyrazol-3-yl] -1H-benzoimidazole H H 2- [5- (3-Bromo- | 185-benzyloxy) -2H-pyrazol-3-yl] -lH-benzoimidazole 3- [5- (1H-Benzoimidazol-186 2-yl) -lH-pyrazol-3-yloxymethyl] -benzonitrile F F 2- [5- (Trifluoromethyl-187-benzyloxy) -2H-pyrazol-3-yl] -IH-benzoimidazole H H 2- [5- (3,4-Dichloro-188-benzyloxy) -2H-pyrazol-3-yl] -lH-benzoimidazole H H 2- [5- (Biphenyl-4,13-ylmethoxy) -2H-pyrazol-3-yl] -lH-benzoimidazole H H 0 Ester 5- (lH-benzo-imidazol-2-yl) -1H-194 pyrazol-3-ylcoic acid 2,3-dichloro H H benzenesulfonic 2- [5- (2-Morpholin-4-yl-195-ethoxy) -2H-pyrazol-3-yl] -lH-benzoimidazole 2- [5- (2-Piperidin-l-ii- 196 ethoxy) -2H-pyrazol-3-yl] - IH-benzoimidazole 2- [5- (3 ~ Methoxy-197-benzyloxy) -2H-pyrazol-3-yl] -lH-benzoimidazole H H - - Ester 5- (lH-benzo-214 imidazol-2-yl) -1H-pyrazol-3-yl of isonicotinic acid Ester 5- (lH-benzo ~ imidazol-2-yl) -1H- CX 215 pyrazol-3-yl-2-dimethyl-H H propionic acid Ester 5- (?? - benzo-216 imidazol-2-yl) -1H-pyrazole-3-yl of benzyloxy-acetic acid Ester 5- (lH-benzo-217 imidazol-2-yl) -1H-pyrazol-3-ylco of benzoic acid Ester 5- (lH-benzo-218 imidazol-2-yl) -1H-pyrazol-3-yl-4-ethoxy-benzoic acid Example 229: Pharmaceutical composition Tablets corresponding to the following formula were prepared: Product of Example 1 0.2 g Excipient for a finished tablet containing 1 g (details of the excipient: lactose, talcum, starch and magnesium stearate). Example 1 is taken as an example of pharmaceutical preparation, it being possible for this preparation to be produced, if desired, with other products in the examples of the present application. EXAMPLE 230 (a) 5,6-Dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H-benzoimidazole A mixture of 5,6-dimethyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilyl-ethoxymethyl) -1 H -benzoimidazole [90 mg, Reference Example 1 ( a)], hydrochloric acid (2 ml, 4 N) and ethanol (4 ml) was heated to room temperature reflux for 16 hours and then cooled to room temperature. The pH of the reaction mixture was adjusted to 7 by the addition of saturated sodium bicarbonate solution. The resulting solid was filtered, then washed with water and then dried in a vacuum oven to provide 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H- benzoimidazole (38 mg). LC-MS (METHOD A): RT = 2.22 minutes; 259 (M + H) +. (b) 6-Chloro-5-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-ylV1 H-benzoimidazole Proceeding in a manner similar to that of Example 230 (a) above, but using 6-chloro-5-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1- (2-trimethylsilane) -ethoxymethyl) -1H-benzoimidazole [Reference Example 1 (b)] was prepared 6-chloro-5-methyl-2 - ("5-methylsulfanyl-1H-pyrazol-3-yl) -1H-benzoimidazole. (c) 6-Chloro-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole Proceeding in a manner similar to Example 230 (a) above but using 6-chloro-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1- (2-trimethylsilanyl- ethoxymethyl) -1 H-benzoimidazole [Reference Example 1 (c)] was prepared 6-chloro-2- (5-ethylsulfanyl-1 H-pyrazol-3-yl) -5-methyl-1 H-benzoimidazole . d) 2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1H-benzoimidazole Proceeding in a manner similar to Example 230 (a) above but using 2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H- Benzoimidazole [Reference Example 1 (d)] was prepared 2- (5-methylsulfanyl-1 H -pyrazol-3-yn-5-trifluoromethyl-1 H-benzoimidazole. (e) 2- (5-Cι-cypropropylmethyl sulfanil -1 H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazo Proceeding in a manner similar to Example 230 (a) above but using 2- (5-cyclopropylmethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1- (2-trimethylsilane-ethoxymethyl) -1H- Benzoimidazole [Reference Example 1 (e)] was prepared 2- (5-cyclopropylmethysulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole. LC-MS (METHOD A): Rj = 2.47 minutes; 299 (M + H) +. 2- (5-Ethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethy1-H-benzoimidazole Proceeding in a manner similar to Example 230 (a) but using 5,6-dimethyl-2- (5-ethylsulfani-1H-pyrazol-3-yl) -1- (2-tr ymethylsilane-ethoxymethyl) - 1 H-benzoimidazole [Reference Example 1 (f)] gave 2- (5-ethylsulfanyl-1 H -pyrazol-3-yn-5,6-dimethyl-1H-benzoimidazole LC-MS (METHOD A): Rj = 2.32 minutes; 273 (M + H) +. (G) 5,6-Dimethyl-2-r5- (pyridin-3-ylmethylsulfanyl) -1H-pyrazol-3-yn-1 H-benzoimidazole By proceeding in a manner similar to Example 230 (a) above but using 5,6-dimethyl-2- [5- (pyridin-3-yl) methylsulfanyl-1 H -pyrazol-3-yl] -1- (2-trimethylsilane) 1-ethoxymethyl) -1H-benzoimidazole [Reference Example 1 (g)] produced 5,6-dimethyl-2-r 5 - (pyridin-3-ylmethylsulfanyl) -1 H -pyrazol-3-yn-1 H-benzoimidazole in the form of a colorless solid .. 5-Fluoro-2-r5-methylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole Proceeding in a manner similar to Example 230 (a) above but, using 5-fluoro-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole [Reference Example 1 (h)] was prepared i fl uoro-2- [5-methylsulfanyl) -1 H -pyrazol-3-yl-1 H-benzoimidazole. MS: 249 (M + H) +. (i) 5,6-Dimethyl-2- (5-phenethylsulfanyl-1 H -pyrazol-3-yl) -1H-benzoimidazole Proceeding in a manner similar to Example 230 (a) above but using 5,6-dimethyl-2- (5-phenethylsulfanyl-1 H -pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H -benzoimidazole [Reference Example 1 (i)] was prepared dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1H-benzoimidazole. (j) 4- etl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H-benzoimidazole Proceeding in a manner similar to Example 230 (a) above but using 4-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 - (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazpl [Example Reference 1 (j)] was prepared 4-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1H-benzoimidazole. S: 245 (+ H) +. (k) 5,6-Dimethyl-2- (5-benzylsulfanyl-1 H -pyrazol-3-yl) -1 H-benzoimidazole Proceeding in a manner similar to Example 230 (a) above but using 2- (5-benzylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H- Benzoimidazole [Reference Example 1 (k)] was prepared 5,6-dimethyl-2- (5-benzylsulfanyl-1H-pyrazol-3-yl) -1H-benzoimidazole. (1) 6-Chloro-5-methyl-2- (5-morfoin-4-yl-1 H -pyrazol-3-yl) -1H-benzoimidazole By proceeding in a manner similar to Example 230 (a) above but using 6-chloro-5-methyl-2- (5-morpholin-4-yl-1 H -pyrazol-3-yl) -1- (2- trimethylsilyanoxy-ethoxymethyl) -1H-benzoimidazoI [Reference Example 1 (1)] was prepared 6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazol-3-yl) -H- benzoimidazole (m) 5,6-Dimethyl-2- [5- (thiophen-2-ylmethylsulfanin-1H-pyrazol-3-yn-1H-benzoimidazole By proceeding in a manner similar to Example 230 (a) above but using 5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1 H -pyrazol-3-yl] -1- (2-trimethylsilane) ethoxymethyl) -1H-benzoimidazole [Reference Example 1 (m)] was prepared 5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1 H -pyrazol-3-yl-1H-benzoimidazole. EXAMPLE 231 (2- (5-Ethylsulfanyl-1 H -pyrazol-3-iQ-5-methoxy-1 H-benzoimidazole hydrochloride A mixture of 3,3-bis-ethylsulfanyl-1- [5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -propenyone [~ 0.78mmol, Reference Example 2 (j )] and hydrazine hydrate (500 μl) in ethanol (6 ml) was heated to reflux temperature for 18 hours and then evaporated. The residue is purified on the Flashmaster device to provide 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methoxy-1- (2-trimethylalanyl-ethoxymethyl) -1H-benzoimidazole which was treated with ethanol (6 ml) and hydrochloric acid (3 ml). This mixture was heated at reflux temperature for 18 hours and then evaporated to yield 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methoxy-1 H-benzoimidazole hydrochloride. LC-MS (METHOD A): Rj = 2.17 minutes; 275 (M + H) +. EXAMPLE 232 (a) 5-Met l-2- (5-methylsulfanyl-4-propyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole A mixture of 2- (bis-methylsulfanyl-methylene) -1- (5-methyl-1 H -benzoimidazol-2-yl) -pentan-1-one [-0.49 mmol, Reference Example 2 (l)] and hydrazine hydrate (200 pl) in ethanol (6 ml) was heated at reflux temperature for 2 days and then evaporated. The mixture was then treated with hydrochloric acid (4 ml, 4 N) and the heating was continued at the reflux temperature for an additional 24 hours. The reaction mixture was cooled, then neutralized by the addition of sodium hydroxide solution (4 N) and then extracted with dichloromethane. The extract was evaporated to give 5-methyl-2- (5-methylsulfanyl-4-propyl-1 H -pyrazol-3-yl) -1 H-benzoimidazole. MS: 287 (M + H) +. (b) 2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole Proceeding in a manner similar to Example 233 (a) above but using 2- [bis- (4-methoxy-benzylsulfanyl) -methylene] -1- (5-methyl-1 H -benzoimidazol-2-yl) -pentan -1-one [Reference Example 2 (m)] was prepared 2 ^ (5- (4-methoxy-benzylsulfanyl) -4-propyl-1H-pyrazol-3-yl) -5-methyl-1 H-benzoimidazole.
MS: 393 (+ H) +. (c) 2- (5-Benzylsulfanyl-4-isopropyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole Proceeding in a manner similar to Example 232 (a) above but using 2- (bis-benzylsulfanyl-methylene) -3-methyl-1 - [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H -benzoimidazol-2-yl] -butan-1-one [Reference Example (2n)] was prepared 2- (5-benzylsulfanyl-4-isopropyl-1 H -pyrazol-3-yl) -5-methyl-1 H -benzoimidazole. MS: 363 (M + H) +. 2- (5-Met! [Sulfanyl-4-methyl-1 H -pyrazol-3-yl) -5-methoxy-1H-benzoimidazole Proceeding in a manner similar to Example 232 (a) above but using 1- [5-methoxy-1- (2-trimethylisilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -2-methyl-3- (bis- methanesulfanyl) -1-propenone [Reference Example 2 (r)] was prepared 2- (5-methylsulfanyl-4-methyl-1 H -pyrazol-3-yl) -5-methoxy-1H-benzoimidazole. (e) 2- (5-Methylsulfanyl-4-methyl-1 H -pyrazol-3-n-5-methyl-1 H-benzoimidazole Proceeding in a manner similar to Example 232 (a) above but using 1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -2-methyl-3- (bis-) methanesulfanyl) -1-propenone [Reference Example 2 (t)] was prepared 2- (5-methylsulfanyl-4-methyl-1 H-pyrazol-3-yl) -5-methyl-1 H-benzoimidazole. EXAMPLE 233 3- (5-Chloro-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine A solution of 5-chloro-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole [91 mg, Example 239 (a)] in ethanol (40 ml), under nitrogen, was treated with palladium on carbon (spatula tip, 5%). The mixture was stirred under hydrogen for 3 hours and then filtered through Celite. The filter cartridge was washed well with dichloromethane. The filtrate and combined avant liquids were evaporated to provide 3- (5-chloro-1H-benzoimidazol-2-in-1 H-pyrazol-4-ylamine (16 mg) LC-MS (METHOD A) : R = 2 minutes; 234 (M + H) +. (b) 3- (5,6-Dichloro-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5,6-dichloro-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole [Example 239 (b)] was prepared 3- (5,6-dichloro-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine.
LC-MS (METHOD A): Rj = 2.37 minutes; 268 (M + H) +. (c) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5,6-dimethyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole [Example 249 (a)] was prepared 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine as a brown solid. LC-MS (METHOD B): Ry = 2.29 minutes; 228.25 (M + H) +. (d) 3- (5-Ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5-ethyl-6-methyl-2- (4-nitro-1H-pyrazol-3-yl) -1H-benzoimidazole [Example 249 (b)] is prepared 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine as a brown solid. LC-MS (METHOD B): Rj = 2.14 minutes, 242.20 (M + H) +. (e) | 3- (6-chloro-5-methoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 6-chloro-5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole [0.7g, Example 249 ( c)] was prepared 3- (6-chloro-5-methoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine (0.54 g) as a brown foam. MS 264 (M + H) + - (f) 3- (5-Methoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5-methoxy-2- (4-nitro-1H-pyrazol-3-yl) -1 H -benzoimidazole [373 mg, Example 257 (f)] 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine (257mg) was prepared as a dark brown solid. LC-MS (METHOD H): Rj = 1, 23 minutes, 230.25 (M + H) +, 228.25 (MH). "(G) 3- (5-Ethoxy-1 H-benzoimidazole-2- il) -1 H-pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5-ethoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole [407 mg, Example 252 (c)] is prepared 3- (5-ethoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine (375 mg) as a dark brown oil. LC-MS (METHOD H): Rj = 1.43 minutes, 244.26 (M + H) +, 242.28 (MH). "H) 3- (5-Fluoro-6-methyl-1 H-benzoimidazole-2-yl- 1 H-pyrazole-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5-fluoro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole [Example 249 (d)] 3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine (0.590q) was prepared as a brown solid. LC-MS (METHOD J): Rj = 2.25 minutes, MS: 232.29 (M + H) +. (i) 3- (5-Trifluoromethoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine Proceeding in a manner similar to Example 233 (a) above but using 5-trifluoromethoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole [Example 249 (e)] - was prepared - (5-trifluoromethoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine (0.920 g) as a brown solid. LC-MS (METHOD J): Rj = 2.76 minutes, 284.23 (M + H) +. (j) 3- (5-Trifluoromethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine By proceeding in a manner similar to Example 233 (a) above but using 5-trifluoromethyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole [Example 249 (f)], 3- was prepared (5-trifluoromethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine (0.150 g) as a brown solid. LC-MS (METHOD B): RT = 3.00 minutes, 268.16 (M + H) + (k) 2- (4-Amino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester Proceeding from a Similar to Example 233 (a) above but using 2- (4-nitro-H-pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester [Example 249 (h)] methyl ester was prepared of 2- (4-amino-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (1.10 g) as a white off solid. Rj = 2.40 minutes, 258, 7 (M + H) +.
EXAMPLE 234 (a) 3-y 1 H-Benzoimidazol-2-yl) -1 H-indazole A mixture of 1,2-diaminobenzene (108 mg), indazole-3-carboxylic acid (1 18 mg) and polyphosphoric acid (1 ml) was heated at 50-60 ° C for 24 hours. The mixture was cooled, then diluted with ice-water (10 ml) and then treated with ethyl acetate (10 ml). The aqueous layer was basified by the addition of solid potassium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases were dried and then evaporated. The residue was chromatographed on silica eluting with a mixture of heptane and ethyl acetate to provide 3- (1 H-benzoimidazole-2-α-1 H-indazole (78 mg) LC-MS (METHOD A): Rj = 1, 28 minutes; 235 (M + H) +. (B) 3- (5-Methoxy-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 234 (a) above but using 4-methoxy-1,2-diaminobenzene hydrochloride, 3- (5- methoxy-1 H-benzoimidazol-2-yl) -1 H-indazole in the form of a solid. Rj = 1, 73 minutes; 339 (M + H) +. (c) f2- (ldazol-3-yl) -1 H-benzoimidazol-5-ill-phenyl-methanone By proceeding in a manner similar to Example 234 (a) above but using 3,4-diaminobenzophenone, [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -phenyl-methanone was prepared as a solid. . HPLC (METHOD A1): LC-MS (METHOD A): Ry = 1.73 minutes; 339 (M + H) +. (d) 2- (1 H-lndazol-3-in-3H-benzoimidazol-4-ol By proceeding in a manner similar to Example 234 (a) above but using 2,3-diaminophenol, 2- (1 H-indazol-3-yl) -3H-benzoimidazol-4-ol was prepared as a solid. LC-MS (METHOD A): Rj = 1, 63 minutes; 251 (M + H) +. (e) 2-Phenyl-1 H-imidazolf4,5-b1pyrazine By proceeding in a manner similar to Example 234 (a) above but using 2,3-diaminopyrazine [Reference Example 9] and benzoic acid, 2-phenyl-1 H-imidazole [4,5-bjpyrazine was prepared as a brown solid pale, mp 239-240 ° C. HPLC (METHOD A1): Rj = 10.18 minutes. (f) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-ylH H-indazole Proceeding in a manner similar to Example 234 (a) above but using 3- (5,6-dimethyl-H-benzoimidazol-2-yl) -1 H-indazole (28 mg). LC-MS (METHOD A): RT = 1, 34 minutes; 263 (M ÷ H) +. (g) 2- (1 H-indazol-3-yl) -3H-imidazo | "4,5-c | pyridine By proceeding in a manner similar to Example 234 (a) above but using 3,4-diaminopyridine, 2- (H-indazol-3-yl) -3H- was prepared imidazo [4,5-c] pyridine in the form of a solid. MS: 236 (M + H) +. HPLC (METHOD A): Rj = 2.48 minutes. (h) 2- (1 H-indazol-3-yl) -3H-imidazor4,5-b1pyridine By proceeding in a manner similar to Example 234 (A) above but using 2,3-diaminopyridine, 2- (1 H-indazol-3-yl) -3H-imidazor4,5-blpyridine was prepared as a solid. MS: 236 (M + H) +. HPLC (METHOD A): R = 2.49 minutes. EXAMPLE 235 (a) 2- (1 H-Pyrazole-3 -n-1 H-benzoimidazole A mixture of 1H-pyrazole-3-carbaldehyde (0.961 g, Reference Example 0), o-phenylenediamine (0.973 g), sodium bisulfite (1.898 g) and dry dimethylformamide (10 ml) was stirred at reflux for 2 hours, then cooled to room temperature and then poured onto crushed ice (35 g). The mixture was filtered and the solid was washed with aqueous sodium bicarbonate and then with water. The solid was dried under vacuum at 70 ° C and then crystallized from ethanol to give 2- (1 H -pyrazol-3yl) -1H-benzoimidazole (0.645 g) in the form of a pale yellowish solid, m.p. 335-338 ° C. [Elemental analysis- C, 62.56%, H, 4.04%, N, 29.14%. Calculated for C10H8N4: - C, 65.19%, H, 4.39%, N, 30.42]. (b) 3- (5,6-Dimethyl-1 H -benzolamdazol-2-yl) -5-methoxy-1 H-indazole By proceeding in a manner similar to Example 235 (a) above but using tert-butyl ester 3-formyl-5-methoxy-indazole-1-carboxylic acid [Reference Example 20 (a)] and 4,5-dimethylbenzene-1, 2-diamine was prepared 3 ^ (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole as a white solid. R = 2.35 minutes; 289 (M + H) +. (c) 3- (5-Ethyl-6-methyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole Proceeding in a manner similar to Example 235 (a) above but using 3-formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [Reference Example 20 (a)] and 4-ethyl-5-methyl-phenylenediamine [Reference Example 30] and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40- 60 oil (1: 1, v / v) was prepared 3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole in the form of a Pale yellow solid. LC-MS (METHOD B): Rj = 2.48 minutes; 307 (M + H) +. (d) 3- (5,6-DimetiM H-benzoimidazol-2-yl) -5-fluoro-1 H-indazole By proceeding in a manner similar to Example 235 (a) above but using 5-fluoro-1 H -indazol-3-carbaIdehyde [Reference Example 6 (c)] and 4,5-dimethylbenzene-1,2-diamine, prepared 3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -5-fluoro-1 H-indazole as a brown solid. LC-MS (METHOD B): R = 2.41 minutes; 281 (M + H) +. (e) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -6-fluoro-1 H-indazole Proceeding in a manner similar to Example 235 (a) above but using 6-fluoro-1 H -indazol-3-carbaldehyde [Reference Example 6 (d)] and 4,5-dimethylbenzene-1,2-diamine was prepared - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-fluoro-1 H-indazole (0.104 g) as a brown solid. MS: 281 (M + H) +. HPLC (METHOD B1): RT = 23.6 minutes. (f) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-1 H-indazole By proceeding in a manner similar to Example 235 (a) above but using 5-methyl-1H-indazole-3-carbaldehyde [Reference Example 6 (e)], 3- (5,6-dimethyl-1H-benzoyl) was prepared dazol-2-yl) -5-methyl-1 H-indazole in the form of a brown solid. LC-MS (METHOD B): Rj = 2.35 minutes; 277 (M + H) +. (g) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -6-methoxy-1 H-indazole By proceeding in a manner similar to Example 235 (a) above but using 6-methoxy-1H-indazole-3-carbaldehyde [Reference Example 6 (f)], 3- (5,6-dimethyl-1H-benzoimidazole) was prepared -2-il) -6-methoxy-1 H-indazole in the form of a pale orange solid. . LC-MS (METHOD B): Rj = 2.52 minutes; 293 (M + H) + (h) 5,6-Dimethyl-2-yl-phenyl-1 H -pyrazol-3-ylVl H-benzoimidazole By proceeding in a manner similar to Example 235 (a) above but using 4-phenyl-1 H-pyrazole-3-carbaldehyde [Reference Example 6 (g)], 5,6-dimethyl-2- (4-phenyl- 1 H-pyrazol-3-yl) -1 H-benzoimidazole as a white solid. LC-MS (METHOD B): Rj = 2.35 minutes; 289 (M + H) +. (i) 3- (5-Ethyl-1 H-benzoimidazol-2-n-1 H-indazole Proceeding in a manner similar to Example 235 (a) above but using 4-ethyl-phenylene diamine [Reference Example 29 (a)] a reaction temperature of 160 ° C and subjecting the reaction product to chromatography from rapid column on silica eluting with a mixture of ethyl acetate and hexane (2: 1) was prepared 3- (5-ethyl-1 H-benzoimidazol-2-iQ-1 H-indazole in the form of an off white solid. LC-MS (METHOD D): R = 23.13 mi¬ nutes, 263.3 (M + H) +. (j) 3- (5-Ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole Proceeding in a manner similar to Example 235 (i) above but using 4-ethyl-5-methyl-phenylene diamine [Reference Example 30 (a)] was prepared 3- (5-ethyl-6-metii-1 H-benzoimidazole -2-il) -1 H-indazole in. shape of a white solid off. LC-MS (METHOD D): Rj = 23.79 minutes, 277.3 (M + H) +. 3- (5-lsopropyl-6-methyl-1 H-benzoimidazol-2-1-H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4-isopropyl-5-methyl-phenylene diamine [Reference Example 30 (b)], 3- (5-isopropyl-6-methyl-1H-benzoimidazole was prepared -2-iQ-1 H-indazole in the form of an off white solid MS: 291.03 (M + H) +. HPLC (METHOD B1): Rj = 23.39 minutes. (I) 3- (5-Bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4-bromo-5-methyl-phenylene diamine [Reference Example 30 (c)], 3- (5-bromo-6-methyl-1 H-benzoimidazole was prepared -2-0.1 H-indazole in the form of an off white solid MS: 329.09 (M + H) +. HPLC (METHOD B1): RT = 22. 74 minutes (m) 3- (5-Bromo-1 H-benzoimidazol-2-Q-1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4-bromo-phenylenediamine [Reference Example 30 (i)], 3 ^ (5-bromo-1 H-benzoimidazol-2-yl) -1 H- was prepared Indazole in the form of a brown solid. LC-MS (METHOD D): Ry = 23.46 minutes, 315.15 (M + H) +. (n) 3- (5- (3-Cyano) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 3 ', 4'-diaminobiphenyl-3-carbonitrile [Reference Example 30 (f)], 3- (5- (3-cyano) phenyl-1H was prepared -benzoimidazol-2-yl) -1 H-indazole in the form of a white solid. MS: 335.3 (M + H) +. HPLC (METHOD B1): Rj = 21, 47 minutes. (o) 3- (5- (Pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 2350) above but using 4- (pyridin-3-yl) benzene-1,2-diamine [Reference Example 30 (g)], 3- (5- (pyrid-3-yl) was prepared ) -1 H-benzoimidazol-2-yl) -1 H-indazoi as a white solid. HPLC (METHOD B1): Rj = 8.58 minutes. (p) 3- (6-Methyl-5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above using 6-methylbiphenyl-3,4-diamine [Reference Example 30 (h)], 3- (6-methyl-5-phenyl-1H- was prepared benzoimidazole-2-α-1 H-indazole as a white solid MS: 325.3 (M + H) + HPLC (METHOD B1): RT = 14.48 minutes (q) 3- (5 -Fenyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4-biphenyl-3,4-diamine [Reference Example 30 (i)], 3- (5-phenyl-1H-benzoimidazole-2-? -? H-indazole in the form of a white solid MS: 31 1.2 (M + H) + HPLC (METHOD D): Rj = 24.54 minutes. (r) 3- (5- (2-Fluoro) phenyl-1 H-benzoimidazol-2-n-1 H-indazole By proceeding in a manner similar to Example 235 (i) above using 2'-fluorobiphenyl-3,4-diamine diamine [Reference Example 30 (j)], 3- (5- (2-fluoro) phenyl- 1 H-benzoimidazol-2-yl) -1 H-indazole as a white solid. MS: 329.2 (M + H) +. HPLC (METHOD B1): R = 22.54 minutes. (s) 3- (5- (3,4-methylenediox'-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4-benzo [1,3] dioxol-5-ylbenzene-1,2-diamine [Reference Example 30 (k)], 3- (5- ( 5,6-methylenedioxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole as a white solid. S: 355.2 (M + H) +. HPLC (METHOD B1): Rj = 22.04 minutes. (t) 3- (5- (2-Methoxyphenyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 2'-methoxybiphenyl-3,4-diamine [Reference Example 30 (l)], 3- (5- (2-methoxy) phenyl-1H- was prepared benzoimidazole-2-iQ-1 H-indazole as a white solid MS: 341.2 (M + H) + HPLC (METHOD B1): Rj = 22.09 minutes (u) 3- (5- (4-Chloro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4'-chlorobiphenyl-3,4-d-amine [Reference Example 30 (m)], 3- (5- (4-chloro) phenyl-1 was prepared H-benzoimidazol-2-yl) -1 H-indazole as a white solid. MS: 345.2 (M + H) +. HPLC (METHOD B1): Rj = 23.71 minutes. 3- (5- (4-Methoxyphenyl-1 H-benzoimidazol-2-ylH H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4'-methylbiphenyl-3,4-diamine diamine [Reference Example 30 (n)], 3- (5- (4-methyl) phenyl-1H was prepared -benzoimidazol-2-yl) -1 H-indazole as a white solid. MS: 325.1 (M + H) +. HPLC (C1 METHOD): Rj = 15.22 minutes. 3- (5-Benzyloxy-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4-benzyloxybenzene-1,2-diamine [Reference Example 30 (o)], 3- (5-benzyloxy-1H-benzoimidazole-2- was prepared il) -1 H-indazoi in the form of a white solid. MS: 339.3 (M + H) +. HPLC (METHOD B1): Rj = 22.32 minutes. (x) 3- (5,6-Methylenedioxy-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using benzo [1,3] dioxol-5,6-diamine [Reference Example 30 (p)], 3- (5,6-methylenedioxy-1 H-) was prepared benzoimidazol-2-yl) -1 H-indazole as a white solid. LC-MS (METHOD B): Rj = 2.25 minutes; 279.22 (M + H) +. (y) 3- (5,6-Dimethoxy-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (!) Above but using 4,5-dimethoxybenzene-1,2-diamine [Reference Example 30 (q)], 3- (5,6-dimethoxy-1H-benzoimidazole- 2-yl) -1 H-indazole as a white solid. LC-MS (METHOD B): R = 2.16 minutes; 295.26 (M + H) +. (z) 3- (5,6-Diethyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 4,5-diethylbenzene-1,2-diamine [Reference Example 30 (r)], 3- (5,6-diethyl-1H-benzoimidazole- 2-yl) -1 H-indazole as a white solid. LC-MS (METHOD B): R = 2.49 minutes; 291, 32 (M + H) + (aa) 3- (4,5-Dimethyl-1 H-benzoimidazole-2-i0-1 H-indazole By proceeding in a manner similar to Example 235 (!) Above but using 3,4-dimethylbenzene-1,2-diamine, 3- (4,5-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole was prepared in the form of a white solid. LC-MS (METHOD B): R = 2.31 minutes; 263.24 (M + H) + (ab) 2- (1H-lndazol-3-yl) -1 H -benzoimidazole-5-carbonitrile By proceeding in a manner similar to Example 235 (!) Above but using 3,4-diaminobenzonitrile-amine, 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carbonitrile was prepared as a white solid . LC-MS (METHOD D): Rj = 21, 81 minutes, MS: 260.10 (M + H) +. (ac) 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 3,4-diaminobenzoic acid methyl ester, 3- (5-methoxycarbonyl-1H-benzoimidazol-2-yl) -1H-indazole was prepared in the form of a solid white. LC-MS (METHOD D): RT = 22.13 minutes, 293.16 (M + H) +. (ad) 3- (5,6-Dimethyl-1 H-benzoirnidazol-2-iO-5-etQXi-1 H-indazole By proceeding in a manner similar to Example 235 (i) above but using 5-ethoxy-3-formyl-indazole-1-carboxylic acid tert-butyl ester [Reference Example 20 (d)], 3- (5.6 -Dimethyl-1H-benzoimidazol-2-yl) -5-ethoxy-1 H-indazo in the form of a pale orange solid. MS: 307 (M + H) +. HPLC (METHOD B1): Rj = 358 minutes. (ae) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-iQ-pyrazole-4-carboxylic acid ethyl ester By proceeding in a manner similar to Example 235 (a) above but using 3-formyl-pyrazole-4-carboxylic acid ethyl ester [Reference Example 6 (i)], 3- (5,6-dimethyl) ethyl ester was prepared -1H-benzoimidazol-2-iP-pyrazole-4-carboxylic acid in the form of a pale brown solid.
LC- S (METHOD B): 2.56 minutes; 285 (M + H) +. (af) 2- (4-lsopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester By proceeding in a manner similar to Example 235 (a) above but using 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Reference Example 6 (j)] and methyl 3,4-diaminobenzoate, 2-methyl-2-methyl ester was prepared. - (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid in the form of a yellow solid. LC-MS (METHOD B): 2.99 minutes; 328 (M + H) +. (ag) 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid ethyl ester By proceeding in a manner similar to Example 235 (a) above but using 3-formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester [Reference Example 6 (k)], 3- (5-ethyl) ethyl ester was prepared , 6-dimethyl-1H-benzoimidazol-2-yl) -5-methy1-pyrazole-4-carboxylic acid in the form of a white solid. LC-MS (METHOD B): Rj = 2.59 minutes; 299 (M + H) +. (ah) Cyclopropylamide "of 3- (1, 5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazole-4-carboxylic acid Proceeding in a manner similar to Example 235 (a) above but using indane-5,6-diamine (130 mg) and 3-formyl-H-pyrazole-4-carboxylic acid cyclopropylamide [150 mg, Reference Example 6 (q) )] and subjecting the reaction product to chromatography on silica [eluting with ethyl acetate / gradient 75 to 0% heptane] followed by trituration with acetone, cyclopropylamide of 3- (5,6,7-tetrahydro- 1, 3-diaza-s-indacen-2-H-pyrazole-4-carboxylic acid (31 mg) in the form of a white solid LC-MS (METHOD A): RT = 2.85 minutes, 308 (M + H ) +. (ai) 3- (5-Methoxy-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazole-4-carboxylic acid isopropylamide By proceeding in a manner similar to Example 235 (a) above but using 3-formyl-pyrazole-4-carboxylic acid isopropylamide [198 mg, Reference Example 6 (j)] and 4-methoxy-5-methyl-benzene-1 , 2-diamine [166 mg, Reference Example 29 (b)] and subjecting the reaction product to flash chromatography on silica eluting with dichloromethane / methanol (95: 5) followed by recrystallization from a mixture of ethyl acetate and n- pentane was prepared 3- (5-methoxy-6-methyl-H-benzolamdazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide (145 mg) as a white solid. LC-MS (METHOD H): RT = 2.09 minutes, 314.27 (M + H) +, 312.29 (M-H) -. (aj) 3-r5- (2-Morpholin-4-yl-ethoxy) -1 H -benzoimidazol-2-n-1 H-indazole Proceeding in a manner similar to Example 235 (f) above but using 4- (2-morpholin-4-yl-ethoxy) -benzene-1,2-diamine [Reference Example 29 (c)] and subjecting the product from reaction to preparative LC-MS was prepared 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1H-indazole (25 mg) in shape of a white solid. S: 364 (M + H) +. HPLC (METHOD B1): R = 19.38 minutes (ak) 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide.
Proceeding in a manner similar to Example 235 (i) above using (4,5-dimethylbenzene-1,2-diamine and 3-formyl-1H-pyrazole-4-carboxylic acid (2-methoxyethyl) -amide [Example of Reference 6 (n)] was prepared (3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-methoxyethyl) acid (87 mg) in the form of a solid color cream LC-MS (METHOD L): Rj = 4.23 minutes, 314.2 (M + H) +. (al) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazole-4-carboxylic acid propylamide Proceeding in a manner similar to Example 6 (i) above but using 4,5-dimethylbenzene-1,2-diamine and propylamide 4,5-dimethylbenzene-1,2-diamine and 3-formyl-1 H -pyrazole- 4-carboxylic [Reference Example 6 (0)] was prepared 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazole-4-carboxylic acid propylamide (73 mg) in the form of a pale yellow solid. LC-MS (METHOD L): Rj = 4.94 minutes, 298.29 (M + H) +. (am) (3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide.
Proceeding in a manner similar to Example 235 (i) above using (tetrahydro-pyran-4-yl) -amide 4,5-dimethyl-1,2-phenylenediamine and 3-formyl-1 H-pyrazole- 4-carboxylic acid [Reference Example 6 (p)] and recrystallization of the reaction product from methanol was prepared (3- (5,6-dimethyl-1 H-benzoimidazole- tetrahydro-pyran-4-iQ-amide). 2-yl) -1 H-pyrazole-4-carboxylic acid (228 mg) in the form of a white solid LC-MS (R METHOD): R = 9.40 minutes, 360 (M + H) +. an) '3- (5-Ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1H-indazole-5-carbonitrile Proceeding in a manner similar to Example 235 (i) above but using 4-ethyl-5-methyl-phenylenediamine [Reference Example 30 (a)] and 3-formyl-1 H-indazole-5-carbonitrile [Reference Example 68 ] 3- (5-ethyl-6-methyl-1H-benzoamidazol-2-yl) -1H-indazole-5-carbonitrile (133 mg) was prepared as a pale yellow solid. MS: 302 (M + H) +. HPLC (METHOD B1): R = 16.45 minutes (ao) 3- (5-difluoromethoxy-1 H-benzoimidazol-2-yl) - H -pyrazole-4-carboxylic acid isopropamide By proceeding in a manner similar to Example 235 (i) above but using 4-difluoromethoxy-benzene-1,2-diamine [Reference Example 30 (y)] and 3-formyl-pyrazole-4-carboxylic acid isopropylamide [Example of Reference 60 ')] isopropylamide of - (5-dif] uoromethoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (1 18 mg) was prepared in the form of a white solid. LC- S (METHOD L): Ry = 10.46 minutes, 336.19 (M + H) +. (ap) Cyclopropylamide "3- (5-difluoromethoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid By proceeding in a manner similar to Example 235 (ao) above but using 3-formyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 6 (q), 3- (5-difluoromethoxy-1) cyclopropylamide was prepared H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (63 mg) as a white solid. LC-MS (METHOD L): Rj = 10.18 minutes, 334.17 (M + H) +. (aq) 3- (6-3-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropamide Proceeding in a manner similar to Example 235 (i) but using 4-ethyl-5-methoxy-benzene-1,2-diamine [200 mg, Reference Example 30 (z)] and 3-formyl-isopropylamide pyrazole-4-carboxylic acid [Reference Example 6 (j)] 3- (6-ethyl-5-methoxy-1H-benzoimidazole-) isopropylamide was prepared 2-IQ-1 H-pyrazole-4-carboxylic acid (115 mg) as an off-white solid. LC-MS (METHOD L): Rj = 11, 34 minutes, 328.24 (M + H) +. (ar) Dihydrochloride. 3- (5,6-3-methyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carbonitrile Proceeding in a manner similar to Example 235 (i) above but (i) using 4,5-dimethylphenylene diamine and 3-formyl-1 H-indazole-5-carbonitrile [Reference Example 68] (i) a suspension of the reaction product in methanol with a solution of hydrochloric acid (4 M) in 1,4-dioxane followed by evaporation of the mixture (iii) trituration of the residue with methanol and (iv) recrystallization from diethyl ether, prepared 3- (5,6-dimethyl-1H-benzoamidazol-2-yl) -1H-indazole-5-carbonitrile dihydrochloride (133 mg) as a white off solid. LC-MS (METHOD B): Rj = 2.32 minutes. MS: 288 (M + H) +. 3- (5-nitro-1 H-benzoimidazol-2-yl) -1 H-indazole By proceeding in a manner similar to Example 235 (a) above but using 4-nitrophenylenediamine, 3- (5-nitro-1 H-benzoimidazole-2-H-indazole was prepared as a red solid MS: 280.17 (M + H) +. HPLC (METHOD B1): R = 3.00 minutes EXAMPLE 236 2- (5-Methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole A mixture of o-phenylenediamine (1.08 g) and 5-methylpyrazole-3-carboxylic acid (1.266 g) was finely ground and the finely ground material was heated at 160 ° C for 3 hours and then cooled to room temperature. ambient. The reaction mixture was recrystallized from ethyl alcohol (50 ml) to give a light blue solid (0.27 g). The filtrate provided another collection (0.1 g) at rest. The combined solids were recrystallized from ethyl alcohol to provide 2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole (223 mg) as a lilac solid, m.p. 322-324 ° C. [Elemental analysis: - C, 66.54%; H, 4.80%; N, 28.14%. Calculated for C1 1 H10N4: - C, 66.64%; H, 5.09%; N, 28.27%]. EXAMPLE 237. 2- (5-Ethoxy-1 H -pyrazol-3-iQ-H-benzoimidazole) A mixture of trifluoroacetic acid (6 ml) and 2- (5-ethoxy-1 H -pyrazol-3-yl) -1 - (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazole (300 mg, Reference Example 1 1) was stirred at 50 ° C for 1.5 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water (pH 10). The organic layer was dried and then evaporated. The residue was chromatographed on silica eluting with a mixture of dichloromethane and methanol (9: 1, v / v) and then recrystallized from toluene to give 2- (5-ethoxy-1H-pyrazol-3-yl) -1H-benzoimidazole (0.1 g) as a colorless solid, mp 217-219.5 ° C. [Elemental Analysis: - C, 62.26%; H, 5.23%; N, 23.44%. Calculated for C12H12N4O: - C, 63.15%; H, 5.30%; N, 24.55%] EXAMPLE 238 2- (5-Methylsulfanyl-isoxazol-3-yl) -1 H-benzoimidazole A mixture of 2- (5-methylsulfanyl-isoxazol-3-yl) -1- (2-trimethylsilyl-ethoxymethyl) -1H-benzoimidazole (160 mg, Reference Example 12), methanol (12 ml) and concentrated aqueous hydrochloric acid (2.45 ml) was heated to reflux for four hours and then cooled and then evaporated. He The residue was treated with aqueous sodium bicarbonate and the mixture was extracted with ethyl acetate. The extracts were dried and then evaporated to give 2- (5-methylsulfanyl-isoxazol-3-ylV1H-benzoimidazole (96 mg) as an off white solid, mp 179-181 ° C. 1H-NMR [(CD3 ) 2SO]: d 4.65 (s, 3H), 9.00 (s, 1H), 9.15-9.6 (m, 4H). EXAMPLE 239 (a) 5-Chloro-2- (4-nitro-1 H -pyrazol-3-yl) -1 H-benzoimidazole A solution of 4-chloro-benzene-1,2-diamine (500 mg) in hydrochloric acid (4 N) was treated with 4-nitro-pyrazoyl-3-carboxylic acid (826 mg) and then heated to the After reflux, under nitrogen, the reaction mixture was cooled to room temperature when the pH was adjusted to 8 by the addition of ammonium hydroxide and the mixture was extracted with ethyl acetate. The extracts were evaporated to give 5-chloro-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole. 5,6-dichloro-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole By proceeding in a manner similar to Example 239 (a) above, but using 4,5-dichloro-1,2-diaminobenzene, 5,6-dichloro-2- (4-nitro-1 H-pyrazol-3-yl was prepared ) -1 H-benzoimidazole. EXAMPLE 240 (Benzoimidazol-2-yl) -5-methylthio-3-p-aceol A mixture of 1 - [(3,3-bis (methylthio)) benzoimidazol-2-yl] propen-2-one [5.5 g, Reference Example 15], hydrazine hydrate (1.02 g) and acetonitrile trilo (50 ml) was stirred at reflux for 18 hours. The reaction mixture was cooled and the precipitate was isolated by filtration. Recrystallization from aqueous ethanol gave benzoimidazol-2-yl) -5-methylthio-3-pyrazole (3.36 g) as a beige crystalline solid, m.p. 242 ° C. [Elemental analysis: Econtrado: C 57,8; H 4.5; N 24.0, Calculated for C11H10N4S: C 57.37; H, 4.38; N, 24.33]. EXAMPLE 241 3- (5,6-Dimethyl-1 H-benzoimidazol-2-in-4,5,6,7-tetrahydro-1 H-indazole mixed 4,5-Dimethylbenzene-1,2-d-amines (90 mg) and acid 4,5,6,7-tetrahydro-1 H-indazole-3-carboxylic acid [110 mg, Reference Example 17 (a)] in a glass vial and then subjected to microwave radiation (900 W, domestic oven) two times for two minutes. The resulting solid was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (85:15, v / v) to provide 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl). ) -4,5,6,7-tetrahydro-1 H-indazole (30 mg) as a pale brown solid. LC-MS (METHOD B): R = 2.28 minutes; 267 (M + H) +. (b) 2- (5-lsopropyl-1 H -pyrazol-3-ii) -5,6-dimethyl-1H-benzoimidazole By proceeding in a manner similar to Example 241 (a) above, but using 5-isopropyl-1 H-pyrazole-3-carboxylic acid [Reference Example 17 (b)], 2- (5-isopropyl-1H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole (80 mg) as a brown solid. LC-MS (METHOD B): R = 2.27 minu¬ cough; 255 (M + H) +. 2- (5-Ethyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazoi Proceeding in a manner similar to Example 241 (a) above but using 5-ethyl-1 H-pyrazole-3-carboxylic acid [Reference Example 17 (c)] and grinding the brown solid reaction product with a mixture of sodium acetate. ethyl and hexane (1: 1, v / v) was prepared 2- (5-ethyl-1 H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole as a light brown solid. LC-MS (METHOD B): RT = 2.22 minutes; 241 (M + H) +. (d) 5,6-Dimethyl-2- (1, 4,5,6-tetrahydro-cyclopentapyrazol-3-iQ-1 H-benzoimidazole Proceeding in a manner similar to Example 214 (a) above but using 1, 4,5,6-tetrahydro-cyclopentapyrazol-3-carboxylic acid [Reference Example 17 (f)] and grinding the reaction product with ethyl acetate. ethyl, ether and methanol, 5,6-dimethyl-2- (1 A5,6-tetrahydro-cyclopentapyrazol-3-yl) -1H-benzoimidazole (50 mg) was prepared as a white off solid. HPLC (METHOD B1): R = 1.17 minutes. . EXAMPLE 242 (a) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -4-fluoro-1 H-indazole A mixture of 4,5-dimethylbenzene-1,2-diamine (70 mg) and 4-fluoro-1 H-indazole-3-carbaldehyde [80 mg, Reference Example 20 (b)] in dimethylformamide (8 ml) was heated at 120 ° C for 30 minutes and then at 100 ° C for 16 hours. The reaction mixture was cooled, then diluted with ethyl acetate and then washed five times with brine. The organic phase was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of 40/60 oil and ethyl acetate (1: 5, v / v) to provide 3- (5,6-dimethyl-1 H-benzoimidazole). 2-yl) -4-fluoro-1 H-indazole (104 mg) as a light brown solid. MS: 281 (M + H) +. HPLC (METHOD B1): R = 10.08 minutes. (b) 4-Chloro-3- (5,6-dimethyl-1 H-benzoimidazole-2-i0-1 H-indazole Proceeding in a manner similar to Example 142 (A) above but using 4-chloro-3-formyl-indazole-1-carboxylic acid tert-butyl ester [Reference Example 20 (c)] 4-Chloro-3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole (25 mg) was prepared as a white off solid. S: 299 (M + H) +. HPLC (METHOD B1): RT = 10.59 minutes. (c) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -5-chloro-1 H-indazole By proceeding in a manner similar to Example 242 (a) above but using 5-chloro-1 H -indazol-3-carbaldehyde [Reference Example 6 (h)], 3- (5,6-dimethyl-1H-benzoimidazole) was prepared -2-yl) -5-chloro-1 H-indazole (25 mg) as a pale brown solid. LC-MS (METHOD D): Rj = 24.24 minutes, 299 (M + H) +. EXAMPLE 243 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazol-5-ol A solution of 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-methoxy-1 H-indazole [34 mg, Example 235 (b)] at 0 ° C was treated with a solution of tribro boron wall in dichloromethane (0.30 m !, 1 N). The mixture was then heated to reflux temperature for 4 hours and then cooled and then treated dropwise with water. The pH was adjusted between 7 and 8 by the addition of saturated aqueous sodium bicarbonate solution and this mixture was then extracted twice with ethyl acetate. The organic extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The pale yellow solid residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and triethylamine (99: 1, v / v) to provide 3- (5,6-dimethyl-1 H-benzoimidazole-2 -yl) -1 H-indazol-5-ol (23 mg) as a white solid. LC-MS (METHOD B): Rj = 2.19 minutes; 279 (M + H) +. EXAMPLE 244 (a) 3- (5-n-Propyl-1 H-benzoimidazol-2-yl) -1 H-indazole A stirred solution of 4-propyl-benzene-1,2-diamine [57 mg, Reference Example 30 (d)] and sodium bisulfite (40 mg) in dimethylformamide (2 ml) was treated with indazole-3-carboxaldehyde [Example of Reference 6 (l)]. The reaction mixture was heated in a Smith Creator microwave at 200 ° C for 13 minutes and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane to provide 3- (5-n-propyl-1H-benzoimidazol-2-iO-1 H-indazole (74 mg) in of a pale brown solid MS: 277.3 (M + H) +. HPLC (METHOD B1): RT = 12.81 minutes. (b) 2- (1 H-lndazol-3-yl) -1 H- benzoimidazole-5-suphonic acid benzylamide By proceeding in a manner similar to Example 244 (a) above but using 3,4-diamino-N-benzyl-benzenesulfonamide [Reference Example 30 (x)] and heating to 230 ° C, benzylamide of 2- (1H-) acid was prepared indazol-3-yl) -1 H-benzoimidazole-5-sulfonic acid (235 mg) as a white solid. LC-MS (METHOD L): R = 6.35 minutes, 404.20 (M + H) +. (c) 3- (5-Methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole Proceeding in a manner similar to Example 244 (a) above but using 4-methanesulfonyl-benzene-1,2-diamine [Reference Example 49 (f)) and by heating to 210 ° C, 3- (5-methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole (105 mg) was prepared as a white solid. EXAMPLE 245 [2- (indazol-3-in-1 H-benzoimidazol-5-n-phenyl-methanol A stirred solution of [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -phenyl-methanone [200 mg, Example 234 (c)] in tetrahydrofuran (10 mL) at -78 ° C and under a nitrogen atmosphere, it was treated dropwise with a solution of dussobutylaluminum hydride in tetrahydrofuran (1.18 ml, 1 N). The reaction mixture was warmed to room temperature, then stirred for 6 hours and then partitioned between ether and sodium hydroxide solution (2 N). The organic phase was washed with water, then with brine and then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (3: 1, v / v) to provide r 2 - (indazol-3-in-1 H-benzoimidazole-5-in. phenyl-methanol (161 mg) as a white solid LC-MS (METHOD D): Rj = 21, 89 minutes, 341.3 (M + H) + EXAMPLE 246 (a) f2- acid ethylamide ( lndazol-3-yl) - H-benzoimidazole-5-n-carboxylic acid A stirred solution of [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid, hydroxybenzotriazole (189 mg) and diisopropyl-ethylamine (732 μ) in dimethylformamide (3 ml) was treated with ethylamine and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (267 mg). The reaction mixture was heated at 80 ° C overnight and then diluted in portions between ethyl acetate and 5% citric acid. The aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium hydrogen carbonate solution, then with brine and then dried over magnesium sulfate and then evaporated. The residual oil was subjected to preparative HPLC to provide f2- (indazol-3-iQ-1 H-benzoimidazole-5-yl-carboxylic acid ethylamide as a white solid.) LC-MS (METHOD B): Rj = 2.37 minutes; 306.27 (M + H) +. (b) [2- (lndazol-3-iP-1 H-benzoimidazole-5-ill-carboxylic acid methylamide.
By proceeding in a manner similar to Example 246 (a) above but using methylamine, F2- (indazol-3-yl) -1H-benzoimidazole-5-in-carboxylic acid methylamide was prepared as a white solid. LC-MS (METHOD B): Rj = 2.28 minutes; 292.30 (M + H) +. (c) [2- (lndazol-3-yl) -1H-benzoimidazole-5-ill-carboxylic acid dimethylamide By proceeding in a manner similar to Example 246 (a) above but using dimethylamine, r2- (indazol-3-yl) -1H-benzoimidazol-5-yl-1-carboxylic acid dimethylamide was prepared as a white solid. LC-MS (METHOD B): Rj = 2.38 minutes; 306.27 (M + H) +. (d) r2- (ldazol-3-yl) -1 H-benzoimidazole-5-in-carboxylic acid, isopropylamide By proceeding in a manner similar to Example 246 (a) above but using isopropylamine, r2- acid isopropylamide (indazole-3) was prepared il) -1H-benzoimidazole-5-yl-carboxylic acid in the form of a white solid. LC-MS (METHOD B): Rj = 2.48 minutes; 320.30 (M + H) +. (e) r2- (ldazol-3-yl) -1H-benzoimidazole-5-yl-carboxylic acid benzylamide By proceeding in a manner similar to Example 246 (a) above but using benzylamine, r2- (benzyl) acid benzylamide was prepared -3-0.1-1-benzoimidazole-5-α-carboxylic acid in the form of a white solid LC-MS (METHOD B): Rj = 2.68 minutes; 368.27 (M + H) +. ) [2- (lndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzamide By proceeding in a manner similar to Example 246 (a) above but using aniline, f2- (indazol-3-yl) -1H-benzoimidazole-5-ifl-carboxylic acid benzylamide was prepared as a white solid. LC-MS (METHOD B): Rj = 2.73 minutes; 354.26 (M + H) +. (g) 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropamide.
Proceeding in a manner similar to Example 246 (a) above but using 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -pyrazolo-4-carboxylic acid and isopropylamine, and subjecting the reaction product to chromatography flash over silica eluting with a mixture of dichloromethane and methanol (19: 1, v / v) 3- (5,6-dimethyl-1 H-benzoimidazol-2-iD-1 H-pyrazole-4-isopropylamide was prepared carboxylic in the form of a white off solid.
(METHOD B): Rj = 2.67 minutes; 298 (M + H) +. (h) 3- (5,6-Ditnetyl-H-benzoimidazol-2-iQ-1 H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethylethyl) -amide) By proceeding in a manner similar to Example 246 (a) above but using 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -pyrazol-4-carboxylic acid and 2-amino-2-methyl--propanol , and subjecting the reaction product to flash chromatography on silica eluting with a mixture of dichloromethane and meta- noi (19: 1, v / v) was prepared (3- hydroxy-1,1-dimethylethyl) amicla of 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole- 4-carboxylic acid in the form of a pale yellow solid. LC-MS (METHOD B): RT = 2.63 minutes; 328 (M + H) +. (i) 2- (4-isopropylcarbamoyl-H-pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide Proceeding in a manner similar to Example 246 (a) above but using 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid [Example 247 (c)] and 3- (aminomethyl) pyridine was prepared (2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -H-benzoimidazole-5-carboxylic acid pyridin-3-ylmethyl-amide as a white solid. -MS (METHOD B): R = 2.49 minutes; 404 (M + H) +. (j) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yO-5-methyl-H-pyrazole-4-carboxylic acid cyclopropylamide Proceeding in a manner similar to Example 246 (a) above but using 3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -5-methyl-pyrazoyl-4-carboxylic acid and cyclopropylamine, and subjecting the product of reaction to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19: 1; v / v) was prepared cyclopropylamide of 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) - 5-Methylene-1 H-pyrazole-4-carboxylic acid in the form of a white solid. LC-MS (METHOD B): Rj = 2.67 minutes; 310 (M + H) +. (k) 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yO-1 H-benzoamidazole-5-carboxylic acid phenylmethylamide By proceeding in a manner similar to Example 246 (a) above but using 2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -H-benzoimidazole-5-carboxylic acid [Example 247 (c)] and benzylamine, phenylmethyl was prepared 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid amide as a pale yellow solid. LC-MS (METHOD B): Rj = 3.17 minu¬ cough; 403 (M + H) +. (I) 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide.
Proceeding in a manner similar to Example 246 (a) above but using 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [Example 247 (c)] and 2- (aminomethyl) pyridine was prepared (2- (4-isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid pyridin-2-ylmethyl-2-ylmethide as a white off solid. -MS (METHOD D): R = 9.33 minutes, 367.28 (M + H) +. (M) (pyridin-3-ylmethyl) -amide of 2- (1 H-indazol-3-iQ-) acid 1 H-benzoimidazo I-5-carboxylic By proceeding in a manner similar to Example 246 (a) above but using 3- (aminomethyl) pyridine, 2- (1 H-indazol-3-yl) -1 pyridin-3-ylmethyl-amide was prepared. H-benzoimidazole-5-carboxylic acid (42.2 mg) in the form of an off white solid LC-MS (METHOD L): Rj = 4.96 minutes, 367.19 (M-H) -. (n) 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide By proceeding in a manner similar to Example 246 (a) above but using 3-methylbenzylamine, 2- (1 H-indazol-3-iQ-1 H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide (33.4 mg) in the form of a white solid MS: 382.52 (M + H) +. HPLC (METHOD B1): R = 16.22 minutes - (or) 4-methyl-benzylamide of 2- (1 H) acid -indazol-3-iQ-1 H-benzoimidazole-5-carboxylic acid By proceeding in a manner similar to Example 246 (a) above but using 4-methylbenzylamine, 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide (63, 5 mg) in the form of a white solid. MS: 382.54 (M + H) +. HPLC (METHOD B1): RT = 16.14 minutes. (p) í3- (2-Oxo-pyrrolidin-1-yl) propyl-1-amino acid 2- (1 H-indazol-3-iQ-1 H-benzoimidazole-5-carboxylic acid By proceeding in a manner similar to Example 246 (a) above but using 1- (3-aminopropyl) -2-pyrrolidinone, [3- (2-oxopyrrolidin-1-iOpropyl-2- (1H-indazole) -amide was prepared. 3-yl) -1 H-benzoimidazole-5-carboxylic acid (68.1 mg) as a white solid MS: 401.13 (MH) -. HPLC (METHOD B1): Rj = 1.1 1, 29 minutes. (q) 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-morpholin-4-ylethyl) amide By proceeding in a manner similar to Example 246 (a) above but using 4- (2-aminoethyl) morpholine, 2- (1 H-indazol-3-yl) 2- (morpholin-4-ylethyl) -amide was prepared ) -1 H-benzoimidazole-5-carboxylic acid (70.8 mg) as a white solid. MS: 389.12 (M-H). "HPLC (METHOD B1): Rj = 8.51 minutes. (r) 2- (1 H-indazol-3-ii) -1 H-benzoimidazole-5-carboxylic acid (2-methoxyethyl) amide By proceeding in a manner similar to Example 246 (a) above but using 2-methoxyethylamine, 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-methoxyethyl) amide ( 55.2 mg) in the form of a white solid. MS: 389.12 (-H) -. MS: 336.52 (M + H) +. HPLC (METHOD B1): RT = 1 1, 30 minutes. (s) 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-cyanoethyl) -amide.
By proceeding in a manner similar to Example 246 (a) above but heating the reaction to 50 ° C and using 3-aminopropionitrile, 2- (1 H-indazol-3-yl) - (2-cyanoethyl) -amide was prepared 1 H-benzoimidazole-5-carboxylic acid (15.4 mg) as a white solid. MS: 331, 15 (M + H) +, 329.17 (M-H). "HPLC (METHOD B1): Rj = 12.72 minutes. (t) (2- (1 H-indazol-3-yl) -1 H-benzoimidazoi-5-carboxylic acid 2-hydroxy-1,1-dimethyletin-amide By proceeding in a manner similar to Example 246 (a) above but heating the reaction to 50 ° C and using 2-amino-2-methyl-1-propanol, it was prepared (2-hydroxy-1,1-dithomethoxylamide). 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (29.6 mg) in the form of a brown oil LC-MS (METHOD L): Rj = 10.57 minutes, 350.16 (M + H) +, 348.18 (MH) "2- (1 H-indazol-3-yl) -1 H-benzoimidazole. (U) (3-imidazol-1-ylpropyl) -amide -5-carboxylic By proceeding in a manner similar to Example 246 (a) above but using 1- (3-aminopropyl) imidazole, 2- (1H-lndazol-3-yl) -1H acid (3-imidazol-1-ylpropyl) -amide was prepared -benzoimidazole-5-carboxylic acid (31.9 mg) in the form of a white solid .. LC-MS (METHOD B): R = 8.45 minutes, 386.22 (M + H) +, 384.26 (M-H) ". (v) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-ylV-H-pyrazole-4-carboxylic acid isobutylamide By proceeding in a manner similar to Example 246 (g) above but using isobutylamine, 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isobutylamide (101 mg) was prepared. ) in the form of a soft solid. LC- S (M-METHOD): Rj = 9.38 minutes, 312 (M + H) +. (w) 3- (5,6-Dimethyl-1H-benzoimidazol-2-iQ-1 H-pyrazole-4-carboxylic acid isopropamide.
By proceeding in a manner similar to Example 246 (g) above but using isopropylamine, 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide (100 mg) was prepared ) in the form of a white solid. LC-MS (METHOD L): R = 7.21 minutes, 298 (M + H) +. (x) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazole-4-carboxylic acid cyclopropylmethylamide By proceeding in a manner similar to Example 246 (g) above but using (aminomethyl) cyclopropane, 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethylamide was prepared. (105 mg) in the form of a white solid. LC-MS (METHOD M): R = 8.77 minutes, 310 (M + H) +. (y) 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide By proceeding in a manner similar to Example 246 (j) above but using tert-butylamine, 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-1 H- tert-butylamide was prepared pyrazole-4-carboxylic acid (57 mg) in the form of a dull white solid. LC-MS (METHOD M): Rj = 13.86 minutes, 326 (M + H) + (z) 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide dihydrochloride Proceeding in a manner similar to Example 246 (j) above but (i) using 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazo-1-carboxylic acid [97 mg , Example 263] and dimethylamine hydrochloride (23 mg), (ii) carrying out the reaction at room temperature overnight, and (iii) subjecting the reaction product to flash column chromatography [eluting with ethyl acetate to ethyl acetate / methanol (97: 3, v / v)] followed by treatment with 4 M hydrogen chloride in 1,4-dioxane and trituration with dichloromethane and diethyl ether was prepared dimethylamide dihydrochloride of 3- (5, 6-dimethyl-1 H-benzoimidazol-2-yl) -1 H -indazole-5-carboxylic acid (8 mg) as a white solid. LC-MS (M-METHOD): Rj = 9.37 minutes, 320 (M + H) +. (aa) 2- (4-Isobutyrylamino-1 H -pyrazol-3-yl) -1 H-benzoimidazo I-5-carboxylic acid benzylamide Proceeding in a manner similar to Example 246 (a) above but using 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [Reference example 35] and benzylamine prepared 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid benzylamide (17 mg) as a white solid. LC-MS (METHOD L): Rj = 1 1, 00 minu¬ cough, 403 (M + H) +. (ab) (2- (1 H-lndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-piperidin-1-ylethyl) amide By proceeding in a manner similar to Example 246 (a) above but using 1- (2-aminoethyl) piperidine and heating the reaction mixture at 50 ° C for 6 hours, (2-piperidin-1-ylethyl) amide was prepared 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid acid in the form of an oil. MS: 387.22 (M-H) -. HPLC (METHOD L): Rj = 5.03 minutes. (ac) (Pyridin-2-ylmethyl) -amide of 2- (1 H-lndazol-3-yl) - H-benzoimidazole-5-carboxylic acid By proceeding in a manner similar to Example 246 (ab) above, but using (2-aminomethyl) pyridine, 2- (1 H-indazol-3-yl) -1 H- (pyridin-2-ylmethyl) -amide was prepared. benzoimidazole-5-carboxylic acid in the form of an off white solid. MS: 367.28 (M + H) +. HPLC (METHOD B1): Rj = 9.33 minutes. (ad) r3- (4-Methyl-piperazin-1-yl) -propyl-amide of 2- (1 H-lndazol-3-yl) -1 H -benzoimid-3-zol-5-carboxylic acid By proceeding in a manner similar to Example 246 (ab) above but using 4- (3- (aminopropyl)) -1-methyl piperazine, [3- (4-methylpiperazin-1-yl) propylamide of 2- ( 1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid in the form of an oil. MS: 416.21 (M + H) +. HPLC (METHOD L): Rj = 4.46 minutes. (ae) N-f2- (1 H-indazol-3-ylV1 H-benzoimidazol-5-ill-isobutyramide) By proceeding in a manner similar to Example 246 (ab) above but using isobutyric acid and 2- (1 H-indazol-3-yl) -3H-benzoimidazol-5-amine [Example 265], N-f2- (1 H) was prepared -lndazol-3-yl) -1 H-benzoimidazole-5-in-isobutyramide as an off-white solid. S: 320.23 (M + H) +. HPLC (METHOD B1): Rj = 19.28 minutes. EXAMPLE 247 (a) r2- (Indazol-3-yl) -1 H-benzoimidazole-5-ill-carboxylic acid A stirred solution of 3- (5-methoxycarbonyl-1H-benzoimidazol-2-yl) -1H-indazole [84.5 mg, Example 235 (aq)] and sodium hydroxide (74 mg) in tetrahydrofuran (4 ml) ) and water (2 ml) was heated at 75 ° C overnight. The reaction mixture was evaporated and the oily residue was partitioned between ethyl acetate and water. The aqueous layer was acidified to pH 6 and extracted with ethyl acetate. The organic layers were dried over magnesium sulfate and then evaporated to give [2- (indazol-3-yl) -1 H- acid. benzoimidazole-5-ill-carboxylic acid (80 mg) in the form of an oil. MS: 279.14 (M + H) +. HPLC (METHOD H): Rj = 2.81 minutes. (b) 3- (5,6-Dimethyl-1 H-benzoimidazol-5-yl) -pyrazol-4-carboxylic acid Proceeding in a manner similar to Example 247 (a) above but using 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -pyrazol-4-carboxylic acid ethyl ester [Example 235 (ae)] and by carrying out the reaction at 60 ° C, 3- (5,6-dimethyl-1 H-benzoimidazol-5-yl) -pyrazol-4-carboxylic acid was prepared as a white solid. LC-MS (METHOD B): Rj = 2.17 minutes; 257 (M + H) +. (c) 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid Proceeding in a manner similar to Example 247 (a) above but using 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester [Example 235 (af)] , replacing tetrahydrofura- not with methanol and carrying out the reaction at 65 ° C, 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yn-1 H-benzoimidazole-5-carboxylic acid was prepared as a pale brown solid. which was used without further purification LC-MS (METHOD B): RT = 2.67 minutes; 314 (M + H) +. (d) 3- (5,6-D-methyl-1 H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid Proceeding in a manner similar to Example 247 (a) above but using 3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -5-methyl-pyrazole-4-carboxylic acid ethyl ester [Example 235 ( ag)], replacing tetrahydrofuran with methanol and carrying out the reaction at 65 ° C, prepared 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-pyrazole-4 acid. -carboxylic in the form of a white solid. LC-MS (METHOD B): RT = 2.75 minutes; 271 (M + H) +.
EXAMPLE 248 (a) N-3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-γ-isobutyramide stirred solution of 5,6-dimethyl-1H-benzoimidazoI-2-yl) -1 H -pyrazol-4-ylamine [83 mg, Example 233 (c)] and diisopropylethylamine (256 pL) in di-chloromethane ( mi) was treated with isobutyryl chloride (1 15 μ?). The reaction mixture was stirred for 30 minutes at room temperature and then treated with piperidine (500 pl) and stirring was continued for an additional hour. The reaction mixture was divided in portions between 5% citric acid. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of hexane and ethyl acetate to give N-r3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-in. Isobutyramide (49 mg) as a white solid. MS: 298.28 (M + H) +. HPLC (METHOD B1): Rj = 14.66 minutes. (b) N-3 - (5,6-Dimethyl-1 H-benzoimidazol-2-yn-pyrazol-4-ill-3-methyl-butyramide By proceeding in a manner similar to Example 248 (a) above but using isovaleryl chloride, N-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-3 was prepared -methyl-butyramide in the form of a white solid. MS: 312.28 (M + H) +. HPLC (METHOD B1): RT = 15.28 minutes. (c) N-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ill-2-phenyl-acetamide By proceeding in a manner similar to Example 248 (a) above but using phenylacetyl chloride, N-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yl1 was prepared -2-phenyl-acetamide in the form of a white solid. LC-MS (METHOD B): R = 2.83 minutes, 346.18 (M + H) +. (d) r3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) - H-pyrrazol-4-yl-1-cyclopropanecarboxylic acid amide By proceeding in a manner similar to Example 248 (a) above but using cyclopropanecarbonyl chloride, r3- (5,6-d.methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yl-1 was prepared cyclopropanecarboxylic acid amide in the form of a white solid. MS: 296.28 (M + H) +. HPLC (METHOD B1): Ry = 13.50 minutes. (e) r, 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-in-amide of methoxyacetic acid • By proceeding in a manner similar to Example 248 (a) above but using methoxyacetyl chloride, [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazole-4- was prepared methoxyacetic acid in-amide in the form of a white solid. MS: 300.33 (M + H) +. HPLC (C1 METHOD): Rj = 14.25 minutes. (f) f3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide-cyclopentanecarboxylic acid By proceeding in a manner similar to Example 248 (a) above but using cyclopentylcarbonyl chloride, r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yl-amide was prepared. Cyclopentanecarboxylic acid in the form of a white solid. MS: 324.39 (M + H) +. HPLC (METHOD B1): RT = 17.64 minutes. (g) f3- (5,6-Dimethyl-H-benzoimidazol-2-yl) -1 H -pyrazole-4-ill-amide of trimethylacetic acid By proceeding in a manner similar to Example 248 (a) above but using trimethylacetyl chloride, l-3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide was prepared. of tricymethylacetic acid in the form of solid white uri. MS: 312.39 (M + H) +. HPLC (METHOD B1): Rj = 19.52 minutes. (h) r3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide of tert-butylacetic acid By proceeding in a manner similar to Example 248 (a) above but using tert-butylacetyl chloride, r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yl- tert-butylacetic acid amide in the form of a white solid. MS: 326.29 (M + H) +. HPLC (METHOD B1): Rj = 19.52 minutes. (i) [3- (5,6-Dimethyl-1H-benzoimidazol-2-yn-1 H-pyrazole-4-in-butanoic acid-amide By proceeding in a manner similar to Example 248 (a) above but using butyryl chloride, [3- (5,6-dimethyl-1H-benzoimidazole-2-yl) was prepared.
H-pyrazole-4-in-amide of butanoic acid in the form of a white solid. MS: 298.34 (M + H) +. HPLC (METHOD B1): Rj = 15.07 minutes. (j) í3- (5,6-D ymethyl-1 H-benzo¾midazol-2-yl) -1 H-pyrazole-4-in-amide of isoxazole-5-carboxylic acid By proceeding in a manner similar to Example 248 (a) above but using isoxazole-5-carbonyl chloride, r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4- was prepared Isoxazole-5-carboxylic acid ill-amide in the form of a white solid. HPLC (METHOD B1): Rj = 10.01 minutes. (k) r3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide of S (+) - 2-methylbutanoic acid By proceeding in a manner similar to Example 248 (a) above but using S (+) - 2-methylbutyryl chloride, r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H was prepared -pyramide-4-in-amide of S (+ V2-methylbutanoic acid in shape of a white solid. MS: 312.1.8 (M + H) + HPLC (METHOD B1): Rj = 11, 15 minutes. (I) r3- (5-Ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazole-4-ill-cyclopropanecarboxylic acid Proceeding in a manner similar to Example 248 (a) above but using 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example 233 (d)] and cyclopropanecarbonyl chloride, f3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanocacylic acid was prepared in the form of a solid white. MS: 310.32 (M + H) +. HPLC (METHOD B1): Rj = 8.88 minutes. r3- (6-Chloro-5-methoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazole-4-β-amide of piperidino-1-carboxylic acid Proceeding in a manner similar to Example 248 (a) above but (i) treating a solution of 3- (6-chloro-5-methoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [ 0.2 g, Example 233 (e)] and diisopropylethylamine (392 mg, 4 eq) in tetrahydrofuran (25 ml) with piperidinocarbonyl chloride (450 mg, 4 eq), stirring overnight at room temperature, and evaporating the mixture of reaction, (ii) triturating the product of the reaction with water (30 ml) and ethyl acetate (50 ml) and extracting the aqueous layer with ethyl acetate, (ii) combining the organic phases, drying over magnesium sulfate. and then evaporating (iv) chromatographing the residue on silica gel (ethyl acetate), (v) triturating the partially purified material with ethyl acetate (15 ml) for 1.5 hours and filtering and (vi) evaporating the filtrate and chromatographing the residue on silica gel (20-0% ethyl acetate / heptane gradient) prepared r3- (6-chloro-5-methoxy-1H-benzoxydazole-2) -yl) - H-pyrazole-4-ill-amide of piperidino-1-carboxylic acid (50 mg) as a yellow solid, m.p. > 310 ° C. LC-MS (METHOD E) Rj = 3.25 minutes, 374 (M + H) +. (n) 3-f3- (6-Chloro-5-methoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-ill-1,1-dimethylurea By proceeding in a manner similar to Example 248 (m) above but using α, β-dimethylcarbamoyl chloride, 3-r3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole was prepared. -4-il1-1, 1-dimethylurea in the form of a yellow solid, mp > 300 ° C. LC-MS (METHOD E): Rj = 2.4 minutes, 335 (M + H) +. (o) i3- (5-Methoxy-1 H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide of cyclopropanecarboxylic acid Proceeding in a manner similar to example 248 (a) above but using 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H-prazol-4-ylamine [282 mg, Example 233 (f)] and cyclopropanecarbonyl chloride (0.558 ml) was prepared [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yl-cyclopropanecarboxylic acid (76 mg) as a yellow solid off. LC-MS (METHOD L): R = 5.25 minutes, 298.26 (M + H) +. (p) F3- (5-Ethoxy-1 H-benzoimidazol-2-ylV-1 H-pyrazole-4-ill-cyclopropanecarboxylic acid) Proceeding in a manner similar to Example 248 (o) above but using 3- (5-ethoxy-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [187 mg, Example 233 (g)] was prepared Cyclopropanecarboxylic acid 3- (5-ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-β-amide (112 mg) as a pale yellow solid LC-MS (METHOD H): Rj = 2.26 minutes, 312.23 (M + H) +, 310.30 (MH) -. (Q) 3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl. ) -1-Cyclopropanecarboxylic acid H-pyrazole-4 - ?? - amide Proceeding in a manner similar to Example 248 (a) above but using 3- (5-fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (h)] and cyclopropanecarbonyl chloride, r3- (5-fluoro-6-methyl-H-benzoimidazol-2-yl) -1H-pyrazole-4-yn-amide of cyclopropanecarbonate was prepared. boxyl (135 mg) in the form of a white solid. LC-MS (METHOD M): Rj = 11, 31 minutes, 300.31 (M + H) +. (r) [3- (5-Trifluoromethoxy-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-β-cyclopropanecarboxylic acid amide Proceeding in a manner similar to Example 248 (a) above but using 3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (i)] and cyclopropanecarbonyl chloride G3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yn-cyclopropanecarboxylic acid (275 mg) was prepared as a white solid. LC-MS (METHOD M): Rj = 13.57 minutes, 352.22 (M + H) +. (s) [3- (5-Trifluoromethyl-1 H-benzoimidazol-2-yl) -1-pyrazole-4-ill-cyclopropanecarboxylic acid Proceeding in a manner similar to Example 248 (a) above but using 3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233 (j)] and chloropropanecarbonyl chloride [3- (5-trifluoromethyl-1H-benzoimidazol-2-yn-1 H-pyrazol-4-yl-1-cyclopro-panocarboxylic acid 88 mg) was prepared as a white solid. LC-MS (METHOD M): Rj = 13.62 minutes, 338.12 (+ H) +. N-f3- (5-Trifluoromethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl-isobutyramide By proceeding in a manner similar to Example 248 (s) above but using isobutyryl chloride, N-r3- (5-trifluoromethyl-1H-benzolamdazol-2-yl) -1H-pyrazole-4-yl1 was prepared Isobutyramide (71 mg) as a white solid. LC-MS (METHOD M): Rj = 10.11 minutes, 336.12 (M + H) +. (u) f3- (5-Chloro-6-methyl-1H-benzoimidazole-2-yP-1 H-pyrazole-4-ill-cyclopropanecarboxylic acid Proceeding in a manner similar to Example 248 (a) above but using 3- (5-chloro-6-methyl-1H-benzoimidazoI-2-yl) -1 H -pyrazol-4-ylamine [Example 261] and Cyclopropanecarbonyl was prepared by r3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide of cyclopropanecarboxylic acid (46 mg) as a white solid. LC-MS (METHOD L): Rj = 7.06 minutes, MS: 316.26 (M + H) +. (v) r3- (5,6-Dimethyl-1 H-benzoimidazol-2-ylVl) 3,5-dimethyl-isoxazole-4-carboxylic acid By proceeding in a manner similar to Example 248 (a) above but using [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-β-amide acid-1-chloride. ^ -dimethyl-isoxazole ^ -carboxylic acid (62 mg) as a white solid. LC-MS (METHOD L): RT = 8.45 minutes, 351.32 (M + H) +. (w) N-r3- (5,6-dimethyl-1 H -benzoimidazo) -2-i)) - 1 H-pyrazole-4-in-acetamide By proceeding in a manner similar to Example 248 (a) above but using acetyl chloride, N-f3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-acetamide was prepared. (25 mg) in the form of a white solid. LC-MS (METHOD L): Rj = 6.34 minutes, 270.14 (M + H) +. (x) r3- (5,6-Dimethylmethyl-1 H-benzoimidazol-2-ylV1-furan-3-carboxylic acid furan-3-carboxylic acid By proceeding in a manner similar to Example 248 (a) above but using 3-furoyl chloride, f3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide was prepared. furan-3-carboxylic acid (80 mg) as a white solid. LC-MS (METHOD L): Rj = 7.10 minutes, 322.31 (M + H) +. (y) N-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-n-1 H -pyrazol-4-yl-1-4-methyl-benzamide By proceeding in a manner similar to Example 248 (a) above but using p-toluyl chloride, N- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yn-1 H -pyrazol-4-yl) was prepared -4-methyl-benzamide (42 mg) as a white solid LC-MS (METHOD L): R = 12.24 minutes, 346 (M + H) + EXAMPLE 249 5,6-Dimethyl-2- (4-nitro-1 H-pyrazol-3-yl) -1 H-benzoimidazole stirred solution (2-amino-4,5-dimethylphenyl) 4-nitro-H-pyrazole-3-carboxylic acid amide [5.7 g, Reference Example 36 (a)] in acetic acid (100 ml) was heated at 100 ° C for 1 hour, then cooled to room temperature and then evaporated. The oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated to give 5,6-dimethyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole (5.70 g) as of an orange solid. LC-MS (METHOD B): Rj = 2.30 minutes, 258.1 1 (M + H) +. 5-Ethyl-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole Proceeding in a manner similar to Example 249 (a) above but using 4-nitro-1H-pyrazoyl-3-carboxylic acid (2-amino-4-ethyl-5-methylphenyl) amide [Reference Example 36 (b)] 5-ethyl-6-meityl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole was prepared as a yellow solid. LC-MS (METHOD B): Rj = 2.61 minutes, 272.23 (M + H) + (c) 6-Chloro-5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl ) -1 H-benzoimidazole Proceeding in a manner similar to Example 249 (a) above but using 4-nitro-1 H-pyrazole-3-carboxylic acid (2-amino-5-chloro-4-methoxyphenyl) amide [1.5 g, Example Reference 36 (c)] 6-chloro-5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole (0.7 g) was prepared as a dark solid. MS: 294 (M + H) +. (d) 5-Fluoro-6-methyl-2- (4-nitro-1 H-pyrazol-3-yl) -1 H-benzoimidazole By proceeding in a manner similar to Example 249 (a) above but using 4-nitro-1 H-pyrazole-3-carboxylic acid (2-amino-4-fluoro-5-methyl-phenyl) -amide [Reference Example 36 (f)] 5-Fluoro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole (0.730 g) was prepared as a red solid. LC-MS (METHOD J): R = 2.76 minutes, 262.21 (M + H) +. (e) 2- (4-Nitro-1 H -pyrazol-3-yl) -5-trifluoromethoxy-1 H-benzoimidazole Proceeding in a manner similar to Example 249 (a) above but using 4-nitro-1 H-pyrazoyl-3-carboxylic acid (2-amino-4-trifluoromethoxy-phenyl) -amide [Reference Example 36 (g)] 2- (4-Nitro-1 Hp -razol-3-yl) -5-trifluoromethoxy-1 H-benzoimidazole (1.02 g) was prepared as a red solid. LC-MS (METHOD J): RT = 3.32 minutes, 314.19 (+ H) +. (f) 2-í4-Nitro-1 H-pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole Proceeding in a manner similar to Example 249 (a) above but using 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-trifluoromethyl-phenyl) -amide [Reference Example 36 (h) ] 2- (4-Nitro-1 H -pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole (0.195 g) was prepared as a na- ranja-colored solid. MS: 298.07 (M + H) +. HPLC (METHOD B): R = 3.50 minutes. (g) 5-Chloro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole By proceeding in a manner similar to Example 249 (a) above but using 4-nitro-1 H-pyrazole-3-carboxylic acid (2-amino-4-chloro-5-methyl-phenyl) -amide [Reference Example 36 (i)] 5-chloro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole (0.320 g) was prepared as an orange solid. LC-MS (METHOD C): Rj = 3.36 minutes, 314.19 (M + H) +. (h) 2- (4-Nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester Proceeding in a manner similar to Example 249 (a) above but using 3-amino-4 - [(4-nitro-1 H -pyrazole-3-carbonyl) -aminoj-benzoic acid methyl ester [Reference Example 36 (j) )] 2- (4-nitro-1 H-pyrazol-3-iD-1 H-benzoimidazole-5-carboxylic acid methyl ester (2.50 g) was prepared as a yellow solid LC-MS (METHOD B): R = 2.76 minutes, 288.12 (M + H) +. EXAMPLE 250 (a) 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -, 4,6,7-tetrahydro-pyrazolor-4,3-c 1-pyridine-5-carboxylic acid isopropylamide A solution of 3- (5,6-dimethyl-H-benzoimidazoI-2-yl) -4,5,6,7-tetrahydro-1 H-pyrazolo [4,3-c] pyridine [0.150 g, Example 251 ( a)] in dimethylformamide (4 ml) was treated with diisopropylethylamine (0.54 ml) and then with dimethyl carbamoyl chloride (0.122 ml). After stirring for 1 hour, the reaction mixture was quenched by the addition of methanol (0.1 ml) and then diluted with ethyl acetate. This mixture was washed five times with brine and then evaporated. The residue was treated with tetrahydrofuran (9 ml) and methanol (3 ml) and the resulting solution was then treated with potassium hydroxide (50 mg). This mixture was stirred for 1 one hour, then acidified by the addition of hydrochloric acid (1 M) and then extracted three times with ethyl acetate. The aqueous layer was basified by the addition of sodium carbonate and the resulting suspension was filtered, then washed with water, then air dried and then subjected to azeotropic distillation with toluene to produce 3- (5,6-isopropylamide) -d -methyl-1 H-benzoimidazol-2-l0-1, 4,6,7-tetrahydro-pyrazolo [4,3-c1pyridine-5-carboxylic acid in the form of a brown solid.
MS: 339 (M + H) +. HPLC (F1 METHOD): Rj = 8.67 minutes. (b) Cyclopropyl-3 - (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c1pyridin-5-in-methanone] By proceeding in a manner similar to Example 250 (a) above, but using cyclopropanecarbonyl chloride and stirring the reaction mixture for 16 hours, cyclopropyl-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) was prepared -1, 4,6,7-tetrahydro-pyrazolor4,3-clpyridin-5-in-methanone (68 mg) as a pale yellow solid. LC-MS '(METHOD M): R = 10.57 minutes, 336 (M + H) +. (c) lsopropyl-f3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c1pyridin-5-in-methanone] By proceeding in a manner similar to Example 250 (b) above, but using isopropylcarbonyl chloride and cyclopropylcarbonyl chloride, isopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4 was prepared 6,7-tetrahydro-pyrazolo [4,3-clpyridn-5-n-methanone (68 mg) as a white solid. LC- S (M-METHOD): j = 9.28 minutes, 338 (+ H) + (d) 1 -r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1, 4.67 -tetrahydro-pyrazolor4,3-c1pyridin-5-ill-2,2-dimethyl-propan-1-one By proceeding in a manner similar to Example 250 (b) above, but using trimethylacetium chloride and filtering the precipitate formed after basification with sodium carbonate, followed by azeotropic distillation with toluene, 1 -f3- (5,6-dimethyl) was prepared -1 H-benzoimidazol-2-yl) -1, 4,6,7- tetrahydro-pyrrazolo [4,3-clpyridin-5-ill-2,2-dimethyl-1-propan-1-one (49 mg) as a pale yellow solid. LC-MS (METHOD M): R = 1 1, 39 minutes, 352 (M + H) +. (e) 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,6,6,7-tetra-idro-pyrazole-4,3-c-pyridine-5-carboxylic acid methyl ester By proceeding in a manner similar to Example 250 (b) above but using methyl chloroformate, 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,617-tetrahydro-pyrazole-4-methyl ester was prepared. , 3-Clpyridine-5-carboxylic acid (89 mg) as a pale brown solid. LC-MS (METHOD M): RT = 8.95 minutes, 326 (M + H) +. EXAMPLE 251 (a) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-n-4,5,6J-tetrahydro-1 H-pyrazolo [4,3-c1pyridine] A solution of 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino- tert -butyl ester. 5-carboxylic acid [1.014 g, Example 252 (a)] in methanol (20 mL) was treated with a solution of hydrogen chloride in dioxane (5 mL, 4 M). After stirring for 16 hours, the reaction mixture was evaporated. The resulting beige solid was triturated with methanol to yield 3- (5,6-dimethyl-1 H -benzoimidazol-2-n-4,5,6,7-tetrahydro-1H-pyrazolor4,3-clpyridine (0.523 g) in the form of a pale yellow solid LC-MS (METHOD B): R = 0.63 minutes; 268 (M + H) +. (b) 3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c1pyridine] Proceeding in a manner similar to Example 251 (a) above, but using 3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -1, 4,6,7- tert -butyl ester tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic [Example 252 (d)] was prepared 3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -4,5,6, 7-tetrahydro-1H-pyrazolo [4,3-clpyridine (223 mg) as a white solid. LC-MS (K METHOD): Rj = 3.91 minutes, 288/290 (M + H) +. (c) 3- [5- (2-Morpholin-4-yl-ethoxy-1 H-benzoimidazole-2-in-4,5,6,7-tetrahydro-1H-pyrazolor4,3-c] pyridine Proceeding in a manner similar to Example 251 (A) above, but using 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1-tert -butyl ester, 4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic [Example 252 (e)] was prepared 3- [5- (2-morpholin-4-yl-ethoxy) -1 H- benzoimidazol-2-n-4,5,6,7-tetrahydro-1 H-pyrazolo [4,3-c1pyridine (200 mg) as a off-white solid. LC-MS (N METHOD): Rj = 2.55 minutes, 369.19 (M + H) +. (d) 3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine By proceeding in a manner similar to Example 251 (a) above but using 3- (5-trifluoromethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo-tert -butyl ester [4] , 3-c] pyridino-5-carboxylic acid [Example 252 (g)] was prepared 3- (5-trifluoromethyl-1H-benzoimidazol-2-yn-4,5,6,7-tetrahydro-1 H-pyrazolo [4 , 3-Clpyridine (500 mg) as an off white solid LC-MS (METHOD N): Rj = 3.21 minutes, 308.17 (M + H) +.
EXAMPLE 252 (a) 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-ClDiridino-5-) tert-butyl ester carboxylic A suspension of 5-tert-butyl ester of 3- (2-amino-4,5-dimethylphenyl) amide of 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5- dicarboxylic acid [1.091 g, Reference Example 39 (a)] in acetic acid (5 ml) was heated at 100 ° C for 12 minutes in a Smith Creator microwave. The mixture was carefully neutralized by the addition of solid sodium hydrogen carbonate and then extracted twice with ethyl acetate. The combined extracts were evaporated to yield 3- (5,6-dimethyl-1H-benzoimidazol-2-yn-1 ^, 67-tetrahydro-pyrazolor-4-pyridine-5-carboxylic acid tert -butyl ester LC-MS ( METHOD B): Rj = 2.79 minutes; 368 (M + H) +. (B) 5-Methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole By proceeding in a manner similar to Example 252 (a) above but (i) using (2-amino-4-methoxy-phenyl) -amide of 4-nitro-1 H-pyrazole-3- acid carboxylic acid [410 mg, Reference Example 36 (d)] and heating at 120 ° C for 5 minutes, (ii) pouring the reaction mixture into water, adjusting to pH 14 with 2 N sodium hydroxide and filtering, and (iii) ) by adjusting the pH of the filtrate to 6 with 2 N hydrochloric acid and collecting the precipitate by filtration, 5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole (327 mg. ) in the form of a yellow powder. LC-MS (METHOD H): Rj = 1, 61 minutes, 260.25 (M + H) +, 258.26 (M-H) -. (c) 5-Ethoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole Proceeding in a manner similar to Example 252 (b) above but using 4-nitro-1 H-pyrazole-3-carboxylic acid (2-amino-4-ethoxy-phenyl) -amide [824 mg, Reference Example 36 ( e)] 5-ethoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole (407 mg) was prepared in the form of a light brown powder. LC-MS (METHOD H): R j = 1, 82 minutes, 274.26 (M + H) +, 272.30 (MH) "(d) 3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1,6,6,7-tetrahydro-pyrazolo [4,3] tert-butyl ester -C1pyridine-5-carboxylic acid By proceeding in a manner similar to Example 252 (b) above but using 3- (2-amino-4-cyoro-5-methyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo tert -butyl ester [ 4,3-c] pyridine-5-carboxylic acid [Reference Example 39 (c)] and heating at 1 10 ° C for 15 minutes, 3- (5-chloro-6-methyl) -butyl tert-butyl ester was prepared 1 H-benzoimidazol-2-yl) -, 4,6,7-tetrahydro-pyrazolor4,3-clpyridine-5-carboxylic acid (391 mg) in the form of a brown solid. LC-MS (J METHOD): Rj = 3.53 minutes, 388 (M + H) +. (e) 3-r5- (2-Morpholin-4-yl-ethoxy-1H-benzoamidazol-2-yl-1, 4,6-tetrahydro-pyrazoloyl-4,3-clpyridine tert-butyl ester) -5-carboxylic Proceeding in a manner similar to Example 252 (b) above, but using 3- [2-amino-4- (2-morpholin-4-yl-ethoxy) -phenylcarbamoyl] -1- 4,6-tert-butyl ester. , 7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid [example Reference 39 (d)] was prepared 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-tetrahydro-tert-butyl ester β-polyrazor4,3-c1pyridino-5-carboxylic acid (350 mg) as a brown solid. LC-MS (N METHOD): Rj = 3.53 minutes, 469.24 (M + H) +. (f) 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyranor-4-clirazole By proceeding in a manner similar to Example 252 (a) above but using 1,4,6,6-tetrahydro-pyran [4,3-c] pyrazole (2-amino-4,5-dimethyl-1-phenyl) -amide -3-carboxylic acid [Reference Example 39 (e)] and heating to 3 [deg.] C. for 3 minutes was prepared 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7 -tetrahydro-pyranor4,3-c | pyrazole (49 mg) as a pale brown solid. MS: 269 (M + H) +. HPLC (C1 METHOD): Rj = 19.68 minutes. (g) 3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrrazolo [4,3-clpyridino-5-tert -butyl ester] carboxylic By proceeding in a manner similar to Example 252 (a) above but using 3- (2-amino-4-trifluoromethyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo-tert -butyl ester [4, 3-c] pyridine-5-carboxylic acid [Reference Example 39 (f)] was prepared 3- (5-trifluoromethyl-H-benzoimidazol-2-in-1, 4,6,7-tetrahydro) tert-butyl ester -pyrazolor4,3-clpyridine-5-carboxylic acid (950 mg) in the form of a brown solid LC-MS (N METHOD): Rj = 3.90 mi¬ nutes, 408 (M + H) +. EXAMPLE 253 (a) N-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yn-2-morpholin-4-yl-acetamide A stirred solution of 3- (5,6-dimethyI-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [100mg, Example 233 (c)] and diisopropylethylamine (307μ) in dichloromethane (10ml) was treated with chloroacetyl chloride (105 μ?). The reaction mixture was stirred for 30 minutes at room temperature and then treated with morpholine (575 pl) and then kept at room temperature overnight and then evaporated. The oily residue was partitioned between ethyl acetate and water and the organic phase was washed with water, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash chromatography on silica eluting with ethyl acetate to give N-3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ill-2-morpholine. -4-α-acetamide (49.9 mg) as an off-white solid. MS: 355.68 (M + H) +. HPLC (METHOD B1): R = 8.28 minutes. (b) 2-Dimethylamino-N-r3- (5,6-dimethyl-1 H-benzoimidazol-2-in-1 H-pyrazol-4-in-acetamide By proceeding in a manner similar to Example 253 (a) above but using dimethylamine hydrochloride, 2-dimethylamino-N-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4 was prepared -ill-acetamide (52 mg) as a white solid. LC-MS (M-METHOD): Rj = 8.28 minutes, 355.68 (M + H) +. (c) N- [3- (5,6-Dimethyl-1 H-benzoimidazol-2-i0-1 H-pyrazol-4-yl-1-piperidin-1-yl-acetamide By proceeding in a manner similar to Example 253 (a) above but using piperidine, N-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-yn-2-piperidin- 1-yl-acetamide (4 mg) as a white solid. LC-MS (METHOD M): RT = 7.69 minutes, 353.68 (M + H) +. EXAMPLE 254 (a) N-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-n-1 H-pyrazoyl-2- (1 H-1, 2,3,4-tetraazole -l-yl) -acetamide A stirred solution of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (295.7 mg) and diisopropylethylamine (269 pl) in dimethylformamide (19 ml) was treated with 3- ( 5,6-DimetiI-1H-benzoimidazol-2-yl) - H -pyrazol-4-ylamine and 2- (1 H-1,2,3,4-tetraazol-1-y!) Acetic acid (197.8 mg) The reaction mixture was stirred for 72 hours and then further treated with 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (295.7 mg), diisopropylethylamine (269 pl) and 2- (2H) acid. -1, 2,3,4-tetraazol-1-yl) acetic acid (197.8 mg) The stirring was continued for a further 48 hours and then the reaction mixture was partitioned between ethyl acetate and water. The organic was evaporated and the residue was treated with 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran (1: 4, 8 ml). After 1 hour this mixture was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and then evaporated to dryness. The residue was subjected to preparative HPLC to provide N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl-2- (1 H-1, 2, 3,4-tetraazol-1-yl) -acetamide (13.7 mg) in the form of an off white solid. MS: 338.14 (M + H) +. HPLC (METHOD B1): RT = 7.26 minutes. (b) N-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ill-isonicotinamide By proceeding in a manner similar to Example 254 (a) above but using isonicotinic acid, N- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yn-1 H-pyrazol-4-yl-1-isonicotinamide ( 9 mg) in the form of a white solid LC-MS (METHOD L): Rj = 8.71 minutes, 331, 21 (M + H) +. (C) 2-Cyclopropyl-N-r3- (5.6 -dimethyl-1 H-benzoimidazol-2-n-1 H-pyrazol-4-ill-acetamide By proceeding in a manner similar to Example 254 (a) above but using cyclopropylacetic acid, 2-cyclopropyl-N-F3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4- was prepared ill-acetamide (98 mg) as a light pink solid. LC-MS (METHOD M): R = 1 1, 04 minutes, MS: 310 (M + H) +. EXAMPLE 255 (a) 1-f3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yn-3-methyl-urea A solution of 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -H-pyrazol-4-ylamine [0.500 g, Example 233 (c)] in tetrahydrofuran (5 ml) was treated with iso- methyl cyanate (0.502 ml) and the mixture was stirred at room temperature for 16 hours. The mixture was then concentrated in vacuo and the residue redissolved in 1N potassium hydroxide in a mixture of methanol and tetrahydrofuran. trahydrofuran (1: 3, 5 ml). The mixture was stirred for an additional 1 hour, then concentrated and then partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting initially with a mixture of ethyl acetate and hexane (1: 1, v / v) and then with ethyl acetate to provide 1 -3- (5.6-). dimethyl-1 H-benzoimidazole-2-iQ-1 H-pyrazol-4-yn-3-methyl-urea (230 mg) as a white solid MS: 269 (M + H) +. HPLC (METHOD D1 ): Ry = 5.97 minutes (b) 1-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-ylV1 H -pyrazol-4-yl-3-isopropyl-urea) By proceeding in a manner similar to Example 255 (a) above but using isopropyl isocyanate, 1- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-ill- was prepared. 3-isopropyl urea in the form of a white solid. MS: 313 (M + H) +. HPLC (METHOD D1): R = 10.94 minutes. (c) 1-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-ylV 1 H -pyrazol-4-ill-3-phenyl-urea By proceeding in a manner similar to Example 255 (a) above but using phenyl isocyanate, 1 -r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-3 was prepared -phenyl-urea in the form of a white solid.
MS: 347 (M + H) +. HPLC (METHOD B1): Rj = 16.16 minutes. (d) 1-Benzyl-3- (3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-in-urea By proceeding in a manner similar to Example 255 (a) above but using benzyl isocyanate, 1 -benzyl-3 - ["3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-p was prepared. Razol-4-urea-urea in the form of a white solid MS: 361 (M + H) +. HPLC (METHOD D1): RT = 7.78 minutes (e) 3- (5, 6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolor4,3-c1pyridine-5-carboxylic acid Proceeding in a manner similar to Example 255 (a) above but using 3- (5,6-dimethyl-1 H-benzoimidazol-2-y!) - 4,5,6,7-tetrahydro-1 H-pyrazolo [4] , 3-c] pyridine [Example 251 (a)], and by subjecting the reaction product to flash column chromatography eluting with ethyl acetate / methanol (19: 1, v / v) wasopropylamide of 3- ( 5,6-dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolor-4,3-clpyridine-5-carboxylic acid (93.3 mg) as an off-white solid. LC-MS (METHOD M): Rj = 10.15 minutes, 353 (M + H) +. EXAMPLE 256 (a) r3- (5-Ethoxy-6-ethyl-1H-benzoimidazole-2-in-H-pyrazole-4-ylamide of cyclopropanecarboxylic acid A solution of [3- (5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid [0.3 g, Reference Example 48 (a)] and p-toluenesulfonic acid hydrate (1.2 g) in ethanol (25 ml) was heated at 80 ° C in an oil bath for 1 hour, then cooled and poured into aqueous sodium bicarbonate solution. The aqueous mixture was extracted twice with ethyl acetate (75 ml). The combined extracts were evaporated and the residue redissolved in a mixture of methylene chloride (100 ml) and methanol (10 ml). This solution was washed with aqueous sodium bicarbonate to remove some residual p-toluenesulfonic acid, then evaporated to give [3- (5-ethoxy-6-ethyl-1 H-benzoimidazol-2-yl) -1 H- pyrazole-4-inamide of cyclopropa-nocarboxylic acid (120 mg) as a white solid. LC-MS (METHOD E): Rj = 2.36 minutes, 340 (M + H) +. (b) 3- (, 5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H -pyrazole-4-ylamine Proceeding in a manner similar to Example 256 (a) but using 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 - (tetrahydropyran-2-yl) -1 H-pyrazole-4-ylamine [0.9 g, Reference Example 49 (d)] and p-toluenesulfonic acid (1.0 g) in ethanol (100 ml) and carrying out the reaction at 55 ° C for 2 hours, 3- (1, 5,6,7-tetrahydro-, 3-diaza-s-indacen-2-yl) -1 H-pyrazol-4-ylamine (800 mg) was prepared in the form of a brown solid. LC-MS (G METHOD): R = 2.68 minutes, 240 (M + H) +. (c) Í3- (1, 5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-ylV1-4-methyl-piperazin-1-carboxylic acid 4-methyl-piperazin-1-yl) Proceeding in a manner similar to Example 256 (a) but (i) using [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-ndacen-2-yl) -1- (tetrahydropyran 4-Methylpiperazino-1-carboxylic acid [2-yl] -1H-pyrazol-4-yl] -amide [171 mg, Reference Example 48 (b)], (ii) and carrying out the reaction at 55 ° C for 1.5 hours and then at 70 ° C for 1 hour and (iii) subjecting the reaction product to silica gel chromatography (ethyl acetate / gradient 0 to 20% methanol) was prepared G3- (1 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl-1-H-pyrazole-4-inamide of 4-methylpiperazino-1-carboxylic acid (55 mg) as a solid - white LC-MS (METHOD E): R = 1, 53 minutes, 366 (M + H) +. (d), 1-Dimethyl-3-r3- (, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H-pyrazole-4-illurea Proceeding in a manner similar to Example 256 (c) but using 1,1-dimethyl-3- [3- (, 5,6,7-tetrahydro-s-indacen-2-yl) -1- (tetrahydropyran-2- il) -H-pyrazol-4-yl] urea (230 mg) and p-toluenesulfonic acid hydrate [40 mg, Reference Example 48 (c)] was prepared, 1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H-pyrazol-4-inurea (106 mg) as a tan solid. LC-MS (METHOD E): Rj = 1, 97 minutes, 3 (M + H) +. EXAMPLE 257 (a) [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazole-4-ylamide of cyclopropanecarboxylic acid A solution of [3- (6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid [90] mg, Reference Example 48 (d)] in a 1/1 mixture of trifluoroacetic acid and dichloromethane (30 ml) was stirred for 5 hours and then evaporated. The residue was mixed with ethyl acetate (30 ml) and aqueous sodium bicarbonate (30 ml). The organic layer was evaporated to provide [3- (6-ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl-1-yl-cyclopropanecarboxylic acid (44 mg). LC-MS (METHOD E): Rj = 2.34 minutes, 330 (M + H) +. (b) t3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazole-4-ylamide of tetrahydropyran-4-carboxylic acid Proceeding in a manner similar to Example 257 (a) but using [3- (6-ethoxy-5-fluoro-1 H-benzimidazoI-2-iI) -1- (tetrahydropyran-2-yl) -1H-pyrazole 4-yl] tetrahydropyran-4-carboxylic acid amide [120 mg, Reference Example 48 (e)] was prepared r3- (6-ethoxy-5-fluoro-1 H-benzimidazole-2-yi) - 1 H-pyrazole-4-amide tetrahydropyran-4-carboxylic acid (65 mg). LC-MS (METHOD E) Rj = 2.17 minutes, 374 (M + H) +. (c) f3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-i0-1 H-pyrazole-4-ylamide of morpholino-4-carboxylic acid Proceeding in a manner similar to Example 257 (a) but using [3- (6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 - (tetrahydropyran-2-yl) -1 H -pyrazole- 4-yl] morpholino-4-carboxylic acid amide [140 mg, Reference Example 48 (f)] was prepared [3- (6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazole-4-illamide of morpholino-4-carboxylic acid (65 mg). LC-MS (METHOD E): Rj = 2.62 minutes, 375 (M + H) +. (d) r3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yn-1 H-pyrazole-4-ylamide of piperidino-4-carboxylic acid Proceeding in a manner similar to Example 257 (a) but using [3- (6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 - (tetrahydropyran-2-yl) -1 H -pyrazole- 4-yl] piperidino-4-carboxylic acid amide [127 mg, Reference Example 48 (g)] was prepared [3- (6-ethoxy-5-fluoro-1 H-benzimidazole-2-i0-1 H- pyrazole-4-illamide of piperidino-4-carboxylic acid (65 mg) LC-MS (METHOD E): R = 3.15 minutes. MS 373 (M + H) +. (e) 3-r6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H-pyrazole-4-ill-1,1-diethylurea Proceeding in a manner similar to Example 257 (a) but using 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 - (tetrahydropyran-2-H) -1 H-pyrazole-4 -yl] -1,1-diethylurea (1 10 mg, Reference Example 48 (h)] 3'-6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazole-4 was prepared -yl] -1, 1-diethylurea (65 mg). LC- S (METHOD E): Rj = 3.13 minutes, 361 (M + H) +. (f) 5-Methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole Proceeding in a manner similar to Example 257 (a) but using 5-methoxy-2- [4-nitro-1 - (tetrahydro-pyrano-2-yl) -1 H -pyrazol-3-yl] -1H-benzoimidazole (282 mg, Reference Example 50 (d)] 5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole (373 mg) was prepared as a red powder.
LC-MS (METHOD H): R = 1, 60 minutes, 260.22 (M + H) +, 258.23 (MH) ". (G) | 3- (5,6-dimethyl-1 H-benzoimidazole-2 -i0-1 Morpholino-4-carboxylic acid H-pyrazole-4-ylmethyl-amide Proceeding, in a manner similar to Example 257 (a) but using 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 - (tetrahydropyran-2-yl) -1 H -pyrazole- 4-yl] -1, 1 -diethylurea (110 mg, Reference Example 48 (h)] was prepared 3; r6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H-pyrazole -4-yl] -, 1 -diethylurea (65 mg). LC-MS (METHOD E): Rj = 3.13 minutes, 361 (M + H) +. (f) 5-Methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole Proceeding in a manner similar to Example 257 (a) but using 5-methoxy-2- [4-nitro-1 - (tetrahydro-pyran-2-yl) -1 H-pyrazole-3-yl] -1H-benzoimidazole (282 mg, Reference Example 50 (d)] 5-methoxy-2- (4-nitro-1 H -pyraz) -3-yl) -1H-benzoimidazole (373 mg) was prepared as a red powder . LC-MS (METHOD H): Rj = 1, 60 minutes, 260.22 (M + H) +, 258.23 (MH). "(G) r3- (5,6-dimethyl-1 H-benzoimidazole-2- il) -1-morpholino-4-carboxylic acid H-pyrazole-4-ylmethyl-amide Proceeding in a manner similar to Example 257 (a) but using (2,4-dimethoxy-benzyl) - [3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1- (tetrahydro-pyrano- 2-yl) -1H-pyrazol-4-ylmethyl] -amide of morpholino-4-carboxylic acid (Reference Example 59), subjecting the reaction product to flash chromatography on silica gel [eluting with dichloromethane ad] -chloromethane / methanol (9: 1)] and recrystallization from water / acetonitrile followed by trituration with diethyl ether was prepared [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazole-4 Morpholino-4-carboxylic acid-methylmethinamide (6.5 mg) as a white solid. LC-MS (METHOD M): Rj = 6.97 minutes, MS: 355.36 (M + H) +, 353.39 (MH) ". (H) 3- [3- (5-Difluoromethoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-Y11-1, 1 -diethyl-urea Proceeding in a manner similar to Example 257 (a) above but using 3- [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1- (tetrahydro-pyrano-2-yl) -1H-pyrazole -4-yl] -1, 1 -diethyl urea [Reference Example 48 (j)] was prepared 3 ^ [3- (5-difluoromethoxy-1 H-benzoimidazol-2-yn-1 H-pyrazole-4-) ifl-, 1-diethyl urea (60 mg) in the form of a white solid LC-MS (METHOD L): R = 10.61 minutes. 1 H NMR (CD3OD): d 1, 24 (t, 6H), 3.43 (q, 4H), 6.72 (bt, 1 H), 6.98 (d, H), 7.26 (s, 1 H), 7.47 (d, 1 H), 7.91 (s, 1 H). (i) f3- (5-Difluoromethoxy-1 H-benzoimidazol-2-iD-1 H-pyrazole-4-in-amide of piperidino-1-carboxylic acid Proceeding in a manner similar to Example 257 (a) above but using [3- (5-difluoromethoxy-1 H-benzoimidazol-2-yl) -1- (tetrahydro-pyrano-2-yl) -1 H -pyrazole- 4-yl] -amide of piperidino-1-carboxylic acid [Reference Example 48 (k)] r3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-ill- was prepared piperidino-1-carboxylic acid amide (52 mg) as a white solid. HPLC (METHOD E1): RT = 10.78 minutes. 1 H NMR (CD3OD): d 1.69 (bm, 6H), 3.64 (bm, 4H), 6.82 (bt, 1 H), 7.09 (bm, 1 H), 7.39 ( bm, 1 H), 7.61 (bm, 1 H), 8.05 (bm, 1 H).
EXAMPLE 258 (a) [3- (6-chloro-5-methoxy-1 H-benzoimidazol-2-in-1 H-pyrazole-4-in-amide of cyclopropanecarboxylic acid A solution of 3- (6-chloro-5-methoxy-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-ylamine [50 mg, Example 233 (e)] and diisopropylethylamine (40 μ) in Di-chloromethane (20 ml), stirred at room temperature, was treated with cyclopropanecarbonyl chloride (51 μl, 3 eq). After stirring for an additional 20 hours, the reaction mixture was evaporated and the residue was chromatographed on silica gel (ethyl acetate / heptane 1/1) to give the bis-acylated product (60 mg) as a solid orange. MS 400 (M + H) +. The bis-acylated product was dissolved in methanol (5 ml), then treated with potassium hydroxide solution (0.5 ml, 5 N), then stirred at 60 ° C for 1 hour, then cooled and then It vanished. The residue was treated with water (15 ml) and the pH of the aqueous mixture was adjusted to 5 and then extracted twice with ethyl acetate (25 ml). The combined extracts were dried over magnesium sulfate, then evaporated and the residue was triturated with diisopropyl ether, filtered and the precipitate was dried under vacuum at 60 ° C to provide [3- (6-chloro-5-methoxy). 1 H-benzoimidazole-2 il) -1 H-pyrazole-4-yl-cyclopropanecarboxylic acid (1 mg) as an off white solid, m.p. 225-226 ° C. LC-MS (METHOD E): Rj = 2.92 minutes, 332 (M + H) +. (b) [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1-pyrazole-4-ynamide of cyclopropanecarboxylic acid Proceeding in a manner similar to Example 258 (a) above but (i) treating a solution of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H -pyrazol-4-ylamine [310 mg, Example 256 (b)] and triethylamine (4 eq) in tetrahydrofuran (15 ml) with cyclopropanecarbonyl chloride (4 eq), (ii) stirring the reaction mixture at 60 °. C for 2 hours, (iii) treating the resulting bis-adhered product with methanolic potassium hydroxide (20 ml, 1.05 g KOH) at 40 ° C for 1 hour followed by treatment with aqueous ammonium chloride (200 ml) , (iii) extracting this mixture three times with ethyl acetate (100 ml), (iv) evaporating the combined extracts and (v) chromatographing the residue on silica gel (ethyl acetate / gradient of 50-0% heptane) G3- (1, 5,6,7-tetrahydro-1, 3-diaza-s-indacen-2-yl) -1H-pyrazole-4-ynamide of cyclopropanecarboxylic acid (50 mg) was prepared in the of a yellow solid. LC-MS (METHOD E) R = 2.05 minutes, 308 (M + H) +. (c) G3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H -pyrazole-4-β-amide of n-nolopholino-4-carboxylic acid By proceeding in a manner similar to Example 258 (b) above but using morpholino-4-carbonyl chloride, F3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) was prepared. -1H-pyrazole-4-H1-morpholino-4-carboxylic acid amide in the form of an orange solid. LC-MS (METHOD E) Rj = 2.45 minutes, 353 (M + H) +. (d) r3- (5-Methoxy-1H-benzoamidazole-2-ii) -1-piperazine-4-in-amide of piperidino-1-carboxylic acid Proceeding in a manner similar to Example 258 (a) above by treating 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine [257 mg, Example 233 (f)] with chloride of 1-piperidinocarbonyl in the presence of dusso-propylethylamine and using tetrahydrofuran as solvent was prepared (3- (5- methoxH H-benzoimidazole-2-IV1 H -pyrazole-4-ill-1-piperidino-carboxylic acid (46.1 mg) as a white solid. LC-MS (METHOD L) Ry = 6.43 minutes, 341, 28 (+ H) +. (e) 3-f3- (5-Methoxy-1 H-benzoimidazol-2-iD-1 H-pyrazole-4-ill-1,1-dimethyl-urea) By proceeding in a manner similar to Example 258 (d) above but using dimethylcarbamoyl chloride, 3- [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylH, 1 - dimethyl urea in the form of a white solid. LC-MS (METHOD M): R = 7.64 minutes, 301, 35 (M + H) +. (f) [3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-in-1 H-pyrazole-4-in-1-carboxylic acid-piperidino acid) Proceeding in a manner similar to Example 258 (d) above but (i) using 3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-y!) - 1 H -pyrazol-4-ylamine, 1-piperidinocarbonyl chloride (1.25 ml) and dilsopropylethylamine (1.74 ml) with tetrahydrofuran (20 ml) as solvent, and stirring the reaction mixture at room temperature for 48 hours and then at 50 ° C for 24 hours, (ii) treating the bis-acylated product with 1 M potassium hydroxide in methanol / tetrahydrofuran (1: 3, 20 ml) at room temperature and (iii) subjecting the product to flash column chromatography on silica eluting with ethyl acetate. ethyl / hexane (1: 1, v / v) to ethyl acetate / hexane (3: 1, v / v)] was prepared [3- (5-ethyl-6-methyl-H-benzoimidazole-2-yl) ) -1 H-pyrazole-4-in-amide of piperidinocarboxylic acid (425 mg) as a white solid. LC-MS (METHOD L): Rj = 7.55 minutes, 353.34 (M + H) +. (g) 3- [3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ill-1,1-dimethyl-urea Proceeding in a manner similar to Example 258 (f) but using 3- (5-fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example 233 (h)] and ?, '' -dimethylcarbamoyl chloride was prepared 3-r3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4 - ?? -, 1-dimethyl-urea ( 32 mg) in the form of a white solid. LC-MS (METHOD M): RT = 10.40 minutes, 303.34 (M + H) +. (h) [3-l5-Trifluoromethyl-1 H-benzoimidazol-2-yl) -1-pyrazol-4-yl-amide of morpholin-4-carboxylic acid Proceeding in a manner similar to Example 258 (f) above but using 3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [Example 233Q ')] and morpholino- 1 -carbonite was prepared G3- (5-trifluoromethyl-1H-benzoimidazol-2-iD-1 H-pyrazole-4-ill-amide of morpholino-4-carboxylic acid 131 mg) as a white solid. MS: 379.08 (MH). "HPLC (METHOD E1): R = 10.61 minutes (i) 3- (5,6-Dimethyl-H-benzoimidazol-2-yl) -1, 4-diethylamide , 6,7-tetrahydro-pyrazolo [4,3-c1pyridino-5-carboxy ico] Proceeding in a manner similar to Example 258 (f) above but using 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H- pyrazoo [4,3-c] pyridine [Example 251 (a)] and diethylcarbamoyl chloride, and subjecting the reaction product to flash column chromatography eluting with ethyl acetate to ethyl acetate / methanol (49: 1 , v / v) was prepared diethylamide of 3- (5,6-dmethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c1pyridine] -5-carboxylic acid (20.9 mg) in the form of an off white solid. LC- S (METHOD J): RT = 3.44 minutes, 367 (M + H) +. 0) r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolor4,3-clpyridin-5-in-pyrrolidin-1-yl-methanone By proceeding in a manner similar to Example 258 (1) above using 1-pyrrolidincarbonyl chloride and triturating the reaction product with ethyl acetate, methanol and dichloromethane, 3- (5,6-dimethyl-1) was prepared. H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolof4,3-c1pyridin-5-in-pyrrolidin-1-yl-methanone (68 mg) as an off white solid. 365 (M + H) +. HPLC (METHOD E1): Rj = 10.32 minutes. (K) r3- (5,6-Dimethyl-1 H-benzoimidazole-2-i0-1, 4,6,7- tetrahydro-pyrrazolo [4,3-c1pyridin-5-yl-1-piperidin-1-yl-methanone] Proceeding in a manner similar to Example 258 (f) above but using. 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -4, 5,6,7-tetrahydro-1H-pyrazolo [4,3-c] pyridine [Example 251 (a)] and subjecting the reaction product to flash column chromatography eluting with ethyl acetate / oil (5: 1, v / v) at 100% ethyl acetate to ethyl acetate / methanol (19: 1, v / v) was prepared ["3- (5,6-dimethyl-H-benzoimidazol-2-yl) -1, 4,6,7-tetra idro-pyrazolor4,3-clpyridin-5-in-piperidin-1-yl-methanone (93.3 mg) as an off-white solid LC-MS (METHOD L ): RT = 6.77 minutes, 379 (M + H) +. (I) f3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1, 4,6,7-tetrahydro-pyrazolor4 , 3-c] pyridin-5-in-morpholin-4-yl-methanone By proceeding in a manner similar to Example 258 (k) above, but using 1-morpholinocarbonyl chloride and subjecting the reaction product with azeotropic distillation with toluene and dichloromethane, [3- (5,6-dimethyl-1H β-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolor-4,3-clpyridin-5-yl-1-morpholin-4-yl-methanone (32 mg) as an off-white solid. MS: 381 (M + H) +. HPLC (METHOD E1): Rj = 9.39 minutes. (m) 3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolof4,3-c1pyridino-5-carboxylic acid diethalamine Proceeding in a manner similar to Example 258 (a) above but (i) using 3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H -pirazolo [4,3-c] pyridine [Example 251 (b)] and diethylcarbamoyl chloride, and (ii) subjecting the reaction product to flash column chromatography, eluting with ethyl acetate to ethyl acetate / methanol (47: 3, v / v) followed by trituration with eta ol, diethylamide of 3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -1, 4,6,7- tetrahydro-pyrrazolo [4,3-chloropino-5-carboxylic acid (35.6 mg) in the form of a pale yellow solid. MS: 387/389 (M + H) +. HPLC (METHOD E1): Rj = 11, 07 minutes. (n) r3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-arnide of morpholino-4-carboxylic acid Proceeding in a manner similar to Example 258 (p) above but using 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example-p. 233 (c)] and 1-morphoinocarbonyl chloride was prepared. Morpholino-4-carboxylic acid 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) - H -pyrazole-4-in-amide (206 mg) in form of a white solid LC-MS (METHOD L): R = 7.36 minu¬ cough, 341 (? +?) + · (o) f3- (5,6-Dimethyl-1 H -benzoimidazole-2-yl) -1 H -pyrazole-4-yl-piperazine acid -1-carboxylic By proceeding in a manner similar to Example 258 (p) above but using 1-piperidinocarbonyl chloride, r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-amide was prepared. of piperidino-1-carboxylic acid (185 mg) as a white solid. LC-MS (METHOD M): Rj = 10.79 mi¬ nutos, 339 (M + H) +. (p) 3- [5- (2-Morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yn-1,4,6,7-tetrahydro-pyrazolor-4-trifluoride-5-diethylamide -carboxylic By proceeding in a similar manner Example 258 (a) above but using 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -4,5,6,7-tetrahydro -1 H-pyrazole or [4,3-c] pyridine [Example 251 (c)] and diethylcarbamoyl chloride was prepared diethylamide of 3-r5- (2-morpholin-4-yl-ethoxy) -1 H- benzoimidazol-2-in-1, 4,6,7-tetrahydro-pyrazolor4,3-c1pyridino-5-carboxylic acid (28 mg) as a white solid. MS: 468.30 (M + H) +. HPLC (METHOD E1): Rj = 9.47 minutes. (q) 3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) - 1,4,6,7-tetrahydro-pyrazolor-4,3-c-pyridine-5-carboxylic acid diethylamide Proceeding in a manner similar to Example 258 (a) above but using 3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-pyrazolo [4.3- c] pyridine [Example 251 (d)] and diethylcarbamoyl chloride was prepared 3- (5-trifluoromethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetra idro-pyrazolor 4,3-diethylamide -Clpyridine-5-carboxylic acid (103 mg) as a white solid. S: 407.17 (M + H) +. HPLC (METHOD E1): Rj = 10.81 minutes.
By proceeding in a manner similar to Example 258 (p) above but using dimethylcarbamoyl chloride, 3- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yn-1 H-pyrazole-4-yl- 1,1-dimethyl-urea MS: 299 (M + H) +. HPLC (METHOD E1): RT = 8.24 minutes.
EXAMPLE 259 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2H-Tetrazol-5-yl) -etin-amide A stirred solution of 2- (1H-indazol-3-yl) -H-benzoimidazole-5-carboxylic acid (2-cyanoethyl) -amide [150 mg, Example 246 (s)] and azido-tributyl-tin (2-cyanoethyl) -amide mi) was heated at 95 ° C for 24 hours. The reaction was cooled to room temperature and stirred for 2 hours with acetonitrile (20 mL), tetrahydrofuran (10 mL) and acetic acid (20 mL). The reaction mixture was washed with isohexane (6 x 80 mL) and concentrated in vacuo. The residue was subjected to preparative HPLC to provide 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [2- (2H-tetrazol-5-yl) -etin-amide acid ( , 9 mg) in the form of a brown solid. LC-MS (METHOD L): Rj = 9.80 minutes, 374.21 (M + H) +. EXAMPLE 260 (a) 1-Cyclopropyl-3- [3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-n-1 H -pyrrazole-4-urea-urea To a stirred solution of 3- (5-etii-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylamine [250 mg, Example 233 (d)] in tetrahydrofuran (20 ml) was added 1,1-carbonyldiimidazoi (740 mg) and the reaction was heated to reflux for 60 hours. The reaction mixture was cooled to room temperature and the solvent was removed in vacuo. The residue was added to 2 N cyclopropylamine in tetrahydrofuran (15 mL). The reaction mixture was transferred to a pressurized tube and heated to reflux for 48 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and water. The aqueous layer was extracted three times with ethyl acetate and the combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated. The residue was subjected to flash column chromatography on silica eluting with ethyl acetate / hexane (1: 1, v / v) to 100% ethyl acetate to provide 1-cyclopropyl-3-r3- (5-ethyl). -6-methyl-1 H-benzoimidazol-2-yl) - H-prazol-4-ill-urea (95 mg) as a white solid.
LC-MS (M-METHOD): Rj = 9.40 minutes, 325.32 (M + H) +. 1 - [3- (5-Ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazole-4-ill-3-methyl-urea By proceeding in a manner similar to Example 260 (a) above but using 2 M methylamine in tetrahydrofuran, H 3 - (5-ethyl-6-methyl- 1 H-benzoimidazol-2-yO-1 H-pyrazol-4-yl-3-methyl-urea (36 mg) as a white solid. LC-MS (METHOD M): Rj = 7.08 minutes, 299.34 (M + H) +. (c) r3- (5-Ethyl-6-methyl-1H-benzoimidazol-2-yl) -1-pyrazole-4-yn-4-methyl-1-yl-1-carboxylic acid By proceeding in a manner similar to Example 260 (a) above but using 2 M 1-methylpiperazine in tetrahydrofuran, r3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4- was prepared 4-methyl-piperazino-1-carboxylic acid in -amide (247 mg) as a white solid. LC-MS (METHOD M): Rj = 5.21 minutes, 368.32 (M + H) +. (d) r3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-iQ-1 H-pyrazole-4-α-β-piperidino-1-carboxylic acid amide) Proceeding in a manner similar to Example 260 (a) above but using 3- (5-fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example 233 (h)] and 2 M piperidine in tetrahydrofuran was prepared [3- (5-fluoro-6- [1- H-benzoimidazol-2-yl] -1 H-pyrrazol-4-in-amide of picperidino-1-carboxylic acid (140 mg) as a white solid. LC-MS (METHOD L): R = 8.29 minutes, 343.26 (M + H) +. (e) 1-f3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl-3-methyl-urea By proceeding in a manner similar to Example 260 (d) above but using 2M methylamine in tetrahydrofuran, 1-r3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4 was prepared -l1-3-methyl-urea (61 mg) as a white solid). LC-MS (METHOD L): Ry = 4.85 minutes, 289.26 (M + H) +. (f) r3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazole-4-yl-amide of morpholino-4-carboxylic acid By proceeding in a manner similar to Example 260 (d) above but using 2 M morpholine in tetrahydrofuran, r3- (5-fluoro-6-methyl) was prepared. 1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yn-amide of morpholino-4-carboxylic acid (49 mg) as a white solid. LC-MS (METHOD L): Rj = 6.26 minu¬ cough, 345.33 (M + H) +. (g) r3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1-pyrazole-4-in-amide of 4-methyl-piperazino-1-carboxylic acid By proceeding in a manner similar to Example 31 (d) above but using 2 M-methylpiperazine in tetrahydrofuran, [3- (5-fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole- 4-Methyl-piperazino-1-carboxylic acid 4-in-amide (58 mg) as a white powder. LC-MS (P METHOD): Rj = 7.72 minutes, 358.19 (M + H) +. (h) 1 -Meti-3-f3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-ill-urea Proceeding in a manner similar to Example 260 (a) above but using 3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example 233 (j)] and 2 M methylamine In tetrahydrofuran, 1-methyl-3- [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-ill-urea (99 mg) was prepared in the form of a solid white. LC-MS (METHOD L): Rj = 6.51 minutes, 325 (M + H) +. i) 1-r3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ill-3-methyl-urea Proceeding in a manner similar to Example 260 (a) above but using 3- (5-chloro-6-metit-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example 261] and methylamine 2 M in tetrahydrofuran was prepared from 1-f3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ill-3-methyl-urea (45 mg) in the form of a solid white. LC-MS (METHOD L): Rj = 5.85 minutes, 305/307 (M + H) +. (j) r3- (5-Chloro-6-methyl-1 H-benzoimidazole-2-i0-1 4-methyl-piperazine-1-carboxylic acid H-pyrazole-4-ill-amide By proceeding in a manner similar to Example 260 (i) above but using 2 M 1-methylpiperazine in tetrahydrofuran, r3- (5-chloro-6-methyl-1H-benzoimidazole-2-yl) -1 Hp -razol- was prepared. 4-Methyl-piperazino-1-carboxylic acid 4-yl-1-amide (60 mg) in the form of a pale yellow odor. LC-MS (METHOD M): Ry = 6.35 minutes, 374 (M + H) +. (k) 1-tert-Butyl-3-r3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-ill-urea Proceeding in a manner similar to Example 260 (a) above but using 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine [Example 233 (c)] and tert. -butylamine was prepared 1-tert-butyl-3 - ["3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-yl-1-urea (21 mg) in the form of a white solid.
LC-MS (METHOD L): Ry = 5.38 minutes, 327 (M + H) +. (I) 1-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-n-3 By proceeding in a manner similar to Example 260 (k) above but using 2M ethylamine in tetrahydrofuran, 1-r3- (5,6-dimethyl-1H-benzoimidazol-2-n-1 H-pyrazole-4-) was prepared. N-3-ethyl-urea (39 mg) as a white solid LC-S (METHOD L): Rj = 3.95 minutes, 299 (M + H) +. (M) r3-f5.6 4-Methyl-piperazine-1-carboxylic acid -Dimethyl-1H-benzoimidazole-2-in-1 H -pyrazole-4-in-amide By proceeding in a manner similar to Example 260 (k) above but using 2 M 1-methylpiperazine in tetrahydrofuran, G3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4- was prepared. 4-Methyl-piperazino-1-carboxylic acid n-amide (113 mg) as a white solid. MS: 354 (M + H) +. HPLC (METHOD E1): Rj = 10.21 minutes. (n) 1-cyclopropyl-3-r3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazole-4-urea-urea By proceeding in a manner similar to Example 260 (k) above but using cyclopropylamine, 1-cyclopropyl-3- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4- was prepared in-urea in the form of a white solid. MS: 31 1 (M + H) +. HPLC (METHOD E1): Rj = 10.36 minutes. (o) 3- [3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ε -1,1-diethyl urea By proceeding in a manner similar to Example 260 (k) above but using 2M diethylamine in tetrahydrofuran, 3-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4? ? -? , 1-diethyl urea (61 mg) as a white solid. MS: 327 (M + H) +. HPLC (METHOD E1): Rj = 11, 36 minutes. (p) 1-r3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yn-3-isobutyl-urea By proceeding in a manner similar to Example 260 (k) above but using 2 M isobutylamine in tetrahydrofuran, 1-r3- (5,6-dimethyl-1 H- benzoamidazol-2-yn-1 H-pyrazol-4-yl-3-isobutyl urea (58 mg) as a white solid. MS: 327 (M + H) +. HPLC (METHOD E1): Rj = 10.95 minutes. (q) 1-Cyclopropylmethyl-3-r3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-in-urea By proceeding in a manner similar to Example 260 (k) above but using 2 M (aminomethyl) cyclopropane in tetrahydrofuran, cyclopropylmethyl-3-r3- (5,6-dimethyl-1H-benzoimidazole-2-yl) was prepared - H-pyrazole-4-urea-urea (29 mg) in the form of a white solid. MS: 325 (M + H) +. HPLC (METHOD E1): Rj = 10.63 minutes. EXAMPLE 261 3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine A stirred solution of 5-chloro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole [0.320g, Example 249 (g)] and tin chloride ( 1.10 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140 ° C for 10 minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution at pH 8 and extracted with ethyl acetate. The organic pa was dried over magnesium sulfate and concentrated to give give 3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine as a pale brown solid. . LC-MS (METHOD B): Ry = 2.28 minutes, 248.13 (M + H) +. EXAMPLE 262 3- (5-Ethyl-6-methyl-1H-benzoimidazol-2-ylVlH-indazole-5-carboxylic acid amide dihydrochloride A stirred suspension of 3- (5-ethyl-6-methyl-1H-benzoimidazoi-2-yl) -1H-indazoI-5-carbonitrile [100 mg, Example 235 (an)] in acetic acid (1 ml) and Concentrated hydrochloric acid (1 ml) was heated at 80 ° C for 30 minutes and then at 100 ° C for 4 hours. The reaction was cooled to room temperature and stirred for 16 hours. The reaction was then heated at 80 ° C for 2.5 hours and then at 100 ° C for 2 hours. The reaction mixture was cooled to room temperature and neutralized with aqueous sodium carbonate solution. The resulting white precipitate was collected by filtration and the aqueous layer was extracted with ethyl acetate, combined with the precipitate and concentrated in vacuo. The residue was collected in methane!, Transferred to a solid phase cartridge containing MP-carbonate resin (100 mg) and stirred for 16 hours. The reaction was then filtered, the resin was washed with methanol and the combined organic layers were concentrated in vacuo. The residue was triturated with diethyl ether, taken up in methanol and acidified with 4 M hydrogen chloride in 1,4-dioxane. The solvent was removed in vacuo to give 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -H-indazole-5-carboxylic acid amide dihydrochloride (58 mg) as a solid. pale brown. LC-MS (M-METHOD): Rj = 9.40 minutes, 320 (M + H) +. EXAMPLE 263 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazole-5-carboxylic acid A stirred suspension of 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-indazole-5-carbonitrile dihydrochloride [200 mg, Reference Example 6 (aq)] in acetic acid / acid Concentrated hydrochloric acid (4 ml, 1: 1, v / v) was heated at 100 ° C for 16 hours. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with water and dried under vacuum to provide 3- (5,6-dimethyl-1 H-benzoimidazol-2-iQ-1 H-indazole-5-carboxylic acid (195 mg) as a white solid LC-MS (METHOD B): Rj = 2.52 minu¬ cough, 307 (M + H) +.
EXAMPLE 264 2- (4-lsobutyrylamino-1 H -pyrazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid To a stirred solution of 2- (4-amino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester [20 mg, Example 233 (k)] in tetrahydrofuran (5 mg). mi) was added diisopropylethylamine (545 μm) and isobu-thylyl chloride (327 μm) dropwise and the reaction was stirred for 30 minutes. The reaction mixture was concentrated in vacuo and the residue was taken up in 1 M potassium hydroxide in tetrahydrofuran / methanol (1: 3, v / v) (5 mL) and stirred for 1 hour. The reaction mixture was concentrated in vacuo and the residue was taken up in 1 M sodium hydroxide in water / methanol (5 ml) and stirred for 1 hour. The solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water and the layers were separated. The aqueous layer was acidified to pH 3-4 with 5% citric acid solution, extracted with ethyl acetate and the organic layer was washed with brine. The organic layer was then dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to give 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (140). mg) in the form of a white solid. LC- S (METHOD C): Rj = 2.87 minu¬ cough, 313.33 (M + H) +.
EXAMPLE 265 2- (1 H-lndazol-3-yl) -3H-benzoimidazol-5-amine A stirred solution of 3- (5-nitro-1 H-benzoimidazol-2-yl) -1H-indazole [90.8 mg, Reference Example 233 (a) j in methanol (1 ml) was treated with Tin (616 mg). The reaction was heated to reflux for 16 hours and then cooled to room temperature. The pH of the reaction mixture was adjusted to pH 8 by the addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give an oil. The crude product was subjected to flash column chromatography on silica eluting with ethyl acetate and 10% triethylamine to provide 2- (1 H -indazol-3-yl) -3H-benzoimidazol-5-amine (826 mg). MS: 250, 31 (M + H) +, 248.31 (M-H) ~. HPLC (METHOD B): Rj = 2.03 minutes. REFERENCE EXAMPLE 1 5,6-Dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 - (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazole A mixture of 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -3,3-bis-methylsulfanyl-propenyone [318 mg, Reference Example 2 (a)], hydrazine (2 mL) and ethanol (12 mL) was heated at reflux temperature for 1 hour. The reaction mixture was then cooled to room temperature, then stirred at room temperature overnight, then heated to 60 ° C for 2 hours, then heated to reflux temperature for 3 hours, then kept at room temperature. for 3 days and then evaporated. The residue was dissolved in dichloromethane and this solution was washed with water plus a little brine to facilitate the separation and the aqueous phase was washed with d, -chloromethane and then with ethyl acetate. The combined organic phases were dried over magnesium sulfate and then evaporated to give 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 - (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole (90 mg) as a colorless solid. '(b) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2- iI] -3,3-bis-methylsulfanyl-propenone [Example of Reference 2 (b)] was prepared 6-chloro-5-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 - (2-trimethylsilyl-ethoxymethyl) -1H-benzoimidazole. (c) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazoI-2-yl] - 3,3-bis-ethylsulfanyl-propenone [Reference Example 2 (c)] was prepared 6-chloro-5-methyl-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -1 - (2- trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole (d) by proceeding in a manner similar to Reference Example 1 (a) above but using 3 > 3-bis-methylsulfanyl-1- [5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -H-benzoimidazol-2-yl] -propenyone [Reference Example 2 (d)] was prepared 2- (5-Methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1- (2-trimethylsilane-1-ethoxymethyl) -1H-benzoimidazole (e) Proceeding in a manner similar to Reference Example 1 ( a) above but using 3,3-bis-cyclopropylmethylsulfanyl-1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -propenone [Reference Example 2 ( e)] was prepared 2- (5-cyclopropylmethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole. (f) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -H-benzoimidazol-2-yl] -3.3 bis-ethylsulfanyl propenone [Reference Example 2 (f)] was prepared 5,6-dimethyl-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1 H-benzoimidazole (g) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [5,6-dimethyl-1- (2-trimethylsilyanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -3, 3-bis- (pyridin-3-ylmethylsulfanyl) -propenone [Reference Example 2 (g)] was prepared 5,6-dimethyl-2- (5- (pyridin-3-yl) methylsulfanyl-1 H -pyrazole-3 0-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole. (h) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [5-fluoro- 1- (2-trimethylsilane-ethoxymethyl) -1H-. Benzoimidazol-2-yl] -3,3-bis-methylsufanyl-propenyone [Reference Example 2 (h)] 5-fluoro-2- ( 5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole. (I) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [ 5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -3,3-bis-phenethylsu-beyl-propenyone [Reference Example 2 (i)] was prepared 5, 6-dimethyl-2- (5-phenethylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimet ilsilanyl-ethoxymethyl) -1 H-benzoimidazole. (j) Proceeding in a manner similar to Reference Example 1 (a) above but using 3,3-bis-methylsulfanyl-1- [4-methyI-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2- il] -propenone [Reference Example 2 (k)] was prepared 4-methyl-2- (5-methylsulfanyl-1H-pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole. (k) Proceeding in a manner similar to Reference Example 1 (a) above but using 3,3-bis-benzylsulfanyl-1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole- 2-yl] -propenone [Example of Refe- 2 (o)] was prepared 2- (5-benzyl-sulfanyl-1 H -pyrazol-3-IV5.6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole. (I) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -3-methylsulfanyl- 3-morpholin-1-yl-propenone [Reference Example 13] was prepared 6-chloro-5-methyl-2- (5-morpholin-4-yl-1H-pyrazol-3-yl) -1- (2- tr ymethylsilanyl-ethoxymethyl) -1H-benzoimidazole (m) Proceeding in a manner similar to Reference Example 1 (a) above but using 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -H) -benzoimidazol-2-yl] -3,3-bis- (thiophen-2-ylmethylsulfanyl) -propenone [Reference Example 2 (s)] was prepared 5,6-dimethyl-2- [5- (thiophen-2- ilmethylsulfanyl) - H -pyrazol-3-yl1-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole REFERENCE EXAMPLE 2 (a) 1 -f5,6-Dimethyl-1- (2-trimethylsilanyl) ethoxymethyl-1 H-benzoimidazol-2-yl] -3,3-bis-methylsulfanyl-propenyone A stirred suspension of sodium tert-butoxide (350 mg) in benzene (6 ml) at -5 ° C was treated with a solution of 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1. H-benzoimidazol-2-yl] -ethanone [240 mg, Reference Example 3 (a)] in benzene (5 ml) followed by carbon disulfide (230 μg).
The resulting orange solution was stirred for 1 hour at -5 ° C, then treated with methyl iodide (180 μ), then allowed to warm to room temperature and then stirred at room temperature overnight. An orange precipitate formed. The reaction mixture was poured onto ice-water and this mixture was then extracted with dichloromethane. The combined organic extracts were washed with water, then dried over sodium sulfate and then evaporated to give 1-r5,6-dimethyl-1-f2-trimethylsilanyl-ethoxymethyl) -1H-benzoxydazole-2-n. -3,3-bis-methylsulfanyl-propenone (318 mg) in the form of an orange oil which was used without further purification. (b) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] - ethanone [Reference Example 3 (b)] was prepared 1-r6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-in-3,3-bis-methylsulfanil -propenone. (c) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] - ethanone [Reference Example 3 (b)] and ethyl iodide was prepared 1- [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-n-3 , 3-bis-ethylsulfanyl-propenone. (d) Proceeding in a manner similar to Reference Example 2 (a) above but using 1 - [5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Example of Reference 3 (c)] prepared 3,3-bis-methylsulfanyl-1-r5-trifluoromethyl-1 - (2-trimethylalanyl-ethoxymethyl) -1H-benzoimidazol-2-n-propenyone. (e) By proceeding in a manner similar to Reference Example 2 (a) above but using bromomethylcyclopropane, 3,3-bis-cyclopropylmethylsulfanyl- -r 5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 was prepared H-benzoimidazol-2-ill-propenone. (f) By proceeding in a manner similar to Reference Example 2 (a) above but using ethyl iodide, 1 - [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2- was prepared in-3,3-bis-ethylsulfanyl-propenone. (g) By proceeding in a manner similar to Reference Example 2 (a) above but using 3-picolyl chloride, 1-f5,6-dimethyl-1- (2-trimethylsilyl-ethoxymethyl) -1H was prepared. -benzoimidazol-2-ill-3,3-bis- (pyridin-3-ylmethylsulfaniQ-propenone.) (h) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [5-fluoro- 1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Reference Example 3 (d)] was prepared 1-G5-fluoro-1- (2-tritymethylsilanyl-ethoxymethin-1) H-benzoimidazol-2-yl1-3,3-bis-methylsulfani-propenone (i) By proceeding in a manner similar to Reference Example 2 (a) above but using phenethyl bromide, 1-r5,6-dimethyl was prepared - 1 - (2-trimethylsilyl-ethoxymethiD-1 H-benzoimidazol-2-yl-3,3-bis-phenethylsulfanyl-propenyone. (j) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone [Example of Reference 4 (g)] and ethyl bromide was prepared 3,3-bis-ethylsulfanyl-1-r5-methoxy-2- (trimethylsilanyl) -ethoxymethyl) -1H-benzoimidazole-2-ill-propenone. (k) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [4-methy1-1- (2-trimethylsilyl-ethoxymethyl) -1H-benzoimidazo! -2-yl] -ethanone [Example of Reference 3 (e)] was prepared 3,3-bis-methylsulfanyl-1- (4-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2-in-propenyone. (I) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [5-methy1-1- (2-trimethylsilyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -pentan-1- ona [Reference Example 3 (f)] was prepared 2 ^ (bis-methylsulfanylmethylene) -l- (5-methyl-1H-benzoamidazol-2-n-pentan-1 -one.) (m) Proceeding in a manner similar to Reference Example 2 (a) above but using 1 - [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-ii] -pentan-1-one [Example Reference 3 (f)] and 4-methoxybenzyl chloride was prepared 2- [bis- (4-methoxy-benzylsulfanine-methylene-1- (5-methyl-1H-benzoimidazol-2-yl) -pentan-1- ona. (n) Proceeding in a manner similar to Reference Example 2 (a) above but using 3-methy1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2 -yl] -butan-1-one [Reference Example 3 (g)] and Benzyl chloride was prepared 2- (bis-benzylsulfanylmethylene) -3-methyl-1- [5-methyl-1- (2-triflumethyl-ethoxymethyl) -1H-benzoamidazole-2-yl -butan-1 -ona. (o) By proceeding in a manner similar to Reference Example 2 (a) above but using benzyl chloride, 3,3-bis-benzylsulfanyl-1-f5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) - 1 H-benzoimidazol-2-α-propenone. (p) Proceeding in a manner similar to Reference Example 2 (a) above but using 1- [1- (2-trimethylsilyanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl-ethanone [Reference Example 4 (h) ] with tetrahydrofuran as the solvent and carrying out the reaction at room temperature and then subjecting the reaction product to flash chromatography on silica under gradient elution conditions (20 to 33% ethyl acetate in pentane) was prepared. -methanesulfanyl-1-G1- (2-trimethylsilanyl-ethoxymethiQ-1H-benzoimidazol-2-y-propenyone in the form of an oil that solidified slowly at rest at room temperature.) (q) Proceeding in a manner similar to Example of Reference 2 (a) above but using 1- [6-chloro-5-methyl-1- (2-trimethylsilyanil-ethoxymethyl!) -1 H-benzoimidazol-2-yl] -ethanone [Reference Example 3 (b) ] and methyl iodide was prepared 1 - [6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl-1,3-bis-methylsulfanyl-propeone. r) Proceed in a manner similar to Reference Example 2 (a) above but using 1- [5-methoxy-1- (2-trimethylsilane-ethoxymethyl) -1 H -benzoimidazol-2-yl] -propan-1-one [Example of Reference 4 (i)] and sodium iodide 1 - [5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazole-2-n-2-methyl-3- (bis-m-tannazulfan-1-propenyone. ) By proceeding in a manner similar to Reference Example 2 (a) above but using 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -ethanone [ Reference Example 3 (a)] and 2-chloromethylthiofene [Reference Example 14]) was prepared 1- [5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazole-2-yl-3 , 3-bis- (thiophen-2-ylmethylsulfani ^ propenone.) (T) Proceeding in a manner similar to Refe-renda Example 2 (a) above but using 1- [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) ) - H-benzoimidazole-2-H] -propan-1-one [Reference Example 3 (h)] was prepared 1 - [5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole-2 -yl] -2-methyl-3- (bis-methanesulfanyl) -1-propenyone REFERENCE EXAMPLE 3 (a) 1-r5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl-1H-benzoimidazole) -2-in-ethanone A solution of 5,6-dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole [5.01 g, Reference Example 4 (a)] in dry tetrahydrofuran (55 ml) at -78 ° C was treated with a solution of lithium diisopropylamide in a mixture of tetrahydrofuran and heptane (1.9 ml, 2 M) for 10 minutes. The The mixture was stirred for 15 minutes and then treated dropwise with dimethylacetamide (2.15 ml) for 10 minutes. After stirring at -78 ° C for an additional 30 minutes, the reaction mixture was poured into ice (50 g) and then left until all the ice melted. This mixture was extracted with dichloromethane and the extracts were washed with brine, then with water, then dried over magnesium sulfate and then evaporated. The residual orange oil (5.91 g) was subjected to column chromatography on silica eluting with a mixture of petroleum ether and ethyl acetate (4: 1, v / v) to provide 1 - [5,6-dimethyl-] 1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-ethanone (3.93 g) as a yellow crystalline solid. (b) Proceeding in a manner similar to the Example of Refe-. 3 (a) above but using 6-chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole [Reference Example 4 (b)] was prepared 1- [6-chloro-5- methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -ethanone. (c) Proceeding in a manner similar to Reference Example 3 (a) above but using 5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole [Reference Example 4 (c)] was prepared 1- [5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -ethanone. (d) Proceeding in a manner similar to Reference Example 3 (a) above but using 5-fluoro-1- (2-trimethylsilyl-ethoxymethyl) -1 H -benzoimidazole [Reference Example 4 (d)] was prepared 1- [5-fluoro-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone. (e) Proceeding in a manner similar to Reference Example 3 (a) above but using 4-methyl-1- (2-trimethylsilanyl-eyloxymethyl) -1H-benzoimidazole [Reference Example 4 (e)] was prepared 1- [ 4-Methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -enanone. (f) Proceeding in a manner similar to Reference Example 3 (a) above but using 5-methyl-1- (2-trimethylisilanyl-ethoxymethyl) -1H-benzoimidazole [Reference Example 4 (f)] and dimethylvaleramide [Example of Reference 8 (a)] se. prepared 1- [5-methy1-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -pentan-1-one. (g) Proceeding in a manner similar to Reference Example 3 (a) above but using 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole [Reference Example 4 (f)] and dimethylisovalerylamide [Example of Reference 8 (b)] was prepared 3-methyl-1-f5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-y-butan-1 -one. (h) By proceeding in a manner similar to Reference Example 3 (a) above but using 5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole [Reference Example 4 (f)] and dimethylpropionamide was prepared 1 -5-methyl-1- (2-trimethylsilane-1-ethoxymethyl) -1H-benzoimidazol-2-y-propan-1-one. REFERENCE EXAMPLE 4 (a) 5,6-Dimethyl-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazole A stirred mixture of sodium hydride (1.08 g) in dimethylformamide (80 ml) was treated with a solution of 5,6-dimethyl-1H-benzoimidazole (4.95 g) in dimethylformamide at room temperature for 10 hours. minutes After stirring for an additional 1 hour the mixture was then treated with 2- (trimethylsilanyl) ethoxymethyl chloride (6.4 ml) for 15 minutes and then stirring was continued for 18 hours. The reaction mixture was treated with methanol (15 ml) and water (1 ml) and then evaporated. The residue was treated with water (50 ml) and this mixture was then extracted twice with diethyl ether (80 ml and then 50 ml). The combined organic extracts were washed three times with water (50 ml), then dried over magnesium sulfate and then evaporated. The residual brown oil (10.3 g) was purified by a Flashmaster device using mixtures of ethyl acetate in hexane (20% to 80%) at 40 ml / minute to provide 5,6-dimethyl-1- (2-trimethylsilanyl) -ethoxymethyl) -1 H-benzoimidazole (7.54 g) as an orange oil. (b) By proceeding in a manner similar to Reference Example 4 (a) above but using 6-cioro-5-methyl-1 H-benzoimidazole [Reference Example 5 (a)], 6-chloro-5-methyl- 1- (2-trimethylsilyanil-ethoxymethyl) -1H-benzoimidazole. (c) By proceeding in a manner similar to Reference Example 4 (a) above but using 5-trifluoromethyl-1 H-benzoimidazole [Reference Example 5 (b)] 5-trifluoromethyl-1- (2-trimethylsilanyl-ethoxymethyl) was prepared ) -1H-benzoimidazole. (d) By proceeding in a manner similar to Reference Example 4 (a) above but using 5-fluoro-1H-benzoimidazole [Reference Example 5 (c)], 5-fluoro-1- (2-trimethylsilanyl-ethoxy) was prepared methyl) -1 H-benzoimidazole. (e) By proceeding in a manner similar to Reference Example '4 (a) above but using 4-methi-1H-benzoimidazole [Reference Example 5 (d)], 4-methyl-1- (2 -trimethylsilyl-ethoxymethyl) -1H-benzoimidazole. (f) By proceeding in a manner similar to Reference Example 4 (a) above but using 5-methyl-1 H-benzoimidazole, 5-methyl-1- (2-trimethylsilyanil-ethoxymethyl) -1H-benzoimidazole was prepared. (g) By proceeding in a manner similar to Reference Example 4 (a) above but using 1- (5-methoxy-1H-benzoimidazol-2-yl) -ethanone [Reference Example 6 (a)], 1 - [ 5-methoxy-1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl-1-ethanone. (h) By proceeding in a manner similar to Reference Example 4 (a) above but using (1H-benzoimidazol-2-yl) -1-ethanone and carrying out the reaction in tetrahydrofuran, 1- [1- (2- trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -ethanone in the form of a colorless oil. (i) Proceeding in a manner similar to Referential Example 4 (a) above but using 1- (5-methoxy-1 H-benzoimidazol-2-yl) -propan-1-one [Reference Example 6 (b) )] was prepared 1- [5-methoxy-1- (2-trimethylalanyl-ethoxymethyl) -1 H -benzoimidazol-2-yl] -propan-1 -one REFERENCE EXAMPLE 5 (a) 6-chloro-5-methyl-1 H-benzoimidazole A solution of 5-chloro-4-methyl-1,2-phenylenediamine (7.8 g) in a mixture of formic acid (35 ml) and hydrochloric acid (300 ml) was heated at 50 ° C for 3 hours and then treated with ammonium hydroxide solution until the solution was basic. The reaction mixture was then extracted with dichloromethane. The extracts were evaporated to provide 6-cyoro-5-methyl-1 H-benzoimidazole (7g). (b) By proceeding in a manner similar to Reference Example 5 (a) above but using 4-trifluoromethyl-1,2-phenylenediamine, 5-trifluoromethyl-1H-benzoimidazole was prepared. (c) By proceeding in a manner similar to Reference Example 5 (a) above but using 4-fIuoro-o-phenylenediamine, 5-fluoro-1 H-benzoimidazole was prepared. (d) By proceeding in a manner similar to Reference Example 5 (a) above but using 2,3-diaminotoluene, 4-methyl-1 H-benzoimidazole was prepared. REFERENCE EXAMPLE 6 a) 1 - (5-Methoxy-1 H-benzoimidazol-2-yl) -ethanone A stirred mixture of 1- (5-methoxy-1-benzoamidazole) -1-ethanol [5.14 g, Reference Example 7 (a)] and manganese dioxide (9 g) in chloroform (80 ml) were heated at 60 ° C for 18 hours, then cooled to room temperature and then filtered. The filtrate was evaporated to provide 1- (5-methoxy-1 H-benzoimidazol-2-yl) -ethanone (4.28 g). (b) 1 - (5-Methoxy-1 H-benzoimidazol-2-yl) -propan-1 -one By proceeding in a manner similar to Reference Example 6 (a) above but using using 1- (5-methoxy-1-benzoamidazole) -1-propanol [Reference Example 7 (b)], 1 - (5- methoxy-1 H-benzoimidazol-2-yl) -propan-1-one. (c) 5-Fluoro-H-ndazol-3-carbaldehyde Proceeding in a manner similar to Reference Example 6 (a) above but using (5-fluoro-1 H-indazol-3-yl) -methanol [Reference Example] 25 (a)] with acetone as solvent, a reaction temperature of 55 ° C and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of 40/60 petroleum and ethyl acetate (1). : 1, v / v) 5-fluoro-1H-indazol-3-carbaIdehyde was prepared as a light brown solid. LC-MS (METHOD B): Rj = 2.74 minutes, 65 (M + H) +. (d) 6-Fluoro-1H-indazol-3-carbaldehyde Proceeding in a manner similar to the Reference Example 6 (a) above but using (6-fluoro-1 H-indazol-3-yl) -methanol [Reference Example 25 (b)] with acetone as solvent, a temperature of 55 ° C and subjecting the reaction product to flash column chromatography on silica eluting with a 40/60 mixture of petroleum and ethyl acetate (1: 1, v / v) was prepared 6-fluoro-1 H-indazol-3-carbaldehyde as a light brown solid . LC-MS (METHOD B): RT = 2.74 minutes, 165 (M + H) +. (e) 5-Methyl-1H-indazole-3-carbaldehyde Proceeding in a manner similar to Reference Example 6 (a) above but using (5-methyl-1 H-indazol-3-yl) -methanol [Reference Example 25 (c)] with dichloromethane as solvent, a temperature of react of 40 ° C and subjecting the reaction product to flash column chromatography on silica using a mixture of hexane and ethyl acetate (1: 1, v / v) was prepared (5-methyl-1 H-indazole). 3-yl) -methanol [Reference Example 25 (c)] in the form of a pale brown solid. LC-MS (METHOD B): R = 2.79 minutes, 161 (M + H) +. (f) 6-Methoxy-1 H-indazole-3-carbaldehyde Proceeding in a manner similar to the Reference Example 6 (a) above but using (6-methoxy-1 H-indazol-3-yl) -methanol [Reference Example 25 (e)] with acetone as solvent, a reaction temperature of 55 ° C and subjecting the product of reaction to flash column chromatography on silica using a mixture of 40/60 petroleum and ethyl acetate (1: 1, v / v) was prepared 6-methoxy-1 H-indazole-3-carbaldehyde in the form of a luminous brown solid. LC-MS (METHOD B): R = 2.76 minutes, 177 (M + H) +. (g) 4-Phenyl-1 H-pyrazole-3-carbaldehyde Proceeding in a manner similar to the Reference Example 6 (a) above but using (4-phenyl-1 H-pyrazol-3-yl) -methane I [Reference Example 25 (f)] with acetone as solvent, a reaction temperature of 60 ° C for 2 hours and by subjecting the reaction product to flash column chromatography on silica eluting with a mixture of dichloromethane and methanol (49: 1, v / v) 4-phenyl-1H-pyrazole-3-carbaldehyde was prepared as a white solid . LC-MS (METHOD B): RT = 2.76 minutes; 213 (M + H) +. 5-Chloro-1 H-indazole-3-carbaldehyde Proceeding in a manner similar to the Reference Example 6 (a) above but using (5-chloro-1 H-indazol-3-yl) -methanol [Reference Example 25 (d)] with a mixture of dichloromethane and tetrahydrofuran as a solvent, heating the reflux temperature and by subjecting the reaction product to flash column chromatography on silica eluting with a mixture of hexane and ethyl acetate (1: 1, v / v) 5-chloro-1 H -indazol-3-carbaldehyde was prepared as a solid pale brown. LC-MS (METHOD B): Rj = 2.89 minutes, 181 (M + H) +. (i) 3-Formyl-pyrazole-4-carboxylic acid ethyl ester Proceeding in a manner similar to the Reference Example 6 (a) above but using 3-hydroxymethyl-1H-pyrazoyl-4-carboxylic acid ethyl ester [Reference Example 41 (a)] was prepared 3-formyl-pyrazole-4-carboxylic acid ethyl ester in the form of a brown solid. LC-MS (METHOD B): Rj = 2.65 minutes; 169 (M + H) +. (i) 3-formylpyrazole-4-carboxylic acid isopropylethylamide Proceeding in a manner similar to the Reference Example 6 (a) above but using 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide [Reference Example 41 (b)] was prepared 3-formyl-p.razole-4-carboxylic acid isopropylamide in the form of a waxy orange solid. LC-MS (METHOD B): RT = 2.73 minutes; 182 (M + H) +. (k) 3-formyl-5-methyl-pyrazole-4-carboxylic acid ethyl ester By proceeding in a manner similar to Reference Example 6 (a) above but using 3-hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 41 (c)], ethyl ester of 3-formyl-5-methyl-pyrazole-4-carboxylic acid as a white solid. LC- S (METHOD B): R = 2.80 minutes; 183 (M + H) +. (I) 1 - / - indazol-3-carbaldehyde Proceeding in a manner similar to Reference Example 6 (a) above but using (1H-indazol-3-yl) -methanol [Reference Example 25 (g)] with acetone as solvent and carrying out the reaction at the After reflux for 16 hours, 1 H-indazole-3-carbaldehyde was prepared as a yellow solid. LC-MS [METHOD B]; RT = 2.63 minutes; 147.26 (M + H) +; 145.26 (M-H) -. (m) 4-Nitro-1 - (tetrahydro-pyran-2-iQ-1 H-pyrazole-3-carbaldehyde Proceeding in a manner similar to the Reference Example 6 (a) above but (i) using [4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazol-3-yl] -methanol (663mg, Reference Example 53) and manganese oxide (IV) (2.54 g) with acetone as solvent, (ii) carrying out the reaction at 65 ° C for 2 hours and (iii) subjecting the reaction product to flash silica chromatography eluting with a mixture of pentane and ethyl acetate (70:30, v / v) was prepared 4-nitro-1 - (tetrahydro-pyrano-2-yl) -1 H-pyrazole-3-carbaldehyde (191 mg) as an oil pale yellow. LC-MS (METHOD H): R = 2, 9 minutes, 248.24 (M + H + Na) +. (n) 3-Formii-1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide Proceeding in a manner similar to the Reference Example 6 (a) above but using 3-formyl-1 H-pyrazole-4- (2-methoxy-ethyl) -amide carboxylic acid (325 mg) in the form of a yellow oil. LC-MS (METHOD B): Rj = 2.13 minutes, 198 (M + H) +. (o) 3- Formyl-1 H-pyrazole-4-carboxylic acid propylamide By proceeding in a manner similar to Reference Example 6 (a) above but using 3-hydroxymethyl-1 H-pyrazole-4-carboxylic acid propylamide [Reference Example 41 (e)], 3-formyl-1-propylamide was prepared H-pyrazole-4-carboxylic acid (414 mg) in the form of an orange oil. LC-MS (METHOD B): Rj = 2.42 minutes, 182 (M + H) +. (p) (3-formyl-1 H-pyrazole-4-carboxylic acid tetrahydro-pyrano-4-iQ-amide Proceeding in a manner similar to Reference Example 6 (a) above but using 3-formyl-1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide (400 mg) in the form of a brown oil LC-MS (N METHOD): R = 2.34 minutes, 224.31 (M + H) +. (q) 3-formyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide By proceeding in a manner similar to Reference Example 6 (a) above but using 3-hydroxymethyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide [Reference Example 41 (f)], 3-formyl-1-cyclopropylamide was prepared H-pyrazole-4-carboxylic acid (125 mg) in the form of a yellow oil. REFERENCE EXAMPLE 7 (a) 1- (5-Methoxy-1H-benzoimidazol-2-yl) -ethanol A mixture of 4-methoxy-phenylenediamine dihydrochloride (10 g), L-lactate sodium (10 g) and hydrochloric acid (60 ml, 4 M) was heated at 70 ° C for 48 hours. The reaction mixture was cooled to room temperature and then treated with ammonium hydroxide. The resulting precipitate was filtered and dried to provide 1- (5-methoxy-1H-benzoimidazole-2-iD-ethanol (5.14 g). (B) 1- (5-Methoxy-1-benzoimidazole) - 1-propanol By proceeding in a manner similar to Reference Example 7 (a) above but using 2-hydroxybutyric acid, 1- (5-methoxy-1-benzoimidazo Q-1-propanol was prepared) REFERENCE EXAMPLE 8 (a) Dimethylvaleramide A solution of hydrochloride of dimethylamine (6.76 g) and triethylamine (30 ml) in dichloromethane (100 ml) under nitrogen and at 0 ° C were treated dropwise with valeryl chloride (10 g), after stirring at room temperature overnight The reaction mixture was treated with hydrochloric acid (2 N) and dichloromethane, The organic phase was separated, dried over magnesium sulfate and then evaporated to give dimethylvaleramide as a clear solid. similar to Reference Example 8 (a) above but using isovaleryl chloride, dimethylisovaleramide was prepared REFERENCE EXAMPLE 9 2,3-Diaminopyrazine Liquid ammonia (50 ml) was introduced into a pressure reaction vessel containing a peq Dream ice cube To this was added copper-bronze (1.17 g), copper (II) iodide (0.224 g) and 2,3-dichloropyrazine (4 g). The sealed reaction vessel was heated at 170 ° C for 48 hours, then cooled to room temperature and then a vacuum was applied.
The reaction mixture was treated with water (75 ml) and this mixture was extracted four times with diethyl ether (400 ml). The combined extracts were evaporated to provide 2,3-diaminopyrazine as a white solid (, 3 g). The aqueous layer was extracted continuously with diethyl ether for 18 hours to yield an additional amount of 2,3-diaminopyrazine (1.24 g). i H-NMR [(CD3) 2SO]: d 5.87 (s, 4H), 7.15 (s, 2H). REFERENCE EXAMPLE 10 1 H-pyrazole-3-carbaldehyde (i) Dry dimethylformamide (77.6 ml) was stirred at 80 ° C while adding cyanuric chloride (26.6 g) in portions, while maintaining the temperature of the reaction between 80 and 1 0 ° C. The reaction mixture was stirred at 100 ° C for another 30 minutes and then cooled and allowed to stand at room temperature overnight. The reaction mixture was filtered to give dimethylvinylamine. (ii) The dimethylvinylamine from section (i) was added to dry methanol (260 ml) and the mixture was then treated with pyruvic acid dimethylacetal (51 ml) followed by a solution of sodium methoxide in methanol (30%, 81 ml), then stirred for 2 hours at room temperature, then it was heated at reflux temperature for another hour, then cooled and then filtered. The filtrate was evaporated to give 1,1-dimethoxy-but-3-en-2-one as a brown oil (96.8 g). (iii) A stirred solution of 1,1-dimethoxy-but-3-en-2-one in water (300 ml) was treated dropwise with hydrazine hydrate (21 ml). After After standing at room temperature overnight, the reaction mixture was treated with sodium chloride (108 g) and the mixture was then extracted with methyl t-butyl ether (200 ml and then 100 ml). The combined organic extracts were dried with magnesium sulfate and then evaporated to give 1H-pyrazole-3-carbaldehyde-dimethyl-acetal as a light brown oil (8.47 g). (iv) A solution of IH-pyrazole-3-carbaldehyde-dimethylacetal in water (85 ml) was treated with glacial acetic acid (3.7 ml). After two days, the mixture was filtered to give 1 H-pyrazole-3-carbaldehyde (1.3 g) as a light brown oil. REFERENCE EXAMPLE 1 2- (5-Ethoxy-1 H -pyrazol-3-iD-1 - (2-tr ymethylsilanyl-ethoxymethyl-1 H-benzoimidazole Sodium hydride (0.1 g) was added to ethanol (5 ml) and the mixture was stirred for ten minutes, then treated with 3,3-bis-methanesulfanyl-1- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -propenone [0.5g, Reference Example 2 (p)] and then heated to reflux temperature for six hours. The reaction mixture was cooled, then triturated with hydrazine hydrate (0.27 mmol) and then heated to reflux temperature for four hours. The mixture was then evaporated and the The residue was triturated with water and filtered. The solid was chromatographed on silica gel eluting with ethyl acetate to give -5-ethoxy-1 H -pyrazol-3-yl) -1- (2-trimethylsilanyl-ethoxymethin-1H-benzoimidazole as a solid. yellow REFERENCE EXAMPLE 12 2- (5-Methylsulfanyl-isoxazol-3-yn-1- (trimethylsilanyl-ethoxymethyl) 1 H-benzoimidazole Hydroxylamine hydrochloride (168 mg) was added to a solution of sodium methoxide in methanol [prepared by the addition of sodium hydride (122 mg) to methanol (5 ml)]. The mixture was stirred for ten minutes. It was then treated with 3,3-bis-methanesulfanyl-1- [1- (2-trimethylsilanyl-ethoxymethyl) -1H-benzoimidazol-2-yl] -propenone [500 mg, Reference Example 2 (p)], then it was heated to reflux for six hours, then cooled and then evaporated. The residue was taken up in water and the aqueous mixture was extracted with ethyl acetate. The extracts were dried and evaporated. The residue was chromatographed on silica eluting with methylene chloride to give 2- (5-methylsulfanyl-isoxazol-3-yl) -1- (trimethylsilanyl-ethoxymethyl) 1 H-benzoimidazole (0.16 g) in the form of a colorless oil.
P10 REFERENCE AXIS 13 1-r6-Chloro-5-methyl-1- (2-trimethylsilanyl-ethoxymethyl) -1 H -benzoimidazol-2-ene-3-methylsulfanyl-3-morpholin-1-yl-propenyl A solution of 1- [6-chloro-5-methyl-1- (2-trimethylsilane-ethoxymethyl) -1 H -benzoimidazol-2-yl] -3,3-bis-methanesulfanyl-propenyone [800 mg, Reference Example 2 (q)] in morpholine (3 mL) was heated at 95 ° C for 2 hours and then evaporated to give 1-f6-chloro-5-methyl-1- (2-tri-methylsiian-ethoxymethyl) -1H-benzoimidazol-2-n-3-methylsulfanyl-3-morpholin-1-yl-propenone. P10 REFERENCE AXIS 2-Chloromethyl-thiophene To a three-neck flask equipped with a stir bar, pressure equalization drip tray and inlet / outlet adapter was added thiophene (10 ml) and aqueous hydrochloric acid (5.5 ml). Hydrogen chloride gas was bubbled [generated by dripping sulfuric acid (30 ml) over dry sodium chloride (50 g)] through the reaction mixture with vigorous stirring at 0 ° C. This mixture was then treated dropwise with so- formaldehyde solution (37%, 12.5 ml) and stirring was continued for 45 minutes. The phases were separated and the aqueous phase was extracted three times with diethyl ether (10 ml). The organic phases were then washed twice with water (10 ml), then twice with saturated sodium hydrogen carbonate (10 ml), then magnesium sulfate and then evaporated. The residue was distilled at 20 mm Hg using a heat gun to provide 2-chloromethyl-thiophene which was used immediately without further purification. REFERENCE EXAMPLE 15 Bis (methylthio) -3,3- (benzoimidazol-2-yl) -1-prop-2-en-2-one A mixture of sodium hydride (19.2 g) and toluene (400 ml), at 80 ° C, was treated in portions with tertiary butanol (30.8 g). After 2 hours the reaction mixture was cooled to room temperature and. was treated dropwise with a mixture of dimethylformamide (40 ml), carbon disulfide (12 ml) and 2-acetyl-1- (tetrahydropyran-2-yl) -benzoimidazole (51 g, Reference Example 16) for 90 minutes . After the addition, the red reaction mixture was stirred at 80 ° C for 30 minutes, then cooled to room temperature and then treated with methyl iodide (50 ml). This mixture was stirred at 80 ° C for 30 minutes when a precipitate began to form. The reaction mixture was cooled to room temperature and then filtered. He The filtrate was concentrated to give a viscous red oil, which was dissolved in methanol (300 ml). This solution was treated with p-toluenesulfonic acid (2 g) and water (4 ml), then heated to reflux temperature for 13 hours and then cooled in an ice bath. The resulting solid was filtered, and then washed with isopropyl ether to give bis (methylthio ') - 3,3- (benzoimidazol-2-in-1-prop-2-en-2-one (11.2 g) , mp 224 ° C. REFERENCE EXAMPLE 16 2-Acetyl-1- (tetrahydropyran-2-yl and benzoimidazole Dihydropyran (20.5 ml) was added dropwise to a solution of 2-acetylbenzoylimidazole (32 g) and p-toluenesulfonic acid (2 g) in dichloromethane (280 ml) at reflux. The reaction mixture was stirred at this temperature for 24 hours, then cooled and the insoluble materials were removed by filtration. The filtrate was concentrated to give 2-acetyl-1- (tetrahydropyran-2-yl) -benzoimidazole as an amber oil (51.8 g). TLC: (dicloromethane: methanol, 97: 3) Rp = 0.80. REFERENCE EXAMPLE 17 (a) 4,5,6,7-Tetrahydro-1 H-indazole-3-carboxylic acid A solution of 4,5,6,7-tetrahydro-1 H-indazole-3-carboxylic acid ethyl ester [0.606 g, Reference Example 18 (a)] in methanol (50 ml) was treated with sodium hydroxide ( 0.500 g). The mixture was refluxed for 16 hours, then cooled and then evaporated. The residual white solid was treated with hydrochloric acid (30 ml, 2 N) and the resulting solution was extracted three times with ethyl acetate (50 ml). The combined organic extracts were dried over sodium sulfate and then evaporated to yield 4,5,6,7-tetrahydro-1 H-indazole-3-carboxylic acid (0.424 g) as a white solid. LC- S (METHOD B): Rj = 2.44 minutes; 167 (M + H) +. (b) 5-Isopropyl-H-pyrazole-3-carboxylic acid By proceeding in a manner similar to Example 17 (a) above but using 5-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (b)], 5-isopropyl- 1 H-pyrazole-3-carboxylic acid in the form of a white solid (0.973 g) which was used without further purification.
LC-MS (METHOD B): RT = 2.43 minutes; 155 (M + H) +. (c) 5-Ethyl-1 H-pyrazole-3-carboxylic acid By proceeding in a manner similar to Reference Example 17 (a) above, but using 5-ethyl-1 H-pyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (c)], 5-ethyl- 1 H-pyrazole-3-carboxylic acid in the form of a white solid. LC-MS (METHOD B): Rj = 2.34 minutes; 141 (M + H) +. (d) 3-Ferr-Butyloxymethyl-1 H-pyrazole-4-carboxylic acid By proceeding in a manner similar to Example 17 (a) above, but using 3-urea-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 42]], 3-fer-butyloxymethyl-1H acid was prepared -pyrazole-4-carboxylic acid in the form of a white solid that was used. without additional purification. LC-MS (METHOD B): Rj = 2.75 minutes; 199 (M + H) +. (e) 1, 4,6,7-Tetrahydro-pyran [4,3-c1pyrazole-3-carboxylic acid Proceeding in a manner similar to Reference Example 17 (a) above but using 1,4,6,6-tetrahydro-pyran [4,3-c] pyrazole-3-carboxylic acid ethyl ester [Reference Example 18 (e) )] 1, 4,6,7-tetrahydro-pyran [4,3-c] pyrazole-3-carboxylic acid (161 mg) was prepared as a white solid. LC-MS (METHOD B): Rj = 1, 98 minutes, 169 (M + H) +. (f) 1, 4,5,6-Tetrahydro-cyclopentapyrazol-3-carboxylic acid By proceeding in a manner similar to Example 17 (a) above but using 1, 4,5,6-tetrahydro-cyclopentapyrazol-3-carboxylic acid ethyl ester [Reference Example 18 (f)], acid 1, 4.5 was prepared , 6-tetrahydro-cyclopentapyrazol-3-carboxylic acid (0.641 g) as a white solid. LC-MS (METHOD B): Rj = 2.13 minutes, 153.22 (M + H) +. REFERENCE EXAMPLE 18 (a) 4,5,6,7-Tetrahydro-1 H-indazole-3-carboxylic acid ethyl ester A solution of oxo- (2-oxo-cyclohexyl) -acetic acid ethyl ester [75 g, Reference Example 19 (a)] in acetic acid (150 ml) was treated dropwise with hydrazine monohydrate (1.65 ml). The mixture was refluxed for 8 hours, then cooled and then evaporated. The residue was partitioned between ethyl acetate (200 ml) and saturated sodium bicarbonate solution (200 ml) and the organic layer was dried over sodium sulfate and then evaporated. The residual orange oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 1, v / v) to give ethyl 4,5,6,7-tetrahydro-1 H ethyl ester. -indazole-3-carboxylic acid (606 mg) in the form of an orange oil that solidified at rest. LC-MS (METHOD B): R = 2.79 minutes; 195 (M + H) +. (b) 5-Isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester Proceeding in a manner similar to the Reference Example 18 (a) above but using 5-methyl-2,4-dioxo-hexanoic acid ethyl ester [2.00 g, Reference Example 19 (b)] was prepared with 5-isopropyl-H-pyrazole- 3-carboxylic acid in the form of a bright yellow oil that was used without further purification. LC-MS (METHOD B): Rj = 2.79 minutes; 183 (M + H) +. (c) 5-ethyl-1 H-pyrazole-3-carboxylic acid ethyl ester Proceeding in a manner similar to Reference Example 18 (a) above but using 2,4-dioxo-hexanoic acid ethyl ester [Reference Example 19 (c)] and subjecting the reaction product, an orange oil, to flash chromatography on silica eluting with a mixture of ethyl acetate and hexane (8: 1, v / v), 5-ethyl-1H-pyrazole-3-carboxylic acid ethyl ester was prepared as a yellow oil. LC-MS (METHOD B): Rj = 2.64 minutes; 169 (M + H) +. (d) 3,6-Tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester By proceeding in a manner similar to Reference Example 18 (a) above, but using 3-ethoxyoxyalkyl-4-oxo-piperidino-1-carboxylic acid tert-butyl ester [Reference Example 19 (d)], ester was prepared 3-Ethyl 5-tert-butyl ester of 1,4,6,6-tetrahydro-pyrazolo [4,3-1,3-pyridine-3,5-dicarboxylic acid in the form of a yellow oil. LC-MS (METHOD B): Rj = 2.73 minutes; 296 (M + H) +. (e) 1, 4,6J-Tetrahydro-pyranoí4,3-c1pyrazole-3-carboxylic acid ethyl ester By proceeding in a manner similar to Reference Example 18 (a) above but using tetrahydro-4H-pyrano-4-one, 1,4,6,6-tetrahydro-pyran [4,3-chlorazole-3-ethyl] ethyl ester was prepared -carboxylic in the form of a white solid. LC-MS (METHOD B): RT = 2.43 minutes, 197 (M + H) +. (f) 1, 4,5,6-Tetrahydro-cyclopentapyrazol-3-carboxylic acid ethyl ester By proceeding in a manner similar to Example 18 (a) above but using oxo- (2-oxo-cyclopentyl) -acetic acid ethyl ester [Reference Example 19 (e)], ethyl ester of acid 1, 4,5 was prepared, 6-tetrahydro-cyclopentapyrazol-3-carboxylic acid (2.06 g) as a yellow solid. LC-MS (METHOD B): R = 2.56 minutes, 185 (M + H) +. EXAMPLE OF REFERENCE 19 (a) Oxo- (2-oxo-cyclohexyl) -acetic acid ethyl ester A solution of sodium (1.75 g) in ethanol (100 ml) was treated with a mixture of diethyl oxalate (9.41 ml) and cyclohexanone (7.18 ml). The mixture was heated at 60 ° C for 5 hours, then cooled and then evaporated to yield oxo- (2-oxo-cyclohexyl) -acetic acid ethyl ester as a brown foam (16.635 g). LC-MS (METHOD B): Rj = 3.10 minutes; 197 (M-H) -. (b) 5-Methyl-2,4-dioxo-hexanoic acid ethyl ester By proceeding in a manner similar to Example 19 (a) above but using 3-methyl-2-butanone, 5-methyl-2,4-dioxo-hexanoic acid ethyl ester was prepared as a white solid. LC-MS (METHOD B): Rj = 3.47 minutes; 187 (M + H) +. (c) 2,4-Dioxo-hexanoic acid ethyl ester By proceeding in a manner similar to Reference Example 19 (a) above, but using 2-butanone, 2,4-dioxo-hexanoic acid ethyl ester was prepared in the form of a brown oil which was used without further purification. LC-MS (METHOD B): Rj = 3.28 minutes; 173 (M + H) +. (d) 3-Ethoxyoxalyl-4-oxo-piperidino-1-carboxylic acid tert-butyl ester By proceeding in a manner similar to Reference Example 19 (a) above, but using N-Boc-piperidone, 3-ethoxyoxalyl-4-oxo-p-perindo-1-carboxylic acid tert-butyl ester was prepared in the form of a brown oil that was used without further purification. LC-MS (METHOD B): Rj = 3.43 minutes; 244 (M-tBu) +. (e) Oxo- (2-oxo-cyclopentyl) -acetic acid ethyl ester By proceeding in a manner similar to Reference Example-9 (a) above but using cyclopentanone, ethyl acid ester was prepared oxo- (2-oxo-cyclopentyl) -acetic (9.99 g) as a yellow solid. LC-MS (METHOD B): R = 3.12 minutes, 185 (M + H) +. REFERENCE EXAMPLE 20 (a) 3-Formyl-5-methoxy-indazole-1-carboxylic acid tert-butyl ester A solution of 5-methoxy-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester [282 mg, Reference Example 21 (a)] in tetrahydrofuran (4 ml) and water (1 , 5 ml) was treated with a solution of osmium tetroxide in water (54 μl, 4% by weight) and potassium periodate (400 mg). The reaction mixture was stirred at room temperature for 16 hours and then filtered. The filtrate was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum (1: 9, v / v) to produce 3-fomnyl-5-methoxy-indazole-1-tert-butyl ester. carboxylic acid (162 mg) as a white solid. LC-MS (METHOD B): R = 2.97 minutes; 277 (M + H) + (b) 4-Fluoro-1 H-indazol-3-carbaldehyde By proceeding in a manner similar to Reference Example 20 (a) but using 4-fluoro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester [Reference Example 21 (b)] prepared 4-fluoro-1 H-indazol-3-carbaldehyde as a light brown solid. LC-MS (METHOD B): R = 2.63 minutes; 165 (M + H) +. (c) 4-Chloro-3-formyl-indazole-1-carboxylic acid tert-butyl ester Proceeding in a manner similar to Reference Example 20 (a) but using 4-chloro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester [Reference example 21 (c)] is prepared 4-chloro-3-formyl-indazole-1-carboxylic acid tert-butyl ester (0.217 g) as a brown oil. LC-MS (METHOD B): Rj = 3.49 minutes; 283 (M + H) +. 5-Ethoxy-3-formyl-indazole-1-carboxylic acid tert-butyl ester Proceeding in a manner similar to Example 20 (a) but using 5-ethoxy-3- (2-methoxycarbonyl-vinylo) -ndazole-1-carboxylic acid tert-butyl ester [Reference Example 21 (d) ] 5-Ethoxy-3-formyl-indazole-1-carboxylic acid tert-butyl ester was prepared in the form of a brown oil. TLC (ethyl acetate: hexane, 1: 9, v / v): Rp = 0.25, 1 H NMR (400MHz, CDCl 3): d 1.38 (3H, t), 1.67 (91-1, s), 4.05 (2H, q), 7.12 (1H, d), 7.60 (1H, s), 7 , 98 (1 H, d), 10.20 (1 H, s). REFERENCE EXAMPLE 21 (a) 5-Methoxy-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester A solution of 3-iodo-5-methoxy-indazole-1-carboxylic acid tert-butyl ester [0.500 g, Reference Example 22 (a)] in dioxane and nitrogen atmosphere was treated with triethylamine (1 86 ml) followed by methyl acrylate (1.20 ml), triphenylphosphine (0.105 g) and palladium (II) acetate (60 mg). The resulting mixture was heated at 50 ° C for 16 hours, then cooled to room temperature and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and 40/60 petroleum (1: 9, v / v) to yield 5-methoxy-3- (2-tert-butyl ester). -methoxycarbonyl vinyl) -indazole-1-carboxylic acid (282 mg). LC-MS (METHOD B): RT = 3.33 minutes; 333 (M + H) +. (b) Proceeding in a manner similar to Example 21 (A) but using 4-fluoro-3-iodo-indazole-1-carboxylic acid tert-butyl ester [Reference Example 22 (b)] 4-fluoro-3- (2-methoxycarbonyl-vinyl) -indazole-1-carboxylic acid tert-butyl ester was prepared as a light brown solid. LC-MS (METHOD B): Rj = 3.39 minutes; 321 (M + H) +. (c) By proceeding in a manner similar to Reference Example 21 (a) but using 4-chloro-3-iodo-indazole-1-carboxylic acid tert-butyl ester [Reference Example 22 (c)], tertiary ester was prepared -butyl 4-chloro-3- (2-methoxycarbonyl-vinyl) -indazol-1-carboxylic acid as a brown solid. LC-MS (METHOD B): Rj = 3.48 minutes; 339 (M + H) +. (d) Proceeding in a manner similar to Reference Example 21 (a) but using 5-ethoxy-3-iodo-indazole-1-carboxylic acid tert-butyl ester [Reference Example 22 (d)], tertiary ester was prepared -butylic acid 5-ethoxy-3- (2-methoxycarbonylvinyl) -indazole-1-carboxylic acid in the form of a dull white solid. LC-MS (METHOD B): Rj = 3.41 minutes; 347 (? +?) + · REFERENCE EXAMPLE 22 (a) 3-Vido-5-methoxy-indazole-1-carboxylic acid tert-butyl ester A solution of 3-iodo-5-methoxy-1H-indazole [1, 48g, Reference Example 23 (a)] in acetonitrile (6 ml) was treated with triethylamine (0.98 ml) and N, N-dimethylamine pyr Dyne (0.132 g). The mixture was cooled to 0 ° C and then treated with a solution of di-tert-butyl dicarbonate (1.41 g) in acetonitrile (6 ml). After stirring for 1 hour at room temperature, the reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The pH was adjusted to 2 and the organic layer was dried over magnesium sulfate and then evaporated. The residual orange oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum (1: 4, v / v) to produce tert-butyl acid ester. 3-Vodo-5-methoxy-indazole-1-carboxylic acid (1.72 g) as a yellow solid. LC-MS (METHOD B): RT = 3.45 minutes; 375 (M + H) +. (b) 4-Fluoro-3-iodo-indazole-1-carboxylic acid tert-butyl ester By proceeding in a manner similar to Reference Example 22 (a) above but using 4-fluoro-3-iodo-1 H-indazole [Reference Example 23 (b)], acid tert-butyl ester prepared 4-fluoro- 3-iodo-indazole-1-carboxylic acid in the form of a light brown solid. LC-MS (METHOD B): R = 3.48 minutes; 363 (M + H) +. (c) 4-Chloro-3-iodo-indazole-1-carboxylic acid tert-butyl ester By proceeding in a manner similar to Reference Example 22 (a) above but using 4-chloro-3-iodo-1 H-indazole [Reference Example 23 (c)], tert-butyl 4-chloro-4-yl ester was prepared. -3-iodine-indazole-1- carboxylic acid in the form of a brown solid. LC-MS (METHOD B): Rj = 3.39 minutes; 381 (M + H) +. (d) 5-Ethoxy-3-vodo-indazole-1-carboxylic acid tert-butyl ester By proceeding in a manner similar to Example 22 (a) but using 5-ethoxy-3-vodo-1 H-indazole [Reference Example 23 (d)] 5-ethoxy-3-tert-butyl ester was prepared vodo-indazol-1-carboxylic acid in the form of an off white solid. LC-MS (METHOD B): Rj = 3.49 minutes; 389 (M + H) +. EXAMPLE OF REFERENCE 23 3-vodo-5-methoxy-1 H-indazole A solution of 5-methoxy-1 H-indazole [0.815 g, Reference Example 24 (a)] in dimethyl formamide (8 ml) was treated with iodine (2.80 g) and potassium hydroxide (1.16 g). ). The mixture was stirred at room temperature for 1 hour and then poured into 10% aqueous sodium bisulfite solution (200 ml) and then extracted three times with ethyl acetate. The combined organic extracts were washed with water, then with brine, dried.
They were dried over magnesium sulfate and then evaporated to yield 3-vodo-5-methoxy-1 H-indazole (1.48 g) as a yellow solid. LC-MS (METHOD B): RT = 2.96 minutes; 275 (M + H) +. (b) 4-Fluoro-3-vodo-1 H-indazole Proceeding in a manner similar to Reference Example 23 (a) above but using 4-fluoro-1 H-indazole [Reference Example 24 (b)] as a red solid. LC-MS (METHOD B): Rj = 3.06 minutes; 281 (M + H) +. c) 4-Chloro-3-vodo-1 H-indazole Proceeding in a manner similar to Reference Example 23 (a) above but using 4-chloro-1 H-indazole [Reference Example 24 (c)] as a light brown solid. LC-MS (METHOD B): R = 2.97 mi¬ minutes; 263 (M + H) +. (d) 5-Ethoxy-3-vodo-1 H-indazole Proceeding in a manner similar to the Reference Example 23 (a) above but using 5-ethoxy-1 H-indazole [Reference Example 37] in the form of a light brown solid. LC-MS (METHOD B): Rj = 2.97 minutes; 263 (M + H) +. REFERENCE EXAMPLE 24 5-Methoxy-1 H-indazole A solution of 4-methoxy-2-methylaniline (2 ml) in dichloromethane (10 ml) was treated with triethylamine (3.27 ml). The mixture was cooled to 0 ° C and then treated with acetic anhydride (2.38 ml), then stirred at room temperature for 1 hour and then cooled to 0 ° C when a pink colored solid precipitated. This solid was filtered, then washed with cold dichloromethane and then dissolved in acetic acid (55 ml) and concentrated hydrochloric acid (20 ml). This solution was cooled to -5 ° C, then treated with a solution of sodium nitrite (2.68 g) in water (20 ml), then stirred at that temperature for 1 hour and then treated with water. (100 mi) This mixture was stirred vigorously at 0 ° C for 10 minutes, after which a yellow solid precipitated. This solid was filtered, separated It was then washed with water and then dissolved in toluene (13 ml). This solution was heated at 80 ° C for 1.5 hours, then cooled and then washed with 1 N aqueous sodium carbonate solution. The organic phase was extracted three times with 2 N hydrochloric acid and the acid extracts were cooled and then made alkaline by the addition of 5 N aqueous solution of sodium hydroxide. The aqueous layers were extracted three times with ethyl acetate and then the combined organic layers were dried over magnesium sulfate and then evaporated to yield 5-methoxy-1 H-indazole (0.410 g) as a yellow solid. LC-MS (METHOD B): Rj = 1, 32 minutes; 149 (M + H) +. 4-Fluoro-1 H-indazole To tetrafluoroboric acid (8.2 ml, 48% by weight in water) was added 3-fluoro-2-methylaniline (2.27 ml). The mixture was cooled to 0 ° C when a precipitate formed which was redissolved by the addition of water (8 ml). A solution of sodium nitrite (1) was then added dropwise., 38 g) in water (2.7 ml) and the mixture was then allowed to warm to room temperature and then stirred for an additional 1 hour. The precipitated solid was filtered, then washed with diethyl ether and then dried under suction for 30 minutes. The resulting tetrafluoroborate salt was added to a suspension of potassium acetate (3.92 g) and 18-crown-6 (0.264). g) in chloroform (45 ml). After stirring for 3 hours at room temperature, the bright orange mixture was filtered and the insoluble material was washed with dichloromethane, then subjected to flash column chromatography on silica eluting with a mixture of 40/60 petroleum and ethyl acetate ( 3: 1, v / v) to provide 4-fluoro-1 H-indazole (0.675 g) as an off-white solid. LC-MS (METHOD B): R = 2.70 minutes "137 (M + H) +. 4-Chloro-1 H-indazole By proceeding in a manner similar to Example of Reference 24 (a) above but using 3-chloro-2-methylaniline, 4-chloro-1H-indazole was prepared as a red solid (0.807 g) which was used without further purification. -nal. LC-MS (METHOD B): Rj = 2.90 minutes; 155 (M + H) +. REFERENCE EXAMPLE 25 (a) (5-fluoro-H-indazol-3-ii) -methanol A solution of 5-fluoro-K-indazole-3-carboxylic acid [0.680 g, Reference Example 26 (a)] in anhydrous tetrahydrofuran (15 ml) at 0 ° C, was treated in portions with lithium aluminum hydride ( 0.716 g), then stirred for 2 hours at room temperature and then treated with saturated aqueous sodium sulfate. The reaction mixture was acidified by the addition of hydrochloric acid (1 N) and then extracted three times with ethyl acetate (30 ml). The combined organic extracts were dried over magnesium sulfate and then evaporated. The residual dark brown oil was subjected to flash column chromatography on silica eluting with a mixture of 40/60 petroleum and ethyl acetate (1: 1 to 1: 3, v / v) to produce 5-fluoro-1 H- indazol-3-α-methanol (0.144 g) as a brown solid. LC-MS (METHOD B): RT = 2.40 minutes; 167 (M + H) +. (b) (6-Fluoro-1 H-indazol-3-yl) -methanol Proceeding in a manner similar to Reference Example 25 (a) above but using 6-fluoro-1 H-indazole-3-carboxylic acid [Reference Example 26 (b)] was prepared (6-fluoro-1 H-indazole- 3-yl) -methanol (0.265 g) as a dark gray solid. LC-MS (METHOD B): Rj = 2.40 minutes, 165 (M-H) (c) (5-Methyl-1 H-indazol-3-yl) -methanol Proceeding in a manner similar to Reference Example 25 (a) above but using 5-methyl-1 H-indazoy-3-carboxylic acid [Reference Example 26 (c)] was prepared (5-methyl-1 H- indazol-3-yl) -methanol (0.511 g) as a brown oil. LC-MS (METHOD B): Rj = 2.45 minutes; 163 (M + H) + (5-Chloro-H -indazol-3-yl) -methanol Proceeding in a manner similar to the Reference Example 25 (a) above but using 5-cioro-1 H-indazole-3-carboxylic acid [Reference Example 26 (d)] was prepared (5-chloro-1 H-indazol-3-iQ-methanol in the form of a dark brown oil that solidified at rest LC-MS (METHOD B): Rj = 2.51 minutes; 185 (M + H) +. (e) (6-Methoxy-1 H-indazol-3-in-methanol By proceeding in a manner similar to Reference Example 25 (a) above but using acid using 6-methoxy-1 H-indazole-3-carboxylic acid [Reference Example 26 (e)], 6-methoxy-1 H-indazole was prepared 3-yl) -methanol (0.265 g) as a brown solid. LC-MS (METHOD B): RT = 2.37 mi¬ minutes; 179 (M + H) (4-Phenyl-1 H-pyrazole-3-iO-methanol Proceeding in a manner similar to Reference Example 25 (a) above but using 4-phenyl-1H-pyrazole-3-carboxylic acid [Reference Example 47] and subjecting the reaction product to flash column chromatography on silica eluting with a mixture of dichloromethane and methanol (9: 1, v / v) was prepared (4-phenyl-1 H-pyrazol-3-yl) -methanol. LC-MS (METHOD B): Rj = 2.51 minutes; 175 (M + H) +. (g) (1 - / - indazol-3-yl) -methanol Proceeding in a manner similar to Reference Example 25 (a) above but using indazole-3-carboxylic acid and subjecting the reaction product to column chromatography on silica eluting with a mixture of n-hexane and ethyl acetate (1: 1) to ethyl acetate was prepared (1H-indazol-3-yl) -methanol as a pale yellow solid. LC-MS (METHOD B): Rj = 3.17 minutes; 149.21 ([M + H] +.) REFERENCE EXAMPLE 26 (a) 5-Fluoro-1 H-indazole-3-carboxylic acid A solution of 5-fluoroisatin (2 g) and sodium hydroxide (0.509 g) in water (20 ml) was heated at 50 ° C for 30 minutes, then cooled and then treated with sodium nitrite (0.836 g). This mixture was added over 10 minutes to a solution of concentrated sulfuric acid (2.26 g) in water (200 ml) at 0 ° C, while the temperature below 5 ° C was maintained. After an additional 15 minutes a solution of tin (II) chloride (5.51 g) in concentrated hydrochloric acid (10.5 ml) was added and the resulting mixture was kept at 5 ° C for an additional 30 minutes. The mixture was then stirred for an additional 1 hour while heating to room temperature and then filtered. The luminous brown paste was dissolved in ethyl acetate and the solution was dried over magnesium sulfate and then evaporated to yield 5-fluoro-1 H-indazole-3-carboxylic acid (0.863 g) as a light brown solid. it was used without further purification. LC-MS (METHOD B): Rj = 2.51 minutes; 181 (M + H) +. (b) 6-Fluoro-1 H-indazole-3-carboxylic acid By proceeding in a manner similar to Reference Example 26 (a) above but using 6-fluoro-1 H-indole-2,3-dione [Reference Example 27 (a)], 6-fluoro-1 H-indazole was prepared -3-carboxylic acid (1.962 g) in the form of a light brown solid. LC-MS (METHOD B): R = 2.50 minutes; 181 (M + H) +. (c) 5-Methyl-1 H-indazole-3-carboxylic acid By proceeding in a manner similar to Reference Example 26 (a) above but using 5-metii-isatin, 5-methyl-1 H-indazole-3-carboxylic acid was prepared as a light brown solid. LC-MS (METHOD B): Rj = 2.53 minutes; 77 (M + H) +. (d) 5-Chloro-1 H-indazole-3-carboxylic acid Proceeding in a similar to Reference Example 26 (a) above but using 5-chloro-isatin-chloro-1 H-indazol-5-carboxylic acid 3 was prepared as a light brown solid. LC-MS (METHOD B): RT = 2.58 minutes; 171 (M + H) +. (e) 6-Methoxy-1 H-indazole-3-carboxylic acid By proceeding in a manner similar to Reference Example 26 (a) above but using 6-methoxy-1 H -indodo-2,3-dione [2.50g, Reference Example 27 (b)] 6-methoxy acid was prepared. 1 H-indazole-3-carboxylic acid in the form of a light brown solid. LC-MS (METHOD B): Rj = 2.45 minutes; 193 (M + H) +. REFERENCE EXAMPLE 27 (a) 6-Fluoro-1 H-indole-2,3-dione To vigorously stirred polyphosphoric acid (100 g) at 75 ° C N- (3-fluoro-phenyl) -2-hydroxyimino-acetamide [10.304 g, Reference Example 28 (a)] was added in portions over 30 minutes. The resulting mixture was stirred at 80 ° C for 15 minutes, then it poured on ice, then allowed to stand for 16 hours and then filtered to give a brown paste. The filtrate was extracted four times with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and then evaporated. The residue and brown paste from the previous filtration were combined and treated with aqueous sodium hydroxide (1 N). The mixture was filtered and the filtrate was acidified by the addition of aqueous hydrochloric acid (2 N). The resulting brown solid was filtered and then treated with aqueous sodium hydroxide (1 N). This mixture was filtered and the filtrate was acidified by the addition of aqueous hydrochloric acid (2 N) and then filtered. The combined acidic aqueous filtrates were extracted four times with ethyl acetate. Then they dried over magnesium sulfate and then evaporated to give 6-fluoro-1H-indole-2,3-dione (1, 861 g) as a pale orange solid. LC-MS (METHOD B): Rj = 2.49 minutes; 166 (+ H) +. (b) 6-Methoxy-1 H-indole-2,3-dione Proceeding in a manner similar to the Reference Example 27 (a) above but using 2-hydroxyimino-N- (3-methoxy-phenyl) -acetamide [7.20 g, Reference Example 28 (b)] was prepared 6-methoxy-1 H-indole-2,3- Diona in the form of a brown solid. LC-MS (METHOD B): R = 2.49 minutes; 178 (M + H) +. REFERENCE EXAMPLE 28 (a) N- (3-Fluoro-phenyl) -2-hydroxyimino-acetamide A mixture of doral hydrate (0.819 g) in water (25 ml) was treated with sodium sulfate (5.10 g), 3-fluoroaniline (0.43 ml), concentrated hydrochloric acid (0.3 ml) and hydrochloride hydroxylamine (0.938 g). The mixture was heated at 80 ° C for 2 hours and then allowed to cool and then filtered. The solid was washed with water and then dried in air for 16 hours to give N- (3-fluoro-phenyl-2-hydroxyiminoacetamide (0.756 g) as a yellowish solid.) LC-MS ( METHOD B): Rj = 2.51 minutes; 181 (M + H) + 2-Hydroxyimino-N- (3-methoxy-phenin-acetamide) By proceeding in a manner similar to Reference Example 28 (a) above but using m-anisidine (0.5 ml), 2-hydroxyimino-N- (3-methoxy-phenyl) -acetamide was prepared as a brown solid. LC-MS (METHOD B): R = 2.44 minutes; 195 (M + H) +. EXAMPLE OF REFERENCE 29 (a) 4-Ethyl-phenylene diamine A stirred solution of 5-ethyl-2-nitro-aniline [200 mg, Example of Reference 30 (a)] and tin chloride (2.75 g) in ethanol (2 ml) was heated in a Smith Creator microwave at 140 ° C for 10 minutes. The reaction mixture was basified to pH 8 by the addition of saturated sodium hydrogencarbonate solution and then extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give 4-ethyl-phenylene diamine (140 mg) as a pale orange solid, which was used without further purification. MS: 137.2 (M + H) +. HPLC (METHOD H): RT = 2.91 minutes. (b) 4-Methoxy-5-methyl-benzene-1,2-diamine By proceeding in a manner similar to Reference Example 29 (a) but using 4-methoxy-5-methyl-2-nitro-phenylamine [582 mg, Reference Example 31 (i)], 4-methoxy-5-methyl-benzene was prepared -1,2-diamine (454 mg) in the form of a light brown solid. LC-MS (K METHOD): Rj = 2.39 minutes, 153.20 (M + H) +. 4- (2-Morpholin-4-yl-ethoxy) -benzene-1,2-diamine By proceeding in a manner similar to Reference Example 29 (a) above but using 4- [2- (3,4-dinitro-phenoxy) -ethyl] -morpholine [Reference Example 67], 4- (2-morpholine- 4-yl-ethoxy) -benzene-1,2-diamine (170 mg) in the form of a pale brown oil. LC-MS (N METHOD): Rj = 2.2 minutes, 238.21 (M + H) +. REFERENCE EXAMPLE 30 (a) 4-Ethyl-5-methyl-phenylene diamine A stirred solution of 4-ethyl-5-methyl-2-nitro-aniline [484 mg, Reference Example 31 (b)] in methanol (20 ml) was treated with tin chloride (5.09 g), then heated to reflux for 16 hours and then cooled to room temperature. The pH of the reaction mixture was adjusted to pH 8 by the addition of aqueous sodium bicarbonate and then this mixture was extracted with ethyl acetate. The organic extracts were dried over magnesium sulfate and then evaporated to give provide 4-ethyl-5-methyl-phenylene diamine (374 mg) as a white off solid. LC-MS (METHOD B): RT = 1.80 minutes; 151, 25 (M + H) +. (b) 4-lsopropyl-5"methyl-phenylene diamine Proceeding in a manner similar to the Reference Example 30 (a) above but using 4-isopropy-5-methyl-2-nitro-aniline [Reference Example 31 (c)] 4-isopropyl-5-methyl-phenylene-diamine was prepared as a light brown solid. LC-MS (METHOD C): Rj = 3.30 minutes; 165,16 (M + H) +. 4-Bromo-5-methyl-phenylene diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4-bromo-5-methyl-2-nitride-aniline [Reference Example 31 (d)], 4-bromo-5-methyl- phenylene diamine in the form of an off white solid. LC-MS (METHOD B): R = 2.63 minutes; 203.22 (M + H) +. (d) 4-n-propyl-phenylene diamine By proceeding in a manner similar to Reference Example 30 (a) above but using using 4-n-propyI-2-nitro-aniline [Reference Example 31 (e)], 4-n-propyl-phenylene-diamine was prepared in the form of a dull white solid. LC-MS (METHOD B): Rj = 2.07 minutes, 151, 30 (M + H) +. (e) 4-Bromo-phenylene diamine Proceeding in a manner similar to Reference Example 30 (a) above but using 4-bromo-2-nitroaniline, 4-bromo-phenylenediamine was prepared as a brown solid. LC-MS (METHOD B): Rj = 1, 77 minutes; 187.22 (M + H) +. (f) 3 '; 4'-diaminobophenol-3-carbonitrile By proceeding in a manner similar to Reference Example 30 (a) above but using 4'-amino-3'-nitro-biphenyl-3-carbonitrile [Reference Example 34 (a)], 3 ', 4'-diaminobophenyl- 3-carbontril in the form of an off white solid. LC-MS (METHOD B): R = 2.72 minutes; 210.3 (M + H) +. 4- (pyridin-3-yl) benzene-1,2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 2-nitro-4-pyridin-3-yl-phenylamine [Reference Example 34 (b)], 4- (pyridin-3-yl) benzene was prepared -1, 2-diamine in the form of an off white solid. LC-MS (METHOD B): Rj = 0.37 minutes; 186.3 (M + H) 6-methylbiphenyl-3,4-d-amines By proceeding in a manner similar to Reference Example 30 (a) above but using 2-methyl-5-nitro-biphenyl-4-ylamino [Reference Example 34 (c)], 6-methyl-phenyl-3,4- was prepared diamine in the form of an off white solid. LC-MS (METHOD B): Rj = 2.36 minutes; 199.25 (M + H) +. (i) biphenyl-3,4-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 3-n-trobiphenyl-4-ylamino [Reference Example 34 (d)] biphenyl-3,4-diamine was prepared biphenyl-3 was prepared , 4-diamine in the form of a yellow solid. LC-MS (METHOD B): R = 2.25 minutes; 185.3 (M + H) +. (j) 2'-fluorobiphenyl-3,4-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 2'-fluoro-3-nitro-biphenyl-4-ylamine [Reference Example 34 (e)] 2'-fluorobiphenol-3 was prepared, 4-diamine in the form of a white solid. LC-MS (METHOD B): Rj = 2.73 minutes; 203.31 (M + H) +. (k) 4-benzoM, 3] dioxol-5-ylbenzene-1,2-diamine Proceeding in a manner similar to Reference Example 30 (a) above but using 4-benzo [1,3] dioxo-5-yl-2-nitrophenylamine [Reference Example 34 (f)] was prepared 4-benzoH, 3] dioxol-5-ylbenzene-, 2-diamine as a white solid. LC-MS (METHOD B): R = 2.66 minutes; 229.3 (M + H) +. 2'-methoxybiphenyl-3,4-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 2'-methoxy-3-nitro-biphenyl-4-ylamine [Reference Example 34 (g)], 2'-methoxybiphenyl-3,4- was prepared diamine in the form of a white solid. LC-MS (METHOD B): R = 2.74 minutes; 215.33 (M + H) +. (m) 4'-chlorobiphenyl-3,4-diamine Proceeding in a manner similar to the Reference Example 30 (a) above but using 4'-chloro-3-nitro-b-phenyl-4-yl-amine [Reference Example 34 (h)] 4'-chlorobiphenyl-3,4-diamine diamine was prepared in the form of a white solid. LC-MS (METHOD B): RT = 2.85 minutes; 219.3 (? +?) + · '(N) 4'-methylbiphenyl-3,4-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4'-methyI-3-nitro-biphenyl-4-yl-amine [Reference Example 34 (i)], 4'-methylbiphenyl-3 was prepared, 4-d-amines in the form of a white solid. LC-MS (METHOD B): Rj = 2.39 minutes, 199.25 (M + H) +. (o) 4-benzyloxybenzene-1,2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4-benzyloxy-1,2-dinitrobenzene [Reference Example 35 (a)], 4-benzyloxybenzene-1,2-diamine was prepared in the form of a solid white. LC-MS (METHOD B): Rj = 2.34 minutes, 215.33 (M + H) +. (p) benzoH, 3] dioxol-5,6-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 5,6-dinitro-benzo [1,3] dioxoIe [Reference Example 56 (b)], benzoH, 3] dioxol-5,6- was prepared diamine in the form of an oily solid. LC-MS (METHOD B): Rj = 0.43 minutes, 153.18 (M + H) +. (q) 4,5-dimethoxybenzene-1,2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4,5-dimethoxy-2-nitroaniline, 4,5-dimethoxybenzene-, 2-diamine was prepared as an oily solid. LC-MS (METHOD B): Rj = 0.43 minutes, 169.24 (M + H) +. (r) 4,5-Diethylbenzene-1,2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using using 4,5-diethyl-2-nitroaniline [Reference Example 31 (f)], 4,5-diethylbenzene-1,2-diamine was prepared. used without further purification. LC-MS (METHOD B): Rj = 2.21 minutes, 165.24 (M + H) +. (s) 4-ethoxy-5-ethyl-benzene-1,2-diamine Proceeding in a manner similar to the Reference Example 30 (a) above but using 4-ethoxy-5-ethyl-2-nitrophenylamine [Reference Example 31 (g)] was prepared 4-ethoxy-5-ethyl-benzene-1,2-diamine. (t) 4-Ethoxy-3-ethyl-phenylamine Proceeding in a manner similar to the Reference Example 30 (a) above but using 1-ethoxy-2-ethyl-4-nitrobenzene [Reference Example 32 (h)] and subjecting the reaction product to chromatography on silica gel (heptane, ethyl acetate gradient 25- 35%) 4-ethoxy-3-ethyl-phenylamine (0.6 g) was prepared in the form of an oil. GS-MS one peak, Rj = 7.17 minu¬ cough. MS 165 (M) +. 4-Methoxy-3-methyl-phenylamine Proceeding in a manner similar to the Reference Example 30 (a) above but using 1-methoxy-2-methyl-4-nitrobenzene [2.7g, Reference Example 56 (a)] was prepared 4-methoxy-3-methyl-phenylamine (2.07 g). Rp = 0.5 [ethyl acetate / n-pentane, 1: 1, v / v]. 4-Ethoxy-benzene-1,2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4-ethoxy-2-nitrianiline (1.5 g), 4-ethoxy-benzene-1,2-diamine (1.02 g) was prepared in the form of a brown oil. LC-MS (METHOD J): Rj = 0.50 and 3.88 minutes, 153.30 (M + H) +. (w) 4-Fluoro-5-methyl-benzene-, 2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4-fluoro-5-methyl-2-nitro-phenylamine [Reference Example 31 (j)], 4-fluoro-5-methyl-benzene- 1,2-diamine (1.27 g) as a yellow solid. LC-MS (J METHOD): Rj = 1.93 minutes, 141.25 (M + H) +. 3,4-Diamino-N-benzyl-benzenesulfonamide By proceeding in a manner similar to Reference Example 30 (a) above but using 4-amino-N-benzyl-3-nitro-benzenesulfonamide [Reference Example 61], 3,4-diamino-N-benzyl-benzenesulfonamide (0.350) was prepared g) in the form of a yellow film. LC-MS (METHOD K): RT = 2.87 minutes, 278.28 (M + H) + 4-Difluoromethoxy-benzene-1,2-diamine By proceeding in a manner similar to Reference Example 30 (a) above but using 4-difluoromethoxy-2-nitro-phenylamine [Reference Example 31 (k)], 4-difluoromethoxy-benzene-1,2-diamine ( 2.70 g) in the form of a pale brown solid. LC-MS (METHOD N): Ry = 2.45 minutes, 175 (M + H) +. (z) 4-Ethyl-5-methoxy-benzene-1,2-diamine [200 mg, Reference Example 30 (z)] By proceeding in a manner similar to Reference Example 30 (a) but using 5-ethyl-4-methoxy-2-nitro-phenylamine [2.4 g, Reference Example 31 (1)] 4-ethyl-5- was prepared methoxy-benzene-, 2-diamine (1.6 g) in the form of a black solid. LC-MS (METHOD 1, AMMONIUM ACETATE, 5min): Ry = 3.50 minutes, 167.17 (M + H) +. (aa) 3-Ethyl-4-methoxy-phenylamine Proceeding in a manner similar to Reference Example 30 (a) but using 5-ethyl-4-methoxy-2-nitro-phenylamine [3.6g, Reference Example 31 (1)] and carrying out the reaction for 24 hours , 3-ethyl-4-methoxy-phenylamine (2.5 g) was prepared as a brown solid. LC-MS (METHOD J): RT = 2.04 minutes, 152.2 (M + H) +. EXAMPLE OF REFERENCE 31 (a) 5-Ethyl-2-nitro-aniline A stirred solution of sodium methoxide (0.35 g) in methanol (15 ml) was treated with a solution of 4-ethyl-2-nitride-A / -acetyl-aniline [1 g, Reference Example 32 (a )] in methanol (15 ml). The. The reaction mixture was stirred at room temperature for 24 hours and then poured onto ice-water. The resulting precipitate was filtered and then dried to give 5 ^ \ ^ \ r an \\ ^ (650 mg). LC-MS (METHOD B): R = 3.11 minutes; 167.2 (M + H) +. (b) 4-Ethyl-5-metii-2-nitroannoline Proceeding in a manner similar to Reference Example 31 (a) above but using 4-ethyl-5-methyl-2-nitro-A / -acetyl-aniline [1g, Example Reference 32 (b)] 4-ethyl-5-methyl-2-nitro-aniline was prepared as an orange solid. LC-MS (METHOD B): Rj = 3.16 minutes; 181, 14 (M + H) +. (c) 4-isopropyl-5-methyl-2-nitro-aniline Proceeding in a manner similar to Reference Example 31 (a) above but using 4-isopropyl-5-methyl-2-nitro- / V-acetyl-aniline [1g, Reference Example 32 (c)] in the form of a solid orange. LC-MS (METHOD-B): R = 3.26 minutes; 195.3 (M + H) +. (d) 4-Bromo-5-methyl-2-nitro-aniline Proceeding in a manner similar to the Reference Example 31 (a) above but using 4-bromo-5-methyl-2-nitro-A / -acetyl-aniline [1 g, Reference Example 32 (d)] was prepared 4-bromo-5-methyl-2-nitro -aniline in the form of a brown solid. LC-MS (METHOD B): Rj = 3.24 minutes; 231, 2 (M + H) +. e) 4-n-Propyl-2-nitroannoline By proceeding in a manner similar to Reference Example 31 (a) above but using 2-nitro-4-propyl-A / -acetyl-aniline, 4-n-propyl-2-nitroaniline was prepared as an orange solid. LC-MS (METHOD C): Rj = 3.46 minutes; 181, 2 (M + H) +. (f) 4,5-diethyl-2-nitro-aniline By proceeding in a manner similar to Reference Example 31 (a) above but using 4,5-diethyl-2-nitro-W-acetyl-aniline [Reference Example 32 (f)] 4,5-diethyl 2- was prepared nitro-aniline. LC-MS (METHOD B): Rj = 3.27 minutes; 195.22 (M + H) +. .
N- (4-Ethoxy-5-ethyl-2-nitrophenyl) acetamide [0.2 g, Reference Example 32 (g)] was dissolved in ethanol (25 ml) and sodium hydride (100 mg, 50% dispersion) was added. % in mineral oil, 2 mmol). The mixture was stirred overnight at room temperature, aqueous ammonium chloride (3 mL) was added and the mixture was evaporated. The residue was chromatographed on silica gel (heptane with gradient of 25-50% ethyl acetate) to give 4-ethoxy-5-ethyl- 2-Nitrophenylamine (0.1 g) as a red solid. LC-MS (METHOD E): Ry = 3.4 minutes, 21 (M + H) +. (h) 5-Chloro-4-methoxy-2-nitrophenylamine N- (5-Chloro-4-methoxy-2-nitrophenyl) acetamide (8.0 g, Reference Example 32 (i)) was added to a solution of sodium methoxide (2.0 g, 0.037 mol) in methanol ( 150 ml) and the mixture was stirred at room temperature for 4 hours, the reaction mixture was added to ice-water (750 ml), stirred for 15 minutes and the aqueous mixture was filtered. dried at 60 ° C under vacuum to provide 5-chloro-4-methoxy-2-nitrophenylamine (6.52 g) as an orange solid, mp 128-129 ° C. (i) 4-Methoxy-5- methyl-2-nitro-phenylamine Proceeding in a manner similar to Reference Example 31 (a) above but using using N- (4-methoxy-5-methyl-2-nitro-phenyl) -acetamide [2.53 g, Reference Example 32 (j)] is prepared 4-methoxy-5-methyl-2-nitro-phenylamine (2.05 g) as a bright orange solid. LC-MS (J METHOD): Rj = 3.46 minutes, 183.29 (M + H) +. (j) 4-Fluoro-5-methyl-2-nitro-phenylamine Proceeding in a manner similar to Reference Example 31 (a) above but using N- (4-fluoro-5-methyl-2-nitro-phenyl) -acetamide [2.53 g, Reference Example 32 (k)] was prepared 4-fluoro-5-methyl-2-nitro-phenylamine (2.25 g) as an orange solid. LC-MS (J METHOD): Rj = 3,53 minu¬ cough, 171, 28 (M + H) +. (k) 4-difluoromethoxy-2-nitro-phenylamine By proceeding in a manner similar to Reference Example 31 (a) above but using N- (4-difluoromethoxy-2-nitro-phenyl) -acetamide [Reference Example 32 (l)], 4-difluoromethoxy-2-nitro- phenylamine (10 g) as an orange solid. LC-MS (METHOD N): R = 3.86 minutes, 205 (M + H) +. 5-Ethyl-4-methoxy-2-nitro-phenylamine Proceeding in a manner similar to Reference Example 31 (a) but using N- (5-ethyl-4-methoxy-2-nitro-phenyl) -acetamide [2.4 g, Reference Example 32 (m)] was prepared 5-ethyl-4-methoxy-2-nitro-phenylamine (1.9 g) as a brown solid. LC-MS (K METHOD): Rj = 4.14 minutes, 197.09 (M + H) +. REFERENCE EXAMPLE 32 (a) 4-Ethyl-2-nitro-V-acetyl-aniline A stirred solution of 4-ethyl- / V-acetyl-aniline [3g, Reference Example 33 (a)] in acetic anhydride (8 ml) and acetic acid (4 ml), at -5 ° C, was treated dropwise with a mixture of acetic acid (1.75 ml) and nitric acid concentrated (1, 22 ml). The mixture was heated to 0 ° C, then stirred at 0 ° C for 2 hours and then poured into water. This mixture was evaporated and the resulting oil was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and then evaporated. The residual oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum ether (2: 5) to provide 4-ethyl-2-nitro-A / -acetyl-aniline (1.4 g). ) in the form of an orange oil. LC-MS (METHOD B): Rj = 2.95 minutes; 209.2 (M + H) +. b) '4-Etyl-5-methyl-2-nitro-A / -acetyl-aniline By proceeding in a manner similar to Reference Example 32 (a) above but using 3-methyl-4-ethyl-acetyl aniline, 4-ethyl-5-methyl-2-nitro-A / -acetyl-aniline was prepared in the form of an orange oil. LC-MS (METHOD B): Rj = 3.03 minutes; 223.25 (M + H) +. c) 4-isopropyl-5-methyl-2-nitro- / V-acetyl-aniline By proceeding in a manner similar to Reference Example 32 (a) above but using 3-methyl-4-isopropyl- / V-acetyl aniline [Reference Example 33 (b))] 4-isopropyl-5-methyl- 2-Nitro-A / -acetyl-aniline in the form of an orange solid. LC-MS (METHOD B): Ry = 3.15 minutes; 231, 36 (M + H) 4-Bromo-5-methyl-2-nitro-A / -acetyl-aniline Proceeding in a manner similar to Reference Example 32 (a) above but using 3-methyl-4-bromo - / \ / - acetyl aniline [Reference Example] 33 (c)] was prepared 4-bromo-5-methyl-2-nitro-A / -acetyl-aniline as an orange solid. LC-MS (METHOD B): Rj = 3.06 minutes; 274.2 (M + H) +. (f) 4,5-Diethyl-2-nitride-A / -acetyl-aniline By proceeding in a manner similar to Reference Example 32 (a) above but using 3,4-diethyl- / V-acetyl aniline [Reference Example 33 (d)], 4,5-diethyl-2-nitro-A / was prepared -acetyl-aniline in the form of a naran-ja solid. LC-MS (METHOD B): Rj = 3.18 minutes; 237.4 (M + H) +. (g) N- (4-Ethoxy-5-ethyl-2-nitrophenyl) acetamide N- (4-Ethoxy-3-ethyl-phenyl) acetamide [3.1g, Example of Reference 33 (e)] in acetic anhydride (5 ml), a solution of nitric acid in acetic acid (0.5 ml of 95% nitric acid in 4 ml) was added and the mixture was stirred overnight at room temperature . The mixture was diluted with water (100 ml) and the aqueous mixture was extracted twice with ethyl acetate (100 ml). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane / ethyl acetate 9/1) to give N- (4-ethoxy-5-etl-2-nitrophenyl) acetamide (3.0 g) in the form of a bright yellow solid. LC-MS (METHOD E): Rj = 3.27 minutes, '253 (M + H) +. 1 - . 1-Ethoxy-2-ethyl-4-nitrobenzene A solution of 1-ethoxy-2-ethyl benzene (3.5 g, Reference Example 51) in acetic anhydride (30 ml) was cooled in an ice-water bath. A solution of nitric acid (1.4 ml of excess 90% -30%) in acetic acid (25 ml) was added dropwise and the mixture was stirred overnight at room temperature. The reaction mixture was poured into ice-water (300 ml) and the aqueous mixture was extracted with ethyl acetate (2 x 200 ml). The combined extracts were evaporated and the residue was chromatographed on silica gel (heptane with gradient from 5 to 10% ethyl acetate) to give 1-ethoxy-2-ethyl-4-nitrobenzene (1.4 g) as a transparent liquid. LC-MS (METHOD E) RT = 3.75 minutes, 196 (M + H) +. (i) N- (5-Chloro-4-methoxy-2-nitrophenyl) acetamide A solution of N- (3-chloro-4-methoxyphenyl) acetamide (6.85 g, Reference Example) in a mixture of acetic acid (20 ml) and acetic anhydride (35 ml) was cooled to -5 ° C and added dropwise a solution of fuming nitric acid (3 ml) in acetic acid (4 ml) keeping the reaction temperature below 0 ° C. The mixture was stirred at 0 ° C for 30 minutes, at which time a yellow precipitate developed. After another 1.5 h at 0 ° C, the mixture was poured into water (100 ml) and the aqueous mixture was stirred vigorously for 15 minutes and filtered. The yellow precipitate was washed with water and dried under vacuum at 60 ° C to give the product (8.0 g) as a yellow solid, m.p. 152-153 ° C. (M + H) +. (j) N- (4-Methoxy-5-methyl-2-nitro-phenyl) -acetamide Proceeding in a manner similar to the Reference Example 32 (a) but using N- (4-methoxy-3-methyl-phenyl) -acetamide [2.65 g, Reference Example 33 (f)] was prepared N- (4-methoxy-5-methyl-2- Nitro-phenyl-acetamide (2.53 g) as an orange solid LC-MS (METHOD J): Rj = 3.30 minutes, 225.29 (+ H) +, 223.29 (M-H) ". (K) N- (4-Fluoro-5-methyl-2-nitro-phenyl) -acetamide By proceeding in a manner similar to Example 32 (a) above but using N- (4-fluoro-3-methyl-phenyl) -acetamide [2.65 g, Reference Example 33 (g)], N- (4-fluoro) was prepared -5-methyl-2-nitro-phenyD-acetamide (2.25 g) as a yellow solid LC-MS (METHOD J): R = 3.31 minutes, 21 1, 26 (M-H) ". (i) N- (4-Difluoromethoxy-2-nitro-phenyl) -acetamide By proceeding in a manner similar to Example 32 (a) above but using N- (4-difluoromethoxy-phenyl) -acetamide [Reference Example 33 (h)], N- (4-difluoromethoxy-2-n-phenyl) was prepared ) -acetamide (450 mg) as a yellow solid. LC-MS (K METHOD): Rj = 3.72 minutes, MS: 245 (M-H) -. (m) N- (5-Ethyl-4-methoxy-2-nitro-phenyl) -acetamide By proceeding in a manner similar to Example 32 (a) but using N- (3-ethyl-4-methoxy-phenyl) -acetamide [2.9 g, Reference Example 33 (¡)] N- (5) was prepared Ethyl-4-methoxy-2-nitro-phenyl) -acetamide (2.4 g) as a yellow solid. LC-MS (K METHOD): R = 4.04 minutes, MS: 239.16 (M + H) +. REFERENCE EXAMPLE 33 4-Ethyl-A / -acetyl-aniline A stirred solution of 4-ethylaniline (2 g) and triethylamine (13.91 ml) in dichloromethane (40 ml) at 0 ° C under nitrogen was treated dropwise with acetic anhydride (4.67 ml). The mixture was warmed to room temperature, then stirred for 16 hours at room temperature, then washed with (i) 10% citric acid (40 ml), (ii) water (40 ml) and (iii) brine (40 ml). my). The organic phase was dried over magnesium sulfate and then evaporated to give 4-ethyl-N-acetyl-aniline (2.36 g) as a pale orange solid which was used without further purification. LC-MS (METHOD B): Rj = 2.80 minutes; 164.2 (M + H) +. (b) 3-Methyl-4-isopropyl- / V-acetyl aniline By proceeding in a manner similar to Reference Example 33 (a) above but using 3-methyl-4-isopropylaniline, 3-methyl-4-isopropyl-ZV-acetyl aniline was prepared as an orange solid. LC-MS (METHOD B): Rj = 2.97 minutes; 192.3 (M + H) +. (c) 3-Methyl-4-bromo- / / -acetyl aniline By proceeding in a manner similar to Reference Example 33 (a) above but using 3-methyl-4-bromoaniine, 3-methyl-4-bromo- A / -acetyl aniline in the form of a brown solid. LC-MS (METHOD B): R = 2.88 minutes; 228.12 (M + H) +. (d) 3,4-Diethyl-A / -acetyl aniline By proceeding in a manner similar to Reference Example 33 (a) above but using 3,4-diethylaniline, 3,4-diethyl- / V-acetyl aniline was prepared which was used without further purification. LC-MS (METHOD B): Rj = 3.03 mi¬ minutes; 192.30 (M + H) + (e) N- (4-Ethoxy-3-ethyl-phenyl) acetamide To a solution of 4-ethoxy-3-ethyl-phenylamine [0.6 g, Reference Example 30 (t)] in pyridine (5 mL) was added acetic anhydride (1 mL) and the mixture was stirred 18 hours at room temperature. ambient. The reaction mixture was diluted with water (100 ml) and the aqueous mixture was extracted twice with ethyl acetate (100 ml). The combined extracts were evaporated to give (4-ethoxy-3-ethyl-phenylacetamide (0.6 g) as a pink foam GC-MS one peak, R = 9.16 minutes, MS 207 (M) +. (f) N- (4-Methoxy-3-methyl-phenyl) -acetamide Proceeding in a manner similar to Reference Example 33 (a) above but using 4-methoxy-3-methyl-phenylamine (2.07 g, Reference Example 30 (u) and subjecting the reaction product to flash chromatography on silica N- (4-methoxy-3-methyl-phenyl) -acetamide (2.65 g) was prepared in the form of a crystalline solid using a mixture of ethyl acetate and n-pentane (1: 1, v / v). pale pink LC-MS (METHOD J): R = 2.94 minutes, 180.30 (M + H) +. N- (4-Fluoro-3-methyl-phenyl) -acetamide Proceeding in a manner similar to the Reference Example 33 (a) above but using 4-fluoro-3-methylaniline was prepared N- (4-fluoro-3-methyl-phenyO-acetamide (3.82 g) as an orange solid LC-MS (METHOD J) : Rj = 3.08 minutes, 168.24 (M + H) +. N- (4-difluoromethoxy-phenyl-acetamide) By proceeding in a manner similar to Reference Example 33 (a) above but using 4-difluoromethoxyaniline, N- (4-difluoromethoxy-phenylacetamide (5.90 g) was prepared as an orange solid.
(METHOD K): R = 3.62 minutes, 202 (M + H) +. i) N- (3-Ethyl-4-methoxy-phenyl) -acetamida By proceeding in a manner similar to Reference Example 33 (a) but using 3-ethyl-4-methoxy-phenylamine [2.5g, Reference Example 30 (aa)], N- (3-ethyl-4-methoxy) was prepared phenyl) -acetamide (2.9 g) as a light brown solid. LC-MS (K METHOD): R = 3.92 minutes, 194.16 (M + H) +. REFERENCE EXAMPLE 34 4'-Amino-3'-nitro-biphenyl-3-carbonitrile A stirred solution of 3-cyanophenyl-boronic acid (812 mg) and tetrakis (triphenylphosphine) palladium (150 mg) in tetrahydrofuran (4 ml) under a nitrogen atmosphere was treated with 4-bromo-2-nitroaniline in tetrahydrofuran (10 ml). ). The The reaction mixture was heated at 85 ° C for 48 hours, then cooled to room temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 2, v / v) to provide 4'-amino-3'-nitro-biphenyl-3-carbonitrile ( 224 mg) in the form of a yellow solid. LC- S (METHOD B): Rj = 3.21 minutes, 240.3 (+ H) +. (b) 2-ntr-4-pyridin-3-yl-phenylamine By proceeding in a manner similar to Reference Example 34 (a) above but using pyridin-3-boronic acid, 2-nitro-4-pyridin-3-yl-phenylamine was prepared as a yellow solid. LC-MS (METHOD B): Rj = 2.09 minutes, 216.24 (M + H) +. (c) 2-methyl-5-nitro-biphenyl-4-yl-amine By proceeding in a manner similar to Reference Example 34 (a) above but using phenyl boronic acid, and 4-bromo-5-methyl-2-nitroaniline [Reference Example 31 (d)], 2-methyl- 5-Nitro-biphenyl-4-yl-amine in the form of an orange solid. LC-MS (METHOD B): R = 3.30 minutes, MS: 229.23 (M + H) + (d) 3-nitrophenyl-4-ylamine By proceeding in a manner similar to Reference Example 34 (a) above but using phenyl boronic acid, 3-nitrophenyl-4-ylamine was prepared as a red solid. LC-MS (METHOD B): R = 3.43 minutes, 215.06 (M + H) +. (e) 2'-fluoro-3-nitro-biphenyl-4-ylamine Proceeding in a manner similar to the Reference Example 34 (a) above but using 2-fluorophenyl-boronic acid, 2'-fluoro-3-nitro-biphenyl-4-ylamine was prepared as a red solid. LC-MS (METHOD B): R - 3.33 minutes, 233.3 (M + H) +. (f) 4'-benzof1, 31-dioxo-5-yl-2-nitrophenylamine By proceeding in a manner similar to Reference Example 34 (a) above but using 3,4-metlenedioxyphenylboronic acid, 4 ^ benzofl, 31-dioxo-5-yl-2-nitrophenylamine was prepared as an orange solid. LC-MS (METHOD B): RT = 3.23 minutes, 259.3 (M + H) +. (g) 2'-methoxy-3-nitro-biphenyl-4-ylamine By proceeding in a manner similar to Refence Example 34 (a) above but using 2-methoxypheniomeric acid, 2'-methoxy-3-nitro-biphenyl-4-ylamine was prepared as an orange solid. LC-MS (METHOD B): Rj = 3.30 minutes, 245.3 (M + H) +. (h) 4'-chloro-3-nitro-biphenyl-4-ylamine By proceeding in a manner similar to Reference Example 34 (a) above but using 4-chlorophenyl boronic acid, 4'-chloro-3-nitro-biphenyl-4-ylamine was prepared as an orange solid. LC-MS (METHOD B): Rj = 3.45 minutes, 249.27 (M + H) +. (i) 4'-methyl-3-nitro-biphenyl-4-ylamine By proceeding in a manner similar to Reference Example 34 (a) above but using 4-methylphenylboronic acid, 4'-methyl-3-nitro-biphenyl-4-ylamine was prepared as an orange solid. LC-MS (METHOD B): Rj = 3.33 minutes, 229.2 (M + H) +. REFERENCE EXAMPLE 35 (a) 4-benzyloxy-1,2-dinitrobenzene An agitated solution of 3,4-dinitriphenol (1 g) in dimethylphoramide (30 ml) was treated with benzyl bromide (723 μl) and potassium carbonate (1.13 g). The reaction mixture was stirred at room temperature for 24 hours and then partitioned between ethyl acetate and water. The layer The mixture was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (: 4, v / v) to give 4-benzyloxy-1,2-dinitrobenzene (1.30 g) in the form of a solid yellow. LC-MS (METHOD B): R = 3.31 minutes. H NMR [(CD3) 2CO, ppm): d 5.28 (s, 2H), 7.26-7.42 (m, 6H), 7.57 (d, 1 H), 8.12 (d, 1 HOUR). 1-Ethyl-2-methoxy-benzene Proceeding in a manner similar to the Reference Example 35 (a) above, but using 2-ethylfenol (5 ml) and iodomethane (2.6 ml) with acetone as solvent and heating at 70 ° C for 24 hours in a sealed pressure vessel, 1-ethyl-2 was prepared -methoxy-benzene (5.6 g) as a yellow oil which was used without further purification. LC-MS (K METHOD): R = 3.83 minutes. 1 H NMR (cf 6 acetone): d 6.95 (m, 2 H), 6.75 (d, 1 H), 6.68 (t, 1 H), 3.67 (s, 3 H), 2.44. (q, 2H) 0.95 (t, 3H). REFERENCE EXAMPLE 36 (a) (2-Amino-4,5-dimethylphenyl) 4-nitro-1 H-pyrazole-3-carboxylic acid amide Method A. A stirred solution of 4,5-dimethylphenylenediamine (4.32 g) and diisopropylethylamine (30 ml) in dichloromethane (200 ml) was treated with 4-nitropyrazole-3-carboxylic chloride (5 g) in portions at 0 °. C. The reaction mixture was warmed to room temperature and stirred for 30 minutes. The solvent was removed in vacuo and the oily residue was partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulfate and concentrated. The residual oil was recrystallized from ethyl acetate and methanol (10%) to give 4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4,5-dimethylphenyl) amide (6.58 g) in the form of an orange solid. LC-MS (METHOD B): Rj = 2.36 minutes, 276.09 (M + H) +. Method B. Polyphosphoric acid (500 g) was added to a 1 L flask equipped with an overhead stirrer and heated to 70 ° C under nitrogen. A combined mixture of 4-nitro-3-pyrazole carboxylic acid (50 g) and 1,2-diamino-4,5-dimethylbenzene (43.4 g) was added and the mixture was heated to 180 ° C. After 1 hour at this temperature, the reaction mixture was cooled to 130 ° C and poured into ice-water (2.5 kg). This mixture was stirred with a high stirrer and then treated with aqueous ammonium hydroxide (350 ml, 30%) until the pH was 2.1. After stirring for an additional 15 minutes, the mixture The mixture was filtered and the filtered solid was washed three times with water (200 ml), then dried under vacuum to provide 4-nitro-1 H-pyrazole-3- (2-amino-4,5-dimethylphenyl) amide. carboxylic acid in the form of a brown solid. (b) (4-Nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-ethyl-5-methylphenyl) -amide) Proceeding in a manner similar to Reference Example 36 (a), Method A, above but using (2-amino-4-etl-5-methylphenidated 4-nitro-1 H-pyrazole-3-carboxylic acid in the form of a dark red solid LC-MS (METHOD B): Rj = 2.89 minutes, 290.24 (M + H) +. (c) (2-Amino-5-chloro-4-methoxyphenyl) amide of 4-nitro-1H-pyrazole-3-carboxylic acid Proceeding in a manner similar to Reference Example 36 (a), Method A, above but using 4-chloro-5-methoxybenzene-1,2-diamine [1g, Reference Example 49 (b)], diisopropylethylamine (4.1 ml, 4 eq), dichloromethane (50 ml) and a solution of 4-nitropyrazole-3-carbonyl chloride (1 g, 5.8 g. mmol) in dichloromethane (25 ml) and stirring the reaction mixture at room temperature for 18 hours was prepared a mixture of (2-amino-5-chloro-4-methoxyphenyl) amide of 4-nitro-1H-pyrazole-3 -carboxylic and the bis-acylated material, MS 310 (") and 449 (M ~) This material was used without further purification in Example 29 (c). (d) (2-Amino-4-methoxy-phenyl) -amide of 4-nitro-1 H-pyrazole-3-carboxylic acid Proceeding in a manner similar to the Reference Example 36 (a), Method A, above but using 4-methoxy-1,2-phenylenediamine (880 mg) and 4-nitropyrazole-3-carboxylic chloride [prepared by treating a solution of 4-nitropyrazole-3-carboxylic acid (1 g) in dry dichloromethane (70 ml) under nitrogen with oxalyl chloride (1.1 ml) and dimethylformamide under stirring overnight, evaporating the reaction mixture and then azeotropically distilling three times with toluene (10 ml)]. prepared (4-nitro-1H-pyrazole-3-carboxylic acid (2-amino-4-methoxy-phenyl) -amide (800 mg). ). LC- S (METHOD J): Rj = 2.67 minutes, 278.25 (M + H) +, 276.28 (M-H) ". (e) (2-Amino-4-ethoxy-phenyl-4-nitro-1 H-pyrazole-3-carboxylic acid amide Proceeding in a manner similar to the Reference Example 36 (d) above but using 4-ethoxy-benzene-1,2-diamine [1.25g, Reference Example 30 (v)] and subjecting the reaction product to flash chromatography on silica, eluting initially with ethyl acetate. ethyl acetate and then with a mixture of ethyl acetate and methanol (9: 1, v / v), 4-nitro-1 H -pyrazole- (2-amino-4-ethoxy-phenyl) -amide was prepared. 3-carboxylic acid (824 mg) as a black solid. LC-MS (J METHOD): R = 2.90 minutes, 292.27 (M + H) +, 290.30 (M-H) -. (f) 4-Nitro-1 H-pyrazole-3-carboxylic acid 2-Amino-4-fluoro-5-methyl-phenyl) -amide Proceeding in a manner similar to Reference Example 36 (d) above but using using 4-fluoro-5-methyl-benzene-1,2-diamine [Example of Reference 30 (w)] was prepared (4-nitro-1 H-pyrazole-3-carboxylic acid 2-amino-4-fluoro-5-methyl-phene-amide (2.12 g) as a red oil LC-MS (METHOD J): Rj = 3.02 minutes, 280.25 (M + H) +. (G) (2-Amino-4-trifluoromethoxy-phenyl) -amide of 4-nitro-1H- pyrazole-3-carboxylic Proceeding in a manner similar to the Reference Example 36 (d) above but using 4-trifluoromethoxy-benzene-1,2-diamine [Reference Example 30 (x)] was prepared (2-amino-4-trifluoromethoxy-phenyl) -amide from "4-acid" Nitro-1 H-pyrazole-3-carboxylic acid (0.850 g) as a red solid LC-MS (METHOD J): Rj = 3.34 minutes, 332.21 (M + H) +. (h) (2-Amino-4-trifluoromethyl-phenyl) -amide of 4-nitro-1H-pyrazole-3-carboxylic acid Proceeding in a manner similar to Reference Example 36 (d) above but using 4-trifluoromethyl-benzene-1,2-diamine [Example of Reference 30 (y)] was prepared (2-amino-4-trifluoromethyl-phenyl) -amide of 4-nitro-1H-pyrazole-3-carboxylic acid (0.250 g) as a red solid. LC-MS (METHOD B): Rj = 3.35 minutes, 316.14 (M + H) +. (h) 4-Nitro-1 H-pyrazole-3-carboxylic acid (2-amino-4-trifluoromethyl-phenyl) -amide Proceeding in a manner similar to Reference Example 36 (d) above but using 4-trifluoromethyl-benzene-1,2-diamine [Reference Example 30 (y)] was prepared (2-amino-4-trifluoromethyl-phenyD-amide of 4-nitro-1 H-pyrazole-3-carboxylic acid (0.300 g) as a yellow solid LC-MS (METHOD B): Rj = 3.35 minutes, 316.14 (M + H) +. (j) 4-Nitro-H-pyrazole-3-carboxylic acid methyl ester By proceeding in a manner similar to Reference Example 36 (d) above but using methyl 3,4-diaminobenzoate, ester was prepared 3-amino-4-f (4-nitro-1 H-pyrazole-3-carbonyl) -amino-1-benzoic acid methyl ester (2.51 g) in the form of a brown foamy solid. LC-MS (METHOD B): R = 2.83 minutes, 306.21 (M + H) +. REFERENCE EXAMPLE 37 5-Ethoxy-1 H-indazole A solution of 5-hydroxy-1H-indazole [0.5 g, Reference Example 38] in acetone (10 ml) was reacted with potassium carbonate (2.56 g) and then with iodoethane (0.296 ml). ). The mixture was refluxed for 4 hours, then cooled and then evaporated. The residue was partitioned between ethyl acetate and water and the aqueous layer was further extracted twice with ethyl acetate. The combined organic fractions were dried over magnesium sulfate and then evaporated to yield a brown residue which was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 1, v / v) to provide 5-ethoxy-1 H-indazole (0.38 g) as an off-white solid. LC-MS (METHOD B): RT = 2.68 minutes; 163 (M + H) +. REFERENCE EXAMPLE 38 5-Hydroxy-1 H-incazole A solution of 5-methoxy-1 H-indazole [0.410 g, Reference Example 24 (a)] in dichloromethane (7.5 ml) was treated with a solution of boron tribromide in dichloromethane (7.5 ml, 1 M). The mixture was then heated to reflux for 4 hours, then cooled to 0 ° C and then treated dropwise with water (2 ml). The pH of this mixture was adjusted to 7-8 by the addition of 10% aqueous sodium hydrogen carbonate. The mixture was then extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated. The residual brown oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1: 1)., v / v) to provide 5-hydroxy-1 H-indazole (0.3 0 g) as a yellow solid. LC- S (METHOD B): RT = 1, 96 minutes; 135 (M + H) +. REFERENCE EXAMPLE 39 (a) 5-tert-Butyl Ester of 3- (2-amino-4,5-dimethylphenyl) -amide 1,4,6,6-tetrahydro-pyrazolor-4,3-c-pyridine-3,5- dicarboxylic To a solution of 4,5-dimethylbenzene-1,2-diamine (0.841 g) and tert-butyl ester of 1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5- acid dicarboxylic acid (1.5 g, Reference Example 40 (a)) in dimethyl formamide (100 ml) was added diisopropylethylamine (1.08 ml) and 2- (1 H-9-azabenzotriazol-1-yl) hexafluorophosphate. 1,1,3,3-tetramethyluronium (2.35 g). The mixture was stirred for 1.5 hours and diluted with ethyl acetate and then washed six times with brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo to give a pale brown solid. The solid was then triturated with methanol to yield 5-tert-butyl ester of 1,4,6-tetrahydro-pyrazolor4,3-clpyridine-3,5- (2-amino-4,5-dimethylphenyl) amide. dicarboxylic acid (0.99 g) as an off white solid. LC-MS (METHOD B): Rj = 2.94 minutes; 386 (M + H) +. (b) r3- (2-Amino-4,5-dimethyl-phenylcarbamoyl) -1- (tetrahydro-pyrn-2-yl) -1 H -pyrazol-4-ylmethyl- (2,4-dimethoxy) -benzyl) - morpholino-4-carboxylic acid amide Proceeding in a manner similar to Reference Example 39 (a) above but using 4-acid. { [(2,4-dimethoxy-benzyl) - (morfoin-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazoI-3-carboxylic acid [534 mg, Reference Example 40 (b)] was prepared [3- (2-amino-4,5-dimethyl-phenylcarbamoyl ) -1- (tetrahydro-pyrano-2-yl) - H -pyrazol-4-ylmethyl- (2,4-dimethoxy-benzyl-amide of morpholino-4-carboxylic acid (1.66 g) in the form of a yellow oil LC-MS (METHOD B): R = 2.81 minutes, 607.71 (M + H) +. (c) 3- (2-amino-4-chloro-5) tert-butyl ester -methyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-clpyridine-5-carboxylic acid By proceeding in a manner similar to Reference Example 39 (a) above but using 4-chloro-5-methyl-1,2-phenylenediamine, 3- (2-amino-4-chloro-) tert-butyl ester was prepared. 5-methyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolo [4,3-clpyridino-5-carboxylic acid (411 mg) as a brown solid. LC-MS (J METHOD): Rj = 3.66 minutes, 406/408 (M + H) +. (d) 3- [2-Amino-4- (2-morpholin-4-yl-ethoxy) -phenylcarbamoyl-1,4,6,7-tetrahydro-pyrazolor4,3-c1p) tert-butyl ester Ridino-5-carboxylic By proceeding in a manner similar to Reference Example 39 (a) above but using 4- (2-morfoun-4-yl-ethoxy) -benzene-1,2-diamine [Reference Example 29 (c)], tertiary ester was prepared -butyl 3-G2-amino-4- (2-morpholin-4-yl-ethoxy) -phenylcarbamoyl-, 4,6,7-tetrahydropyrazolor4,3-clpyridine-5-carboxylic acid (400 mg) in the form of a brown solid.
LC-MS (N METHOD): Rj = 3.33 minutes, 485.18 (MH) ". (E) (2-Amino-4,5-dimethyl-phenyl) -amide of acid 1, 4,6,7 -Tetrahydro-pyranor-4,3-clirazole-3-carboxylic acid Proceeding in a manner similar to the Reference Example 39 (a) above but using 1, 4,6,7-tetrahydro-pyrano [4,3-c] pyrazoI-3-carboxylic acid [Reference Example 17 (e)] was prepared (2-amino-4,5 1,4,6,6-tetrahydro-pyran [4,3-c] pyrazole-3-carboxylic acid dimethyl-phenyl-amide (116 mg) in the form of a cream-colored solid. LC- S (METHOD B): R = 2.42 minu¬ cough, 287 (M + H) +. (f) 3- (2-Amino-4-trifluoromethyl-phenylcarbamoyl) -1,4,6,7-tetrahydro-pyrazolor-4 -3-c] pyridine-5-carboxylic acid tert-butyl ester Proceeding in a manner similar to the Reference Example 39 (a) above but using 4-trifluoromethyl-1,2-phenylenediamine was prepared 3- (2-amino-4-trifluoromethyl-phenylcarbamoyl) -1-, 4,6,7- tert -butyl ester. tetrahydro-pyrazolo [4,3-clpyridino-5-carboxylic acid (1.00 g) as a brown solid. LC-MS (N METHOD): Rj = 3.75 minutes, 424.10 (M-H) -. REFERENCE EXAMPLE 40 (a) 1, 416,7-Tetrahydro-pyrazolor-4,3-clpyridine-3,5-dicarboxylic acid 5-tert-butyl ester A solution of 1, 4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-3,5-dicarboxylic acid 5-tert-butyl ester 3-ethyl ester [5.105 g, Example Reference 18 (d)] and lithium hydroxide monohydrate (0.870 g) in methanol (30 ml) and water (10 ml) was stirred at 55 ° C for 2.5 hours. The mixture was acidified with saturated aqueous solution of potassium hydrogen sulfate and extracted three times with ethyl acetate. The organic extracts were combined, dried over magnesium sulfate and concentrated in vacuo to yield 1, 4,6,7-tetrahydro-pyrazolof4,3-clpyridino-3,5-dicarboxylic acid 5-tert-butyl ester. (4.42 g) in the form of a pale yellow solid. MS: 268 (M + H) +. HPLC (G METHOD): Rj = 2.86 minutes. (b) 4- Acid. { r (2,4-dimethoxy-benzyl) - (morpholino-4-carbonyl) -amino-1-methyl) -1 - (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid Proceeding in a manner similar to Reference Example 40 (a) above but using 4-ethyl ester. { [(2,4-dimethoxy-benzyl) - (morpholino-4-carbonyl) -amino] -methyl} -1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid [594 mg, Reference Example 48 (i)] was prepared 4- acid. { G (2,4-dimethoxy-benzyl) - (morpholino-4-carbonyl) -amino-1-methyl) -1- (tetrahydro-pyran-2-yl) -1 H -pyrazole-3-carboxylic acid (534 mg) in the form of a white fluffy solid. LC-MS (METHOD B): Rj = 2.71 minutes, 489.21 (M + H) +.
REFERENCE PLQ AXIS 41 (a) 3-Hydroxymethyl-1 H-pyrazole-4-carboxylic acid ethyl ester A solution of 3-fer-butyloxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester [3.46 g, Reference Example 42] in dichloromethane (25 ml) was treated with trifluoroacetic acid (25 ml). The mixture was stirred for 1.5 hours and then concentrated. The residue was partitioned between saturated sodium carbonate solution and ethyl acetate. The organic layer was dried over magnesium sulfate and then evaporated to give 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid ethyl ester (2.49 g) as a brown solid which was used without further purification. LC-MS (METHOD B): Ry = 2.54 minutes; 171 (M + H) +. (b) 3-Hydroxymethyl-1 H-pyrazole-4-carboxylic acid isopropamide Proceeding in a manner similar to Reference Example 41 (a) above but using 3-urea-butyloxymethyl-1 H- isopropylamide pyrazole-4-carboxylic acid [Reference Example 44 (a)] 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid isopropylamide was prepared in a pale yellow solid form, which was used without further purification. LC-MS (METHOD B): Rj = 2.43 minutes; 184 (M + H) +. (c) 3-Hydroxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester Proceeding in a manner similar to the Reference Example 41 (a) above but using 3-ferc-butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester [Reference Example 43] 3-hydroxymethyl-5-methyl acid ethyl ester was prepared -1 H-pyrazole-4-carboxylic acid as an orange solid that was used without further purification. LC-MS (METHOD B): Rj = 2.58 minutes; 185 (M + H) +. (d) (2-methoxy-ethyl) -amide of 3-hydroxymethyl-1H-pyrazole-4-carboxylic acid Proceeding in a manner similar to Reference Example 41 (a) above but using 3-urea-butyloxymethyl-1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide [Reference Example 44 (b)] 3-hydroxymethyl-1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide (398 mg) was prepared as an orange solid. LC-MS (METHOD B): R = 1, 66 minutes, 222 (M + Na) + (e) 3-hydroxymethyl-1 H-pyrazole-4-carboxylic acid propylamide By proceeding in a manner similar to Reference Example 41 (a) above but using 3-urea-butyloxymethyl-1 H-pyrazole-4-carboxylic acid propylamide [Reference Example 44 (c)], 3-hydroxymethyl propylamide was prepared -1 H-pyrazole-4-carboxylic acid (731 mg) in the form of an orange oil. LC-MS (METHOD B): Rj = 2.09 minutes, 206 (M + Na) +. (f) (Tetrahydro-pyrano-4-yl) -amide of 3-hydroxymethyl-1 H-pyrazole-4-carboxylic acid By proceeding in a manner similar to Reference Example 41 (a) above but using (3-tert.-tetrahydro-pyran-4-yl) -amide butyloxymethyl-1 H-pyrazoi-4-carboxylic acid [Reference Example 44 (d)] was prepared 3-Hydroxymethyl-1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide. (4.10 g) in the form of an orange oil. LC-MS (N METHOD): Rj = 1, 89 minu¬ cough, 226 (M + H) +. (g) 3-Hydroxymethyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide Proceeding in a manner similar to the Reference Example 41 (a) above but using acid cyclopropylamide [Reference Example 44 (e)] 3-hydroxymethyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide (2.48 g) was prepared as a white foam. LC-MS (METHOD N): ¾ Rj = 1.85 minutes, 180.15 (M-H) -.
EXAMPLE OF REFERENCE 42.
Ethyl ester of 3-fere-butyloxymethyl-1 H-pyrazole-4-carboxylic acid OEt 'BuOCEL ,.
H A solution of dimethyl formamide-acetal (3.47 ml) and ethyl ester of 4-ferc-butoxy-3-oxo-butyric acid [3.52 g, Reference Example 43] in Toiuene (50 ml) was heated at 65 ° C for 2 hours. The mixture was then concentrated and the residue was redissolved in acetic acid (3 mL). To the mixture was added hydrazine hydrate (0.93 ml) and the whole was allowed to stir at room temperature for 2 hours. The mixture was again concentrated in vacuo and the residue partitioned between ethyl acetate and 5% aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate and then concentrated to yield a brown oil which was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum (3: 7, v / v) to provide ester. Ethyl 3-ferc-butyloxymethyl-1 H-pyrazole-4-carboxylic acid (3.46 g) as a yellow solid. LC-MS (METHOD B): R = 2.79 minutes; 227 (M + H) +. REFERENCE EXAMPLE 43 4-Ferro-Butoxy-3-oxo-butyric acid ethyl ester A suspension of sodium hydride (4.44 g, 60% dispersion in mineral oil) and dimethyl formamide (50 ml) at 0 ° C was treated dropwise with ethyl 4-chloroacetoacetate (5 ml) and then tert-butyl alcohol (7.08 ml). The mixture was kept at 0 ° C for 2 hours, then an additional 2 hours at room temperature and then it was poured onto 2 N hydrochloric acid / ice and then extracted four times with ethyl acetate. The combined extracts were washed with saturated aqueous sodium hydrogen carbonate solution, then with water, followed by brine, then dried over magnesium sulfate and then evaporated. The resulting yellow oil was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and petroleum (1: 9, v / v) to provide 4-ylbutoxy-3-oxo-butyric acid ethyl ester (5, 20 g) in the form of a yellow oil. TLC (silica, 1: 4, v / v ethyl acetate / petroleum): Rf = 0.51, NMR (400MHz, CDCl 3): d 1, 21 (9H, s), 1, 28 (3H, t), 3.55 (2H, s), 4.19 (2H, q). REFERENCE EXAMPLE 44 (a) 3-Ferc-butyloxymethyl-1 H-pyrazole-4-carboxylic acid ispropylamide To a solution of 3-urea-butyloxymethyl-1H-pyrazole-4-carboxylic acid [1, 520 g, Reference Example 17 (d)], hydroxybenzotriazole (3,110 g) and diisopropyl-ethylamine (4,010 ml) in dimethyl- formamide (130 mL) was added isopropylamine (1.960 mL) followed by 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (4.420 g). The mixture was heated at 70 ° C for 2.5 hours, then diluted with ethyl acetate, then washed with water, then brine, then dried over magnesium sulfate and then evaporated. The residue was triturated with a mixture of ethyl acetate and petroleum to produce 3-ferrobutyloxymethyl isopropylamide. 1 H-pyrazole-4-carboxylic acid (652 mg) as an off white solid. LC-MS (METHOD B): 2.99 minutes; 240 (M + H) +. (b) (2-methoxy-ethyl) -amide of 3-fer-butyloxymethyl-1H-pyrazole-4-carboxylic acid By proceeding in a manner similar to Reference Example 44 (a) above but using 2-methoxyethylamine, 3-ferro-butyloxymethyl-1H-pyridine-4-carboxylic acid (2-methoxy-ethyl) -amide (81 1) was prepared. mg) in the form of an orange solid. LC-MS (METHOD B): Rj = 2.43 minutes, 278 (M + Na) +. (c) 3-Ferr-Butyloxymethyl-1 H-pyrazole-4-carboxylic acid propylamide By proceeding in a manner similar to Reference Example 44 (a) above but using n-propylamine, 3-fer-butyloxymethyl-1H-pyrazoi-4-carboxylic acid propylamide (1.12 g) was prepared as an orange oil . LC-MS (METHOD B): Rj = 2.65 minutes, 262 (M + Na) +. (d) (Tetrahydro-pyran-4-yl-amide of 3-ferc-butyloxymethyl-1 H-pyrazole-4-carboxylic acid Proceeding in a manner similar to the Reference Example 44 (a) above but using 3-ferc-butyloxymethyl-1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide (5.50 g) as an orange oil.
LC-MS (N METHOD): Rj = 3.05 minutes, 282 (M + H) +. (e) 3-Ferc-Butyloxymethyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide By proceeding in a manner similar to Reference Example 44 (a) above but using cyclopropylamine, 3-fer-butyloxymethyl-1H-pyrazole-4-carboxylic acid cyclopropylamide (3.27 g) was prepared in the form of an orange oil. . LC-MS (METHOD H): Rj = 2.24 minutes, 238.38 (M + H) +. REFERENCE EXAMPLE 45 3-tert-Butyloxymethyl-5-methyl-1H-pyrazole-4-carboxylic acid ethyl ester To a solution of 2-acetyl-4-fer-butoxy-3-oxo-butyric acid ethyl ester [0.325 g, Reference Example 46] in acetic acid (3 mL) was added hydrazine hydrate (71 μ?). The mixture was stirred at room temperature for 16 hours and then evaporated to remove the acetic acid. The residue was dissolved in ethyl acetate and the solution was washed with 5% sodium hydrogen carbonate solution, then with water, then dried over magnesium sulfate and then evaporated to yield 3-ferric acid ethyl ester. butyloxymethyl-5-methyl-1 H-pyrazole-4-carboxylic acid (0.258 g) as a yellow oil which was used without further purification. LC- S (METHOD B): RT = 3.22 minutes; 241 (M + H) +. REFERENCE EXAMPLE 46 2-Acetyl-4-ferro-butoxy-3-oxo-butyric acid ethyl ester A suspension of magnesium chloride (0.471 g) in dichloromethane (6 ml) was treated with 4-tert-butoxy-3-oxo-butyric acid ethyl ester [1.00 g, Reference Example 43]. This mixture was cooled to 0 ° C, then treated with pyridine (0.80 ml), then stirred for 15 minutes at 0 ° C and then treated with aethyl chloride (0.352 ml). After stirring for an additional 15 minutes at 0 ° C and then for 1 hour at room temperature, the reaction mixture was treated with saturated aqueous solution of ammonium chloride and then extracted twice with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 2-acetyl-4-ferro-butoxy-3-oxo-butyric acid ethyl ester (1.15 g) as a yellow oil which was used without additional purification. LC-MS (METHOD B): RT = 3.16 minutes; 243 (M-H) -. REFERENCE EXAMPLE 47 4-Phenyl-1 H-pyrazole-3-carboxylic acid A solution of 3-methyl-4-phenylpyrazole (1.00 g) in tere-butane (15 ml) and water (25 ml) at 60 ° C was treated portionwise with potassium permanganate (5.47 g). The temperature was then slowly raised to 90 ° C and maintained at that temperature for 5 hours. The mixture was then cooled and filtered through a celite cartridge. The filtrate was concentrated and the pH was adjusted from 10 to 14 by the addition of 5 N aqueous solution of sodium hydroxide. This mixture was washed twice with ethyl acetate. The aqueous layer it was then acidified to pH 3 to 5 and then extracted four times with ethyl acetate. The combined extracts were dried over magnesium sulfate and then evaporated to yield 4-phenyl-1H-pyrazole-3-carboxylic acid (0.512 g) as a white solid, which was used without further purification. MS: 189 (M + H) +. HPLC (METHOD B): Rj = 2.48 minutes. REFERENCE EXAMPLE 48 (a) | 3- (5-Ethoxy-6-ethyl-H-benzoimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazole-4-inamide of cyclopropanecarboxylic acid A solution of 3- (5-ethoxy-6-ethyl-1 H-benzoimidazole-2-yi) -1- (tetrahydropyran-2-yl) -1H-pyrazol-4-ylamine [0, 3 g, Reference Example 49 (a)] and triethylamine (0.8 ml, excess) in tetrahydrofuran (20 ml) was treated dropwise with cyclopropanecarbonyl chloride (0.3 g, 2.4 mmol). This mixture was stirred for 48 hours and then diluted with aqueous sodium bicarbonate solution (100 ml) and then extracted twice with ethyl acetate (100 ml). The combined extracts were evaporated and the residue was dissolved in tetrahydrofuran (50 ml). This solution was treated with a solution of potassium hydroxide (1.1 g) in ethanol (10 ml) and the mixture was stirred for 2 hours, then poured into water (100 ml) and then extracted. twice with ethyl acetate (100 ml). The combined extracts were evaporated and the residue was chromatographed on silica gel eluting with a mixture of heptane and ethyl acetate (1/1, v / v) to give r3- (5-ethoxy-6-ethyl-1H-benzo Midazol-2-yl) -1- (tetrahydropyran-2-yl) -1 H-pyrazole-4-ynamide of cyclopropanecarboxylic acid (0.3 g) as an off-white solid. LC- S (METHOD E): Rj = 2.99 minutes, 424 (M + H) + (b) [3- (1, 5,6,7-Tetrahydro-1,3-diaza-s-indacen-2-iQ- 1- (4- tetrahydropyran-2-yl) -1H-pyrazole-4-ylamide 4-methylpiperazine-1-carboxylic acid Proceeding in a manner similar to Reference Example 48 (a) above but (i) treating a solution of 3- (1,5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) - 1- (tetrahydropyran-2-yl) -1H-pyrazol-4-ylamine [302 mg, Reference Example 49 (d)] and triethylamine (0.94 g, 10 eq) in tetrahydrofuran (10 ml) with 4-chloride methylpiperazine-1-carbonyl (930 mg, 4.67 mmol), (ii) stirring the mixture at 45 ° C for 4 hours, then at 55 ° C for 1 hour, (iii) treating the cooled reaction mixture with sodium bicarbonate. aqueous sodium (200 ml) and extracting this mixture three times with ethyl acetate (100 ml), and (iv) evaporating the combined extracts and chromatographing the residue on silica gel (ethyl acetate / 5-20% gradient). methanol) is pre- stopped r3-n .5,6J-tetrahydro-1,3-diaza-s-indacen-2-yl) -1- (tetrahydropyran-2-yl) -1 H-pyrazole-4-ylamide of 4-methyl acid 1-piperazine-1-carboxylic acid (189 mg) as a purple solid. LC-MS (METHOD F): Rj = 2.28 minutes, 450 (M + H) +. (c) 1,1-Dimethyl-3-r3- (1, 5,6,7-tetrahydro-s-indacen-2-n-1- By proceeding in a manner similar to Reference Example 48 (b) above but using dimethylcarbamoyl chloride (4 eq), 1, 1-dimethyl-3-r3- (1, 5,6,7-tetrahydro-s-indacene) was prepared. 2-yl) -1- (tetrahydropyran-2-yl) -1 H-pyrazol-4-inurea in the form of a beige foam. LC-MS (METHOD F): Rj = 3.22 minutes, 395 (M + H) +. (d) r3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazole-4-ylamide of cyclopropanecarboxylic acid Proceeding in a manner similar to Reference Example 48 (a) above but using 6-ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] - 1 H-benzimidazole [0.45 g, Reference Example 49 (e)] and subjecting the reaction product to silica gel chromatography (hepta-no / ethyl acetate, 7/3, v / v) was prepared - (6-Ethoxy-5-fluoro-H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazole-4-amino acid of cyclopropanecarboxylic acid (90 mg) . LC-MS (G METHOD): Rj = 8.1 minutes, 414 (M + H) +. (e) r3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1H-pyrazole-4-ynamide of tetrahydropyran-4-carboxylic acid Proceeding in a manner similar to Reference Example 48 (a) above but using 6-ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] - 1 H-benzimidazole [0.45 g, Reference Example 49 (e)] and tetrahydropyran-4-carbonyl chloro-ro (0.135 g) and subjecting the reaction product to chromatography on silica gel (heptane / ethyl acetate, 7/3, v / v) was prepared r3- (6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 - (tetrahydropyran-2-yl) -1 H- pyrazole-4-illamicla of tetrahydropyran-4-carboxylic acid (120 mg). LC-MS (G METHOD): R = 8.05 minutes, 458 (M + H) +. (f) r3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1 H-pyrazol-4-amide of morpholino-4-carboxylic acid Proceeding in a manner similar to Reference Example 48 (a) above but (i) treating 6-ethoxy-5-fluoro-2 [4-amino-1- (tetrahydropyran-2-yl) - H -pyrazol-3-yl ] -1 H-benzimidazole [90 mg, Reference Example 49 (e)] and dipossoylethylamine (168 mg) in tetrahydrofuran (4 ml) with morpholi- - 4-carbonyl chloride (194 mg) for 2 days at room temperature, and (ii) by subjecting the reaction product to silica gel chromatography (hepta-no / ethyl acetate, 2/1, v / v), r3- (6-ethoxy-5-fluoro- 1 H-benzimidazol-2-yn-1 - (tetrahydropyran-2-in-1 H-pyrazole-4-inamide morpholino-4-carboxylic acid (140 mg) LC-MS (METHOD G): RT = 7 85 minutes 459 (M + H) +. (G) [3 ^ 6-Ethoxy-5-fluoro-TH-benzimidazol-2-yl) -1- (tetrahydropyran-2-Ib-1 H-pyrazole-4 -pyridin-4-carboxylic acid amide Proceeding in a manner similar to Reference Example 48 (f) above but using piperidino-1-carbonyl chloride (191 mg) was pre-stopped [3- (6-ethoxy-5-fluoro-1 H-benzimidazole-2- il) -1 - (tetrahydropyran-2-yl) -1 H -pyrazole-4-ylamide of pyridine-4-carboxylic acid (127 mg). LC-MS (METHOD G): Rj = 8.2 minutes, 457 (M + H) +. (h) 3-r6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 - (tetrahydropyran-2-yl) -1 H -pyrazol-4-ill-1,1-diethylurea By proceeding in a manner similar to Reference Example 48 (f) above but using diethylcarbamoyl chloride (175 mg), 3 was prepared: f6-ethoxy-5-fluoro-1 H-benzimidazol-2-yn-1- (tetrahydropyran-2-yl) -1 H-pyrazol-4-iH-1. 1 -diethylurea (110 mg). LC-MS (G METHOD) Rj = 7.9 minutes, 445 (M + H) +. (i) 4- Acid. { [(2,4-dimethoxy-benzylH-morpholino-4-carbonyl) -aminol-methyl} -1- (tetrahydro-pyran-2-yl) -1 H -pyrazole-3-carboxylic acid Proceeding in a manner similar to Reference Example 48 (a) above but (i) using 4 - [(2,4-dimethoxy-benzylamino] -methyl] -1- (tetrahydro-pyran-2-ethyl) ethyl ester il) -1 H-pyrazole-3-carboxylic acid (829 mg, Reference Example 60) and 4-morpholinocarbonyl chloride (0.96 ml) and (ii) subjecting the reaction product to flash chromatography on silica elu-going with ethyl acetate, 4- (R (2,4-dimethoxy-benzyl) - (morpholino-4-carbonin-amino-1-methyl-1-methyl-tetrahydro-pyran-2-n-1) acid was prepared. H-pyrazole-3-carboxylic acid (595 mg) in the form of a colorless oil LC-MS (METHOD B): R = 2.96 minutes, 517.30 (+ H) +. 0) 3- [3- (5-Difluoromethoxy-1 H-benzoimidazol-2-yl) -1 - (tetrahydro-pyrano-2-yl) -1 H -pyrazol-4-yn-1, 1 -diethyl- urea Proceeding in a manner similar to Reference Example 48 (A) above but using 3- (5-difluoromethoxy-1 H-benzoimidazol-2-yl) -1 - (tetrahydro-pyrano-2-yl) -1 H -pyrazole- 4-ilamine [Reference Example 49 (g)] and diethylcarbamoyl chloride was prepared 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1-phtetrahydro-pyran-2-yl) -1 H-prazol-4-yl] -1,1-diethyl urea (220 mg) as a pale brown solid. LC-MS (K METHOD): Rj = 4.02 minutes, 447.27 (MH). "(k) f3- (5-Difluoromethoxy-1 H -benzoimidazol-2-yl) -1- (tetrahydro-pyran-2-yn-1 H-pyrazole- 4-in-amide of piperidino-1-carboxylic acid By proceeding in a manner similar to Reference Example 480) above but using piperidino-1-carbonyl chloride, G3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1- (piperidino-tert -amide) was prepared. 1-carboxylic acid (220 mg) in the form of a pale maroon solid LC-MS (N METHOD): Rj = 4.07 minutes, 459.28 (MH). "REFERENCE EXAMPLE 49 (a) 3- ( 5-Ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1- (tetrahydropyran-2-yl) -1 H -pyrazol-4-ylamine A solution of 5-ethoxy-6-ethyl-2- [4-nitro-1- (tetrahydropyran-2-yl) -1H-pyrazol-3-yl] -1H-benzoimidazole [0.8g, Reference Example 50 (a)] in eta-nol (100 ml) was treated with palladium on carbon (0.1 g, 10%) and the mixture was hydrogenated at atmospheric pressure (balloon) for 4 days. The catalyst was removed by filtration, the filtrate was evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 0-10% methanol) to provide 3- (5-ethoxy-6-ethyl-1H- benzoimidazol-2-yl) -1 - (tetrahydropyran-2-yl) -1 H -pyrrazole-4-ylamine (0.3 g) as a solid. LC-MS (METHOD E): Rj = 2.15 minutes, 356 (M + H) +. (b) 4-chloro-5-methoxybenzene-1,2-diamine Proceeding in a manner similar to Reference Example 49 (a) above but using 5-chloro-4-methoxy-2-nitrophenylamine [Reference Example 31 (h)] and subjecting the reaction product to silica gel chromatography ( ethyl acetate with gradient from 40% to 0% heptane) was prepared 4-chloro-5-methoxybenzene-1,2-diamine (1.0 g) as an orange solid. S: 173 (M + H) +. (c) 4-ethoxy-5-ethyl-benzene-1,2-diamine Proceeding in a manner similar to Reference Example 49 (a) above, but using 4-ethoxy-5-ethyl-2-nitrophenylamine [Reference Example 31 (g)] and subjecting the reaction product to silica gel chromatography eluting with ethyl acetate, 4-ethoxy-5-ethyl-benzene-1,2-diamine was prepared as a dark solid. LC-MS (METHOD E): Rj = 8.434 minutes, 180 (M + H) +. (d) 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 - (tetrahydropyran-2-yl) -1 H -pyrazol-4-ylamine Proceeding in a manner similar to the Reference Example 49 (a) above but (i) using a solution of 2- [4-nitro-1- (tetrahydropyran-2-yl) -1 H -pyrazol-3-yl] -1,5,6,7-tetrahydro- 1, 3-diaza-s-indacene [4.1 g, Reference Example 50 (b)] in ethanol (120 ml) and 5% palladium on carbon (320 mg), and (i) using a hydrogenation apparatus of Parr at 4.13 bar for 18 hours was prepared 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1- (tetrahydropyran-2-yl) - 1 H-pyrazol-4-ylamine (368 mg) as a brown solid. LC (G METHOD): Rj = 3,079 minutes, 324 (M + H) + and 346 (M + Na) +. e) 6-Ethoxy-5-fluoro-2 [4-amino-1 - (tetrahydropyran-2-yl) -1 H -pyrazol-3-yl] -1 H-benzimidazole Proceeding in a manner similar to Reference Example 49 (a) above but using 6-ethoxy-5-fluoro-2- [4-nitro-1 - (tetrahydropyran-2-ylJ-1 H-benzimidazole [1, 2g, Example Reference 50 (c)] was prepared 6-ethoxy-5-fluoro-2 [4-amino-1 - (tetrahydropyran-2-yl) -1 H -pyrazol-3-yl-1 H-benzimidazole (1, 2 g) LC-MS (G METHOD): Rj = 6.74 minutes, 346 (M + H) +. 4-Methanesulfonyl-benzene-1,2-diamine By proceeding in a manner similar to Reference Example 49 (a) above but using N * 1 * -benzyl-4-methanesulfonyl-benzene-1,2-diamine [Reference Example 65], 4-methanesulfonyl-benzene-1 was prepared, 2-diamine in the form of a white solid. LC-MS (METHOD J): Rj = 0.98 minutes, 187.32 (M + H) +. (g) 3- (5-Difluoromethoxy-1 H-benzoimidazol-2-yl) -1 - (tetrahydro-pyrano-2-yl) -1H, -pyrazol-4-ylamine Proceeding in a manner similar to Reference Example 49 (a) above but using 5-difluoromethoxy-2- [4-nitro-1- (tetrahydro-pyrano-2-yl) -1 H -pyrazol-3-yl] -1 H-benzoimidazole [Reference Example 50 (e)], 3 ^ (5-d.fluoromethoxy-1H-benzoimidazol-2-yn-1- (tetrahydro-pyrano-2-yl) -1H-pyrazole-4- was prepared ilamine (730 mg) in the form of a pale brown solid LC-MS (N METHOD): Rj = 3.27 minutes, 350.29 (M + H) +.
REFERENCE EXAMPLE 50 (a) 5-Ethoxy-6-etyl -2-r4-nitro-1- (tetrahydropyran-2-yO-1 H -pyrazol-3-ill-1 H-benzoimidazole A mixture of 4-ethoxy-5-ethyl-benzene-1,2-diamine [0.18 g, Reference Example 30 (s)], 4-nitro-1- (tetrahydro-pyrano-2-yl) -1 H- pyrazole-3-carbaldehyde [0.225 g, Reference Example 6 (m)] and sodium bisulfite (0.12 g, 1.2 mmol) in dimethylformamide (10 ml) was heated at 120 ° C for 1 hour. The mixture was cooled, water (100 mL) was added and the aqueous mixture was extracted twice with ethyl acetate (50 mL). The combined extracts were evaporated and the residue was chromatographed on silica gel (ethyl acetate with gradient of 20-0% heptane) to give 5-ethoxy-6-ethyl-2-l4-nitro-1- (tetrahydropyran-2) -yl) -1 H-pyrazol-3-ylH-benzoimidazole (200 mg) in the form of a solid. LC-MS (METHOD E) Ry = 2.85 minutes, 386 (M + H) +. (b) 2-r4-nitro-1 - (tetrahydropyran-2-yl) -1 H -pyrazol-3-n-1, 5,6,7-tetrahydro-1,3-diaza-s-indacene Proceeding in a manner similar to Reference Example 50 (a) but using indane-5,6-diamine (1.05 g, prepared as described by Sui Xiong Cai et al., J. ed. Chem., 1997, 40 , pages 730-738) and 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carbaIdehyde [2.5g, Reference Example 6 (m)] was prepared 2- | 4- Nitro-1 - (tetrahydropyran-2-yl) -1 H -pyrazol-3-yl-, 5,6,7-tetrahydro-, 3-diaza-s-indacene which was used without further purification. (c) 6-Ethoxy-5-fluoro-2- [4-nitro-1 - (tetrahydropyran-2-yl) -1 H-benzimidazole Proceeding in a manner similar to Reference Example 50 (a) but using 4-ethoxy-5-fluoro-benzene-1,2-diamine (2.2 g, prepared according to the method of Uchida, et al, Chem. Pharm. Bull., 1989, volume 37, pages 15, 7 to 1523) was prepared 6-ethoxy-5-fluoro-2- [4-n-tetra-1 - (tetrahydropyran-2-yl-1H-benzimidazole.) LC-MS (METHOD G): Rj = 8.1 minutes, 376 (M + H) +. (D) 5- ethoxy-2- [4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole- 3-ifl-H-benzoimidazole By proceeding in a manner similar to Reference Example 50 (a) but using 4-methoxy-1,2-phenylenediamine (17 mg), 5-methoxy-2- [4-nitro-1 - (tetrahydro-pyrano-2) was prepared -yl) -1 H-pyrazol-3-β-H-benzoimidazole (282 mg) in the form of a dark red oil. LC- S (METHOD H): R - 2.02 minutes, 344.21 (M + H) +, 342.24 (MH). "(E) 5-Difluoromethoxy-2- [4-nitro-1 - (tetrahydro-pyran-2-yl) -1 H-pyrazole-3 -ilI-1 H-benzoimidazole Proceeding in a manner similar to Reference Example 50 (a) above but using difluoromethoxy-benzene-1,2-diamine [Reference Example 30 (y)] and 4-nitro-1- (tetrahydropyran-2-yl) -1 H-pyrazole-3-carbaldehyde [Reference Example 6 (m)], was prepared 5-difluoromethoxy-2-r4-nitro-1 - (tetrahydro-pyrano-2-yl) -1H-pyrazole-3? -? H-benzoimidazole (910 mg) as a pale brown solid. LC-MS (N METHOD): Rj = 3.40 minutes, 380.22 (M + H) +. REFERENCE EXAMPLE 51 1-Ethoxy-2-ethylbenzene To a solution of 2-ethylphenol (6.9 g, 56.5 mmol), triephenylphosphine (15.7 g, 60 mmol) and ethanol (6 ml, excess) in tetrahydrofuran (100 ml) was added DIAD (12.1 g, 60 mmol) was added dropwise. After stirring for 18 hours, the mixture was evaporated and the residue was chromatographed on silica gel (hepta-no / ethyl acetate 9/1) to give 1-eoxy-2-ethylbenzene 1.2 g) in form of a transparent liquid. GC-MS shows a peak, Rj = 5.6 minutes. MS 150 (M +). REFERENCE EXAMPLE 52 N- (3-Chloro-4-methoxyphenyl) acetamide A solution of 3-chloro-4-mtoxyphenylamine (6.3 g) and triethylamine (4.04 g) in dichloromethane (100 ml) was cooled After a bath with ice, acetyl chloride (3.45 g) was added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was extracted with water (2 x 30 mL) and brine (2 x 30 mL) and the organic layer was dried with magnesium sulfate. The drying agent was removed by filtration and the filtrate was evaporated to give N- (3-chloro-4-methoxyphenyl) acetamide (7.45 g) as a dark oil, which solidified on standing. MS: 200 (M + H) +. REFERENCE EXAMPLE 53 I4-Nitrc > -1 - (Tetrahydro-pyran-2-OH-1 H-pyrazole-3-in-methanol A stirred solution of 4-nitro-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid methyl ester [500 mg, Reference Example 54 (a)] in tetrahydrofuran (20 ml) nitrogen at -78 ° C was treated dropwise with a solution of isobutylaluminum hydride in tetrahydrofuran (8.82 ml, 1 M). The reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was taken up in diethyl ether (100 ml) and quenched with water (150 ml). The resulting suspension was filtered through celite and the organic layer was collected from the filtrate, then dried over magnesium sulfate and then evaporated to yield r4-nitro-1 - (tetrahydro-pyran-2-yl) -1 H- pyrazol-3-yl] -methanol (349 mg) in the form of a peach-colored oil. LC-MS (METHOD H): Ry = 2.08 minutes, 250.29 (M + H + Na) +. REFERENCE EXAMPLE 54 (a) 4-Nitro-1- (tetrahydro-pyrnrano-2-yl) -1H-pyrazole-3-carboxylic acid methyl ester A suspension of 4-nitro-1 H-pyrazole-3-carboxylic acid methyl ester (1.3 g, Reference Example 55) and p-toluene sulfonic acid (144 mg) in chloroform (30 ml) at 0 ° C was treated with 3,4-dihydropyran (1.04 ml) dropwise. The reaction mixture was allowed to warm to room temperature during one night. The reaction mixture was washed with saturated sodium bicarbonate (40 ml) and water (3 x 40 ml). The combined aqueous layers were extracted with dichloromethane (3 x 60 mL). The organic layers were combined, dried over magnesium sulfate and concentrated to yield 4-nitro-1- (tetrahydro-pyran-2-yn-1H-pyrazole-3-carboxylic acid methyl ester (2.23 mg) in shape of a viscous brown oil LC-MS (METHOD H): Rj = 2.79 minutes, 278.21 (M + H + Na) +. (b) 4-Formyl-1- (tetrahydro-pyran-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester Proceeding in a manner similar to the Reference Example 54 (a) above but using 4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester (100 mg, Reference Example 57) was prepared 4-formyl-1 - (tetrahydro-pyran) ethyl ester -2-yl) -1 H-pyrazole-3-carboxylic acid (170 mg) in the form of a viscous yellow oil. LC-MS (METHOD J): Rj = 3.29 minutes, 275.30 (M + H + Na) +. REFERENCE EXAMPLE 55 - 4-Nitro-1H-pyrazole-3-carboxylic acid methyl ester A stirred suspension of 4-nitro-3-pyrazolecarboxylic acid g) in dichloromethane under nitrogen at 0 ° C was treated with oxalyl chloride (1.11 ml) followed by dimethylformamide (5 drops). The reaction mixture was warmed to room temperature and stirred overnight. Methanol (10 mL) was added and the reaction mixture was stirred overnight. The solvent was removed under reduced pressure and subjected to azeotropic distillation with toluene twice to produce 4-nitro-H-pyrazole-3-carboxylic acid methyl ester (1.3 g) as a pale green solid. LC-MS (METHOD H): RT = 1.94 minutes, 170.23 (M-H). "REFERENCE EXAMPLE 56 (a) 1-Methoxy-2-methyl-4-nitrobenzene 2-methylanisoI (2.5 ml) was cooled in acetic acid (140 ml) and dichloromethane (150 ml) at 15 ° C. Concentrated nitric acid (20 ml) was added slowly maintaining the reaction temperature below 40 ° C. The reaction was stirred at room temperature for 30 minutes and cooled to 0 ° C. before adding fuming nitric acid (50 ml) dropwise. The reaction mixture was allowed to warm to room temperature slowly and was stirred for an additional 4 days. The reaction mixture was poured into ice-water (600 ml) and the organic layer was washed with water (2 x 40 ml) and with saturated sodium hydrogencarbonate (2 x 40 ml), dried over magnesium sulfate and He concentrated. The residual dark red solid was subjected to flash chromatography on silica eluting with isohexane / ethyl acetate (9: 1) to (7: 3) to yield 1-methoxy-2-methyl-4-nitrobenzene (2.70 g). ) in the form of a dull white solid. LC-MS (METHOD J): Ry = 3.74 minutes, 168.27 (M + H) +. (b) 5,6-Dinitro-benzori, 31dioxol Proceeding in a manner similar to the Reference Example 56 (a) above but using 1, 2-methyldioxybenzene, 5,6-dinitrobenzori, dioxol was prepared as an orange solid. HPLC (METHOD.C): Ry = 2.99 minutes; 490.24 (2M + 1). REFERENCE EXAMPLE 57 4-Formyl-1 H-pyrazole-3-carboxylic acid ethyl ester Phosphorus oxychloride (5.07 ml) was added dropwise to dimethyl formamide (8.4 ml) at 0 ° C under nitrogen. Semicarbazide of ethyl pyruvate (4.3 g, Reference Example 58) was added portionwise to the stirring solution at 0 ° C under positive nitrogen pressure. The reaction mixture was heated at 60 ° C for 2.5 hours and cooled to room temperature before slowly pouring onto ice (30 g). The pH of the reaction mixture was adjusted to pH 12 with 6.25 M sodium hydroxide solution while maintaining the temperature at 0 ° C. The aqueous reaction mixture was heated at 60 ° C for 5 minutes and cooled to 0 ° C. The pH was again adjusted to pH 6 with 1M hydrochloric acid. The resulting precipitate that formed after 1 hour was collected by filtration to produce 4-formyl-1H-pyrazole-3-carboxylic acid ethyl ester ( 1.02 g) in the form of a pale yellow solid. LC- S (METHOD J): RT = 2.55 minutes, 169.27 (M + H) +, 167.30 (M-H). "REFERENCE EXAMPLE 58 Ethyl pyruvate semicarbazide A stirred solution of semicarbazide hydrochloride (11.1 g) and sodium acetate (8.2 g) in water (250 ml) was treated with ethyl pyruvate (10.9 ml) in one portion. The resulting white precipitate was collected by filtration to produce ethyl pyruvate semicarbazide (16.59 g) as a powder White. LC-MS (METHOD J): RT = 2.38 minutes, 174.31 (M + H) +, 172.32 (M-H) -. REFERENCE EXAMPLE 59 (2,4-Dimethoxy-benzyl) - | "3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1- (tetrahydro-pyrano-2-i0-1 H-pyrazole -4-ilmetill-arnide of morpholino-4-carboxylic acid A stirred solution of [332 mg, Reference Example 39 (b)] in acetic acid (5 ml) was heated at 120 ° C for 5 minutes in a Personal Chemistry Smith Greator microwaves. The mixtures of five reactions were combined and the solvent was removed under vacuum to yield (2,4-dimethoxy-benzyl) -r3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1- ( morpholino-4-carboxylic acid tetrahydro-pyrn-2-yn-1 H-pyrazol-4-ylmethylamide (1.22 g) as a dark yellow oil LC-MS (METHOD J ): R = 2.70 minutes, 589.63 (M + H) +.
REFERENCE EXAMPLE 60 4- (R (2,4-Dimethoxy-benzyl) - (morpholino-4-carbonyl) -amino-1-methyl.} -1- (tetrahydro-pyran-2-yl) ethyl ester ) -1 H-pyrazole-3-carboxylic A stirred solution of 4 - [(2,4-dimethoxy-benzylamino) -methyl] -1- (tetrahydro-pyrnrano-2-yl) -1H-pyrazole-3-carboxylic acid ethyl ester [1 g, Reference Example 54 (b)] in tetrahydrofuran (25 ml) was treated with 2,4-dimethoxybenzylamine (0.596 ml). After stirring for 12 hours, sodium triacetoxyborohydride (1.68 g) was added to the reaction mixture and the reaction mixture was stirred for an additional 1 hour before partitioning between ethyl acetate (200 ml) and sodium hydrogencarbonate. saturated (200 mi). The aqueous layer was extracted twice with ethyl acetate (100 ml) and the combined organic layers were dried over magnesium sulfate and then concentrated in vacuo to yield ethyl 4-f! "(2,4-dimethoxy-) ethyl ester. benzin- (morpholino-4-carbonyl) -amino-1-methyl.} -1- (tetrahydro-pyrano-2-yl) -1H-pyrazole-3-carboxylic acid (1.66 g) in the form of a yellow oil LC-MS (METHOD B): RT = 2.27 minutes, 404.17 (M + H) +.
PLO REFERENCE AXIS 61 4-Amino-N-benzyl-3-nitro-benzenesulfonamide To a stirred suspension of (4-Benzylsulfamoyl-2-nitro-phenyl) -carbamic acid ethyl ester (1.50 g, Reference Example 62) in ethanol (30 mL) was added 2M sodium hydroxide solution (5%). 93 mL) and the reaction was heated at 75 ° C for 2 hours. The reaction mixture was cooled to room temperature, poured into ice-water and acidified to pH with 2M hydrochloric acid (30 mL). The resulting precipitate was collected by filtration and dried under vacuum to provide 4-amino-N-benzyl-3-nitro-benzenesulfonamide (1.01 g) as a yellow solid. LC-MS (METHOD J): Rj = 3.41 minu¬ cough, 308.22 (M + H) +. REFERENCE EXAMPLE 62 Ethyl acid ester (4-Benzylsulfamoyl-2-nitro-phenylVcarbamic acid To a stirred solution of (4-chlorosulfonyl-2-nitro-phenyl) -carbamic acid ethyl ester (2 g, Reference Example 63) in dichloromethane (50 g. mi) at 0 ° C, under a nitrogen atmosphere, diisopropylethylamine (2.71 ml) and benzylamine (0.850 ml) were added. The reaction was warmed to room temperature and stirred for 12 hours. The reaction mixture was then washed with water (2 x 20 mL) and brine (2 x 20 mL), dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to provide the title compound (2.29). g) in the form of a brown solid. LC-MS (METHOD J): Rj = 3.83 minutes, 380.12 (M + H) +. EXAMPLE OF, REFERENCE 63 Ethyl ester of (4-chlorosulfonyl-2-nitro-phenol) -carbamic acid To a stirred suspension of (4-chlorosulphonyl-phenyl) -carbamic acid ethyl ester (5 g, Reference Example 64) in concentrated sulfuric acid (25 ml) at 0 ° C, a suspension of nitrate of sodium nitrate was added dropwise. sodium (1.61 g) in concentrated sulfuric acid and the reaction was stirred for 3 hours. The reaction mixture was then poured onto ice, the resulting precipitate was collected by filtration and dried under vacuum to give (4-chlorosulfonyl-2-nitro-phenyl) -carbamic acid ethyl ester (4.80 g) in shape of a yellow solid. LC-MS (METHOD B): Rj = 3.32 minutes, 307.08 (M-H) ~.
REFERENCE EXAMPLE 64 4-Chlorosulfonyl-phenyl) -carbamic acid ethyl ester To a stirred solution of chlorosulfonic acid (20 ml) at 0 ° C was added N-phenylurethane (9.90 g) at a rate such that the temperature did not exceed 20 ° C. The reaction was then heated at 60 ° C for 3 hours, cooled to room temperature and carefully poured into ice. The resulting precipitate was collected by filtration and dried under vacuum to give (4-chlorosulfonyl-phenyl) -carbamic acid ethyl ester (14.50 g) as an off-white solid. LC-MS (METHOD B): Rj = 3.11 minutes, 284.23 (M + H) +. REFERENCE EXAMPLE 65 N * 1 * -Benzyl-4-methanesulfonyl-benzene-1,2-diamine A stirred solution of benzyl- (4-methanesulfonyl-2-nitro-phenyl) -amine (0.300 g, Reference Example 66) and tin chloride (1.86 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140 ° C for 10 minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution at pH 8 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to provide N * 1 * -benzyl-4-methanesulfonyl-benzene-1,2-diamine (0.255 g) as a pale brown solid. LC-MS (METHOD B): Rj = 2.74 minutes, 275.20 (M-H) -. REFERENCE EXAMPLE 66 Benzyl- (4-methanesulfonyl-2-nitro-phenyD-amine To a stirred suspension of 4-fluoro-2-nitrophenyl) methylsulfone (0.50 g) and sodium hydrogen carbonate (0.575 g) in ethanol and water (3: 2) (30 ml) was added benzylamine (0.374 ml) and the reaction was stirred for 16 hours. The reaction mixture was then poured onto ice-water, the resulting precipitate was collected by filtration and dried under vacuum to give benzyl- (4-methanesulfonyl-2-nitro-phenyl) -amine (0.660 g) as a solid. yellow. Rj = 2.97 minutes, 307.04 (M + H) +. REFERENCE EXAMPLE 67 4-f2- (3,4-Dinitro-phenoxy) -etin-morpholine A mixture of 3,4-dinitrophenol (250 mg), 4- (2-chloroethyl) hydrochloride morpholinia (252 mg) and potassium carbonate (375 mg) in dimethylformamide (3 ml) was heated to 120 ° C. for 20 minutes in a microwave Personal Chemistry Smith Creator. The reaction mixture was partitioned between ethyl acetate and water and the organic cap was dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to provide 4-G2- (3,4-dinitrophenoxyethyl-morpholine) (319 mg) in the form of a yellow oil.
(METHOD B): Rj = 2.13 minutes, 298 (M + H) +. REFERENCE EXAMPLE 68 3-Formyl-1 H-indazole-5-carbonitrile To a suspension of 5-cyanoindole (3.93 g) and sodium nitrite (19.07 g) in water was added 6 M hydrochloric acid slowly until the pH was less than 2. The suspension was then stirred for 3 hours at room temperature. The mixture was then extracted with ethyl acetate, dried over magnesium sulfate, filtered and the filtrate was concentrated in vacuo to provide 3-formyl-H-indazole-5-carbonitrile (4.5 g) as a pale brown solid. LC-MS (METHOD B): R = 2.47 minutes, 172.29 (M + H) +. IN VITRO TEST PROCEDURES A. IN VITRO TEST PROCEDURES FOR SYK 1. Inhibitory effects of compounds on SYK kinase The inhibitory effects of compounds on SYK kinase were determined using a fluorescent assay resolved over time. The catalytic domain of SYK kinase (residues A340-N635) was expressed as a fusion protein in yeast cells and purified until homogeneity. The kinase activity was determined in 50 mM Tris-HCl buffer at pH 7.0 containing 50 mM NaCl, 5 mM MgCl 2, 5 mM MnCl 2, 1 μ adenosine triphosphate. and 10 μ? synthetic peptide? Biotin- (p-Aianine) 3-DEEDYEIPP-NH2- Enzyme reactions were determined by the addition of buffer containing 0.4 M KF, 133 mM EDTA, pH 7.0, containing Streptavidin-XL665 conjugate and an antibody Phosphospecific mono-clonal conjugated to europium cryptate (Eu-K). The characteristics of the two fluorophores, XL-665 and Eu-K are provided by G.Matis et al., Anticancer Research, 1997, 17, pages 3011-3014. The XL-665 specific long time signal, produced only when the synthetic peptide is phosphorylated by SYK, was measured on a Packard Discovery microplate analyzer or on a LJL Biosystems Analyst AD microplate reader. The inhibition of SYK activity with the compounds of the invention was expressed as the percentage of inhibition of the control activity exhibited in the absence of the compounds of the invention. test. Particular compounds of the invention inhibit SYK activity with IC50 values in the range of 100 micromolar to 0.1 nanomolar. Preferred compounds of the invention inhibit SYK activity with IC 50 values in the range of 5,000 nanomolar to 0.1 nanomolar. Particularly preferred compounds of the invention inhibit SYK activity with IC50 values in the range of 1000 nanomolar to 0, 1 nanomolar. Especially preferred compounds of the invention inhibit SYK activity with IC50 values in the range of 100 nanomolar to 0.1 nanomolar. The more especially preferred compounds of the invention inhibit the activity of SYK with IC50 values in the range of 10 nanomolar to 0.1 nanomolar. 2. Antigen-induced degranulation of rat bosophilic leukemia (RBL) cells measured by the release of fH31-5-hydroxytryptamine (serotonin) 2.1 Cell culture, RBL-2H3 cell labeling and assay yield. Method A: For each 24-well culture plate that was to be adjusted, 6 x 10 6 RBL-2H3 cells were washed and resuspended in 15 ml of DME-10 containing 25 μ? of 1 mC / ml [3H] -serotonin (final concentration 0.5 \ iCUml) and 1 g / ml (15 ml) of anti-DNP IgE. 0.5 ml of cell suspension was added to each well of a 24-well plate. The cells were incubated for 2 days at 37 ° C, until they reached confluency. The medium was gently aspirated from each well and the cells were They were then washed with assay buffer. A final volume of 200 ml of assay buffer (+ or - the test compounds at the appropriate concentrations) was then added to one out of every three repeated wells. Next, 100 mg / ml of DNP (antigen) was added to all wells (excluding negative control wells, ie, to measure the spontaneous release of [H3] -serotonin in the absence of receptor cross-linking). The cells were incubated for 30 minutes at 37 ° C and the reaction was stopped by transferring 100 μ? of the supernatant material of each sample to a microtitration plate by liquid sonication maintained on ice. Subsequently 200 pl of scintillant-40 was added to each well of the microtiter plate and the plate was read in a Topcount Liquid Scintillation Counter sonicator counter. Method B: RBL-2H3 cells were kept in 375 flasks at 37 ° C and 5% C02, and passed every 3-4 days. For the harvested cells, 5 ml of trypsin-EDTA was used to rinse the flask once, then 5 ml of trypsin was added to each mat and incubated at room temperature for 2 minutes. The cells were transferred to a tube with 14 ml of medium, centrifuged at 1100 rpm at room temperature for 5 minutes and resuspended at 2 x 10 5 / ml. The cells were sensitized by adding 1 μl of DNP-specific IgE (1 mg / ml of stock solution) for each 10 ml of cells. 200 μ? of cells to each well in a 96-well flat bottom plate (40,000 cells / well) and the plate was incubated overnight at 37 ° C and 5% C02. The next day prepared compounds in 100% DMSO at 100 mM. Each compound was then diluted 1: 100 in assay buffer and then further diluted in 1% DMSO assay buffer to obtain final concentrations of 0.03-30 μ ?. 80 μ? Were added to each well. of assay buffer (Hank's balanced salt solution with Ca ^ / Mg **, 2 mg / ml glucose, 0.03% BSA), and then 10 pl of diluted compound. It was then incubated for 5 minutes. 10 μ? Were added to each well. of DNP-HSA (100 ng / ml) and incubated at 37 ° C (without C02) for 30 minutes. As a control, 1% DMSO alone (without compound) was added to a set of wells to determine the total release. As another control, buffer was added in place of DNP-HSA to another set of wells to determine the value of the assay background. After 30 minutes of incubation, the supernatants were transferred to a new 96-well plate, 50 μ? of supernatant to each well of a test plate. 100 μ? of substrate solution (5 mM PNAG in 0.4 M citric acid, 0.2 M Na2HPO4) to each well and incubated at 37 ° C for 90 minutes. 50 μ? of 0.4 M glycine solution to stop the reaction and the plate was read at 405 nm in a Molecular Devices SpectraMax 250 plasma reader. 2.2 Calculation of results Method A (i) The mean ± s.e.m. and from each set of wells in triplicate. (ii) The maximum response was that of the positive control wells containing antigen (10 ng / ml) but not compound. (iii) The minimum response was that of the control wells that did not contain antigen or compound. (iv) Using these values as the maximum (100%) and minimum (0%) values respectively, the data was normalized to provide a percentage of the maximum response. (v) A dose response curve was plotted and the IC50 value of the compound was calculated. Method B (i) The mean ± SD (standard deviation) of each set of wells was calculated in triplicate. (ii) The maximum response was that of the positive control wells containing antigen (100 ng (ml) but not compound. (iii) The minimum response was that of the control wells that consternate buffer (without antigen) and not compound. iv) Using these values as the maximum (100%) and minimum (0%) values respectively, the experimental data were calculated to produce a percentage of the maximum response (indicated% of control). (v) A curve of Response to the dose and the IC50 value of the compound was calculated using a Prism.GraphPad computer program and a nonlinear regression analysis of the least squares.
B. IN VITRO TEST PROCEDURES FOR KDR 1. Inhibitory effects of compounds on KDR The inhibitory effect of the compounds was determined in a phosphorylation assay of a substrate by the KDR enzyme in vitro by means of the flasplate plate technique. 96 wells, NEN). The cytoplasmic domain of the human KDR enzyme is cloned in the form of a GST fusion in the bacuvolirus expression vector pFastBac. The protein is expressed in SF21 cells and purified to approximately 60% homogeneity. The kinase activity of KDR is measured in 20 mM MOPS, 10 mM MgCl 2, 10 mM MnCl 2, 1 mM DTT, 2.5 mM EGTA, 10 mM β-glycerophosphate, pH 7.2, in the presence of 10 mM MgCl 2, 100 μM Na 3 V0 ?, 1 mM NaF. 10 μ? of the compound at 70 μ? of kinase buffer containing 100 ng of KDR enzyme at 4 ° C. The reaction was started by adding 20 μ? of solution containing 2 μg of substrate (SH2-SH3 fragment of PLCy expressed in the form of a GST fusion protein), 2pCi? 33? [???] and cold ATP 2μ ?. After incubation for 37 h at 37 ° C, the reaction was quenched by adding 1 volume (100 μl) of 200 mM EDTA. The incubation buffer was removed and the wells were washed three times with 300 μ? of PBS. Radioactivity was measured in each well using a Top Count NXT instrument (Packard). The background noise was determined by measuring the radioactivity in quadruple wells containing radioactive ATP and the substrate alone.
A control of the activity was measured in quadruplet wells containing all the reagents (? 33? - [???], KDR and the PLCy substrate) and in the absence of compound. The inhibition of KDR activity with the compound of the invention is expressed as a percentage of the inhibition of the activity of the control determined in the absence of compound. Compound SU5614 (Calbiochem) (1 μ?) Is included in each plate as a control of inhibition. The IC50 values for the compounds are calculated by graphically displaying the dose response curves. The IC50 corresponds to the concentration of compound that induces a 50% inhibition of kinase activity. The particular compounds of the invention inhibit KDR activity with IC 50 values in the range of 100 micromolar to 10 na-nomolar. Preferred compounds of the invention inhibit KDR activity with IC50 values in the range of 3000 nanomolar to 10 nanomolar. Particular preferred compounds of the invention inhibit KDR activity with IC50 values in the range of 300 nanomolar to 10 nanomolar. II) Cell activity in endothelial cells 1) Inhibition of VEGF-dependent proliferation of HDMEC The anti-KDR activity of Jas molecules is assessed by incorporating [C1] -thymidine in HDMEC (human dermal microvascular endothelial cells) in response to VEGF.
The HDMEC (Promocell, step 5 to 7) are inoculated in 100 μ [at 5000 cells per well in 96-well Cytostar plates (Amersham) previously coated with binding factor (AF, Cascad Biologics) at 37 ° C, 5% C02, on day 1. On day 2, the complete medium (basal medium supplemented with 5% FCS and a mixture of growth factors) is replaced with minimal medium (basal medium supplemented with 5% FCS) and cells They are incubated for 24 hours. On day 3, the medium is replaced with 200 μ? of fresh medium that has been or has not been supplemented with 100 ng / ml of VEGF (R & D System) and that contained or did not contain the compound of the invention and 0.1 pCi of [C14] -thymidine. The cells are incubated at 37 ° C under 5% CO2 for 4 days. The incorporation of [C] -thymidine is then quantified by counting the radioactivity. The tests are carried out in 3 wells. The final concentration of D SO in the assay is 0.1%. The% inhibition is calculated as follows: [cpm (+ VEGF) - cpm (+ VEGF + cpd) / cpm (+ VEGF) -cpm (BM5% FCS)] x100. 2) Inhibition of TF production (Tissue Factor) by endoteiial cells in response to VEGF. Endoteiial cells are inoculated at 20,000 cells per well in a 96-well plate previously coated with binding factor. After culturing for 8 hours, the medium is changed and the cells are previously incubated with the compound (0.1% final DMSO) in basal medium for 16 hours. The synthesis of TF (tissue factor) is induced by adding VEGF (100 ng / ml final). After incubating for 6 hours, the Cells are lightened and lysed. The tissue factor is then detected by means of the Imubind ELISA assay. 3) Effect of the molecules on the independent growth of HDMEC VEGF The HDMEC (5000 cells per well) are inoculated in complete medium in 96-well Cytostar plates (Amersham) previously coated with binding factor (AF, Cascad Biologics) at 37 ° C, 5% CO2, on day 1. The complete medium is then removed and the cells are incubated in 200 μ? of complete medium containing the molecules of the invention and [C14] -thymidine (0.1 pCi). The incorporation of [C 4] -thymidine is measured using a Wallac counter after incubation for 3 days. The% inhibition is calculated as follows [cpm (CM) -cpm (CM + cpd) / cpm (CM)] x100. Table 5 below provides the results obtained in the above tests for the products indicated as examples in the present patent application.
TABLE 5 IC50 (μ?) On the% inhibition of the phosphorylation inhibition of the phosphorylation of PLCy by KDR (produc¬ Example n ° i PLC PLC for testing at a concentration of 10μ?) 14 1, 2 15 0.8 16 2 20 3.4 21 35 1 0.47 2 0.45 3 91, 8 4 0.45 5 91, 9 6 0.33 7 0.72 8 0.67 9 0.35 10 0.34 11 0.26 12 0.16 13 0.61 18 91 , 2 23 2 The pharmacological results obtained in the above tests for products indicated in the examples in the present application are given in Table 6 below, and the activity grades of the products are indicated by + signs according to the activity ranges indicated in the table. , ie: + for an activity greater than 3 micromolar ++ for an activity between 0.3 and 3 micromolar +++ for an activity less than 0.3 micromolar TABLE 6 38 C21H16N60 368.40 ++ - 39 C22H16BrN50 446.31 ++ 40 C23H19N502 397.44 ++ 41 C23H17N503 411, 42 ++ 42 C24H17N50S 423.50 ++ 43 C21H19N70 385.43 ++ 44 C23H16F3N502 451.41 ++ 45 C23H19N50 381.44 +++ 46 C21H17N50S 387.46 ++ 47 C23H16F3N50 435.41 ++ 48 C28H21N502 459.51 ++ 49 C23H16F3N502 451.41 ++ 50 C21H23N502 377.45 ++ 51 C20H17N7O 371.40 ++ 52 C25H23N50 409.49 ++ 53 C22H19N502 385.43 ++ 54 C24H17N50S 423.50 ++ 55 C26H24N603 468.52 ++ 56 C21H15CIN60 402.84 +++ 57 C24H17N50S2 455.56 ++. 58 C24H19N502 409.45 +++ 59 C23H16N60 392.42 ++ 60 C24H16CIN50S 457.94 + 61 C23H16F3N50 '435,41 + 62 C23H19N50S 413.50 +++ 63 C24H17N50S 423.50 +++ 64 C21H21N502 375.43 ++ 65 C24H19N503 425.45 ++ 66 C20H15N5O2 357.37 ++ 67 C22H16N603 412.41 ++ 68 C20H15N5OS 373.44 ++ 69 C24H21 50 395.47 ++ 70 C24H19N70"421.46 ++ 71 C23H19N50 381.44 +++ 72 C22H16CIN50 401.86 +++ 73 C22H18N603S 446.49 ++ 74 C20H21N5O2 363.42 + 75 C22H16BrN50 446.31 + 76 C26H19N50 417,47 + 77 C20H15N5OS 373,44 + 78 C24H22N60 410.48 + 79 C22H16N603 412,41 + 80 C21H16N60 368.40 ++ 81 C22H16BrN50 446.31 + 82 C23H19N502 397.44 ++ 83 C24H17N50S 423.50 + 84 C28H21 502 459.51 + 85 C23H16F3N502 451.41 + 86 C21 H15CIN60 402.84 + 87 C24H19N502 409.45 + 88 C23H16F3N50 435,41 + 89 C23H19N50S 413.50 +++ 90 C20H15N5O2 357.37 ++ 91 C22H16N603 412.41 ++ 92 C24H21 N50 395.47 ++ 93 C22H16CIN50 401.86 + 94 C21 H15N50 353.38 ++ 95 C22H17N50 367,41 + 96 C23H19N50 381, 44 + 97 C20H14N4 310.36 + 98 C20H12CI2N4 379.25 + 99 C24H16N4 360.42 + 100 C20H13FN4. 328.35 ++ 101 C20H13CIN4 344.80 + 102 C21 H16N40 340.39 ++ 103 C20H12CIFN4 362.79 ++ 104 C20H12CI2N4 379.25 + 105 C26H16N4S2 448.57 + 106 C26H18N4 386.46 + 107 C21 H16N4 324.39 + 108 C21 H16N4 324.39 ++ 109 C21 H16N4 324.39 ++ 110 C18H12N4S 316.39 ++ 134 C22H18N4S 370.48 · + 135 C20H12F2N4 • 346.34 ++ 136 C2 H13F3N40 394.36 + 137 C2 H15FN4 342.38 ++ 138 C22H15FN4 354.39 + 139 C22H15CIN4 370.84 + 140 C23H18N402 382.42 + 141 C21H16N40 340.39 ++ 142 C18H12N40 300.32 ++ 143 C27H20N4O 416.48 + 144 C23H20N4 352.44 ++ 145 C21H16N402S 388.45 + 146 ++ 147 ++ 148 ++ 149 ++ 50 ++ 151 ++ 152 ++ 153 ++ 154 ++ 155 ++ 156 ++ 57 +++ 158 ++ 159 ++ 160 ++ 161 ++ 162 + 163 + 164 + 165 + 166 ++ 167 +++ 168 +++ 169 +++ 170 ++ 171 ++ 172 ++ 173 ++ 174 ++ 175 ++ 176 +++ 177 +++ 178 +++ 79 +++ 180 +++ 181 ++ 182 ++ 183 + 184 ++ 185 ++ 186 + 187 + 188 ++ 189 + 190 + 191 ++ 192 + 193 ++ 194 + 195 + 196- + 197 ++ 198 + 199 + 200 + 201 + 202 + 203 + 204 + 205 + 206 + 207 + 208 + 209 + 210 + 211 + 212 + 213 + 214 ++ 215 + 216 + 217 ++ 218 + 219 + 220 + 221 + 222 + 223 + 224 ++ 225 + 226 + 227 + 228 + C. IN VITRO TEST PROCEDURES FOR ITK 1. Inhibitory effects of compounds on ITK kinase The inhibitory effects of the compounds on ITK kinase were determined using a fluorescence polarization assay. The ITK kinase was produced by a baculovirus expression system. 1.1 Assay technology The assay measures the autophosphorylation of the ITK kinase. The assay is configured based on the polarization method of fluorescence. The enzyme is incubated with ATP and compound. After incubation, a mixture containing fluorescently labeled phospho-peptide tracer and anti-phospho-tyrosine antibody (CoreHTS tyrosine kinase assay kit, P2837, Panvera) is added in order to generate the specific signal that is inversely proportional to the phosphorylation of the enzyme. Phospho-rilated ITK generated from the kinase reaction will compete specifically for the antibody and release the fluorescently labeled tracer. Inhibition of ITK kinase activity will result in an increased FP value. 1.2 Test conditions AND! assay is performed on a BD black 384 super well well plate. For the enzymatic reaction, the final reagent / well: enzyme concentration? 16.5 nM, ATT 50 μ ?, 20 mM Hepes (pH 7.5), 0.15 M NaCl, 3 mM MgCl 2, 1 mM MnCl 2, 0.01% Triton X-100, 1 mM DTT, glycerol 5% and? -globulin 0.1%. Incubation time: 45 minutes. Temperature: 25 ° C. Reaction volume: 10 μ ?. For the immunoreaction, 10 pl of detection stop mixture containing 10 mM EDTA, 1: 2 dilution of antibody and 1: 4 dilution of tracer in 1x dilution buffer (Panve-ra) are added. Incubation time: 90 minutes at 37 ° C followed by ambient temperature for 60 minutes. 1.3 Test procedure: 1. Add 5.0 μ? of ATP solution to each well of the black 384 surface well plate. 2. 1.0 μ? of compounds or 1% DMSO in TBS buffer. 3. Start the reaction by adding 5.0 μ? of enzymatic solution. 4. Incubate at 25 ° C for 45 minutes. 5. 10 μ? of detection stop solution. 6. Incubate for 90 minutes at 37 ° C followed by incubation at room temperature for 60 minutes. 7. Read by means of an LJL Acquest device in FP mode using a fluorescence filter set (Ex = 485 nm, Em = 535 nm) with dichroic mirror FL. Integration time: 200,000 μß. [Factor G depends ,. { Trac 'erOnly - Buffer). tooth of the instrument - -]. { STracerOnly + SBuffer) The inhibition of ITK activity with the compounds of the invention was expressed as a percentage of the inhibition of test activity determined in the absence of test compounds. The IC5o values for the compounds were calculated graphically representing dose response curves. The IC5o corresponds to the concentration of compound that induces a 50% inhibition of kinase activity. The particular compounds of the invention inhibit ITK activity with IC50 values in the range of 100 micromolar to 1 micromolar. IN VIVO TEST PROCEDURES A. IN LIVE TEST PROCEDURES FOR SYK 1. Inhibition of anti-keno-dependent passive cutaneous anaphylaxis The compounds of the invention were tested in the passive cutaneous anaphylaxis (PCA) model of Balb / c mice. The model used in these in vivo studies mimic the relevant characteristics of antigen-dependent activation activated by mast cells and functional responses. These studies demonstrated that the compounds of the invention inhibit the increased edema observed in ears of sensitized mice following antigen challenge. Protocol for awareness and stimulation Balb / c mice were sensitized in the right ear on day 0 with monoclonal anti-DNP IgE (25 pg) administered intradermally in the auditory pavilion. The left ear was injected with PBS to serve as a control. Sixteen to twenty hours after the sensitization, the mice were stimulated with antigen with 150 g of DNP-albumin administered i.v. Protocol for the dosing and calculation of results The test drug was administered orally 15-60 minutes before the stimulation with DNP-albumin antigen. The doses of compounds were administered in logarithmic divisions between 3 and 100 mg / kg. A control group of mice was administered only vehicle, and subsequently treated the same. Each thickness was measured for values of t = 0, 15, 30 or 60 minutes after the stimulation of DNP-albumin antigen, in both ears, by digital calibrators and were expressed in units of mm x 0.01. The thickness of the ears for t = 0 was recorded to serve as a baseline. The net increase in the right and left ear was calculated by subtracting the values for t = 0 from those for t = 15, 30 or 60 minutes. The percentage of inhibition of ear edema was then calculated as [thickness of the ear of the witness - (thickness of the ear of the right ear -the thickness of the ear of the left ear)] / thickness of the ear of the witness x 100 for each value of time measured. Results (i) The compound demonstrated a dose-dependent inhibition of ear edema following oral administration of 3-100 mg / kg. The inhibition of ear edema was observed for t = 15, 30 and 60 minutes after the stimulation with antigen. These results indicate that the compounds of the invention inhibit the activation of mast cells and functional responses when provided orally in a mouse model of passive cutaneous anaphylaxis. 2. Antigen-induced degranulation of rat basophilic leukemia (RBL) cells measured by the release of rH3] -5-hydroxytryptamine (serotonin) 2.1 Cell culture, RBL-2H3 cell labeling and assay performance. Method A: For each 24-well culture plate that was to be established, 6 x 10 6 RBL-2H3 cells were washed, washed and resuspended in 15 ml of DMEM-10 containing 25 μ? of 1mCi / mL [3H] -serotonin (final concentration? .dμ? / ???) and 1 pg / mL (15 mL) of anti-DNP IgE. 0.5 ml of cell suspension was added to each well of a 24-well plate. The cells were incubated for 2 days at 37 ° C, until they reached confluence. The medium was gently aspirated from each well and the cells were then washed with assay buffer. A final volume of 200 ml of assay buffer (+ or - the test compounds at the appropriate concentrations) was then added to each of three repeated wells. Next, 100 ng / ml of DNP (antigen) was added to all wells (excluding negative control wells, that is, to measure the spontaneous release of [H3] -serotonin in the absence of receptor cross-linking). The cells were incubated for 30 minutes at 37 ° C and the reaction was stopped by transferring 2100 μl of the supernatant from each sample to a microtiter plate of liquid sonication maintained on ice. Next, 200 μl of scintillant-40 was added to each well of the microtitre plate and the plate was read on a Topcount Liquid Scintillation Counter liquid sonication counter. Method B: RBL-2H3 cells are kept in T75 flasks at 37 ° C and 5% C02, and are passed every 3-4 days. To collect the cells, 5 ml of trypsin-EDTA is used to rinse the flask once, then add 5 ml of trypsin to each flask and incubate at room temperature for 2 minutes. The cells are transferred to a tube with 14 ml of medium, centrifuged at 1100 rpm at room temperature for 5 minutes and are resuspended at 2 x 105 / ml. The cells are sensitized by adding 1 μl of DNP-specific IgE (1 mg / ml of stock solution) for each 10 ml of cells. 200 μl of cells are added to each well of a 96-well flat bottom plate (40,000 cells / well) and the plate is incubated overnight at 37 ° C and 5% CO 2. The next day, compounds are prepared in 100% DMSO at 100 mM. Each compound is then diluted 1: 100 in assay buffer and then further diluted in 1% DMSO assay buffer to obtain final concentrations of 0, 03-30 μ ?. 80 μ are added to each well. of assay buffer (solution of balanced salts of Hank with Ca ++ / Mg ++, 2 mg / ml of glucose, 0.03% of BSA), followed by 10 μ? of diluted compound. Then incubate for 5 minutes. 10 μ? Are added to each well. of DNP-HSA (100 ng / ml) and incubated at 37 ° C (without CO2) for 30 minutes. As a control, 1% DMSO is added alone (without compound) to a set of wells to determine the total release. As another control, buffer is added in place of DNP-HSA to another set of wells to determine the value of the assay background. After 30 minutes of incubation, the supernatants are transferred to a new 96-well plate. 50 μ? of supernatant to each well of a test plate. 100 μ? of substrate solution (5 mM PNAG in 0.4 M citric acid, 0.2 M Na2HPO4) to each well and incubated at 37 ° C for 90 minutes. 50 μ? of 0.4 M glycine solution to stop the reaction and the plate is read at 405 nm on a Molecular Devices SpectraMax 250 plate reader. 2.2 Calculation of results Method A (i) The mean ± s.e.m. of each set of wells in triplicate. (ii) The maximum response was that of the positive control wells containing antigen (10 ng / ml) but not compound. (iii) The minimum response was that of the control wells that did not contain antigen or compound. (iv) Using these values as the maximum (100%) and minimum (0%) values respectively, the data was normalized to provide a percentage of the maximum response. (v) A dose response curve was plotted and the IC50 value of the compound was calculated. Method B (i) The mean SD was calculated for each set of wells in triplicate. (ii) The maximum response was that of the positive control wells containing antigen (100 ng / ml) but not compound. (iii) The minimum response was that of the control wells that contained buffer (without antigen) and not compound. (iv) Using these values as the maximum (100%) and minimum (0%) values respectively, the experimental data were calculated to produce a percentage of the maximum response (indicated% of control). (v) A dose response curve was graphically plotted and the IC50 value of the compound was calculated using a GraphPad computer program and a nonlinear regression analysis of the least squares.

Claims (1)

  1. CLAIMS 1.- A pharmaceutical composition, comprising a compound of general formula (Ix) wherein X represents C-R2 and W, Y and Z, which may be the same or different, represent CH or CR3; O W represents CH, X represents N, Y represents CH or CR3 and Z represents CH or CR3; or W represents N, X represents CH or CR2, Y represents CH and CR3, and Z represents CH or CR3; or W represents N, X represents CH or CR2, Y represents N, and Z is CH or CR3; or W represents N, X represents CH or CR2, Y represents CH or CR3, and Z represents N; or -848- W represents N, X represents N, Y represents CH or CR3, and Z represents CH or CR3; A5 represents H or alkyl; R1 represents aryl or heteroaryl, each optionally substituted with one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= O) R4, -C (= O) NY Y2, -C (= O) OR4, -N (R6) C (= O) R4, -N (R6) C (= O) NY1Y2, -N (R6) C (= 0) 0R4 -N (R6) S02R4, -N (R6) SO2NY Y2, - ?? 1? 2, -OR4, -OCF2H, -OCF3, -OC (= O) R4 -OC (= 0) NY1Y2, -OS (0) nR4, -S (0 ) nR4, -8 (?) p ???? and -S (O) nOR4; R and R3 are such that: R2 and R3, which may be the same or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= O) R4, -C (= 0) NY1Y2, -C (= 0) OR4, -NY1Y2, -N (R6) C (= O) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= O) OR4, - N (R6) S02R4, -N (R6) S02 Y1Y2, -OR4, -OCF2H, -OCF3, -OC (= O) R4, 15. -OC (= O) NY1Y2, -S (O) nR4, -S (O) NNY1Y2 or -S (O) nOR4; or R represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4 -C (= O) R 4 -C (= O) NY 1 Y 2, -C (= O) OR 4, - 1 1 2, -N (R6) C (= O) R4, --N (R6) C (= O) Y1YI -N (R6) C (= O) OR4, -N (R6) SO2R4, -N (R6) SO2NY1Y2, - OR4 , -OCF2H, -OCF3, -OC (= O) R4, -OC (= O) NY1Y2, -S (O) nR4, -S (O) NNY1Y2 20 or -S (O) nOR4 and R3 represents alkyl, haloalkyl, halogen and OR ^; -849- the groups R2 and R3 in adjacent carbon atoms can form a ring based on carbon atoms of 5 to 6 members containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, and which may be optionally substituted with alkyl; R4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -C (= 0) NY3Y4 , -C (= 0) OR6, - N (R6) C (= 0) NY1 Y2, -NY1Y > -OR5 or alkyl substituted with -NY3Y4; R5 is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R6 is chosen from the values of R5; n is zero or an integer 1 or 2; Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted with one or more groups selected from cyano, aryl, heteroaryl, hydroxy, -C (= 0) OR6, -C (= 0 ) NY3Y4, -NY3Y4 ° -OR5, or the group -NY "Y2 can form a cyclic amine: Y3 and Y4 are independently hydrogen, alkynyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or the group -NY3Y4 can form a cyclic amine; -850- all the alkyl, alk, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are further optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl radicals, cyano, alkyloxy, alkoxy, acylamino (NH-COalk), -C (= 0) OR6, -C (= 0) R6, hydroxyalkyl, carboxyalkyl, S (0) n-alk, S (0) n-NH2 , S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, NO2, aryialkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3Y4 and ??? 4, these latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more radicals selected from halogen atoms and alkyl radicals, free carboxyl radicals, salified or esterified and acylamino NH-C radicals ( 0) R5; and their corresponding N-oxides, and their prodrugs, and their acid bioisoesters; and pharmaceutically acceptable salts and solvates of these compounds and their N-oxides and their prodrugs, and their acid bioisoesters; together with one or more pharmaceutically acceptable carriers or excipients. 2. A pharmaceutical composition according to claim 1, wherein R2 and R3 form a group selected from -O-CH2-O-, -O-CH2-CH2-O-; - -CH2-O-CH2-, -CH2-N (R4) -CH2-, -CH2-CH2-CH2-, -CH2-C (CH3) 2-CH2-, -CH2-0-CH2-CH2-, -CH2-N (R14) -CH2-CH2-, -CH2-CH2-CH2-CH2-, -CH2-C ( CH3) 2-CH2-CH2-, -CH = CH-CH = CH-, -N = CH- -851- CH = CH-, -CH = N-CH = CH-, -CH = CH-N = CH- and -CH = CH-CH = N, where R 4 is H or alkyl. 3. A compound of general formula (Ix) wherein X represents C-R2 and W, Y and Z, which may be the same or different, represent CH or CR3; O W represents CH, X represents N, Y represents CH or CR3, and Z represents CH or CR3; or W represents N, X represents CH or CR2, Y represents CH and CR3 and Z represents CH or CR3; or • W represents N, X represents CH or CR2, Y represents N, and Z is CH or CR3; or W represents N, X represents CH or CR2, Y represents CH or CR3, and Z represents N; or W represents N, X represents N, Y represents CH or CR3, and Z represents CH or CR3; A5 represents H or alkyl; -852- R1 represents aryl or heteroaryl, each optionally substituted with one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -0 (= 0) ???? 2 , -C (= 0) OR4 -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2i -N (R6) C (= 0) OR4 -N (R6) S02R4 -N (R6) S02NY1Y2, -NY Y2, -OR4, -OCF2H, -OCF3, -OC (= O) R4, - OC (= 0) NY1Y2I _0S (0) NR4, -S (0) NR4 -S ( 0) NNY Y2 and -S (0) NOR4; R2 and R3 are such that: R2 and R; which may be the same or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) OR4, -? ??? 2, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N (R6) S02NY1Y2, -OR4, -OCF2H, -OCF3, -OC (= 0) R4, -OC (= 0) NY1 Y2, -S (0) NR4 -S (0) nNYlY20 _S (0) NOR4; or R2 represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) OR4 - ???? 2, -N (R6) C (= 0) R4 -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N (R6) S02NY Y2, -OR4 , -OCF2H, -OCF3, -OC (= 0) R4, -00 (= 0) ???? 2, -S (0) NR4, -8 (0) ????? 2 or -S (0) NOR4 and R3 represents alkyl, haloalkyl, halogen and OR6; or groups R2 and R3 in adjacent carbon atoms can form a ring based on 5 to 6 member carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, and which may be be optionally substituted with alkyl; -853- R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituents selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -C (= 0 ) NY3Y4, -C (= 0) OR6 -N (R6) C (= 0) Y1 Y2, -? 1? 2. -OR5 or alkyl substituted with -3 34 4R5 is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R6 is chosen from the values of R5; n is zero or an integer 1 or 2; Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted with one or more groups selected from cyano, aryl, heteroaryl, hydroxy, -C (= 0) OR6, -C (= 0 ) NY3Y4, -? 3? 4 or _OR5, OR the group - ?? 1? 2 can form a cyclic amine; Y3 and Y4 are independently hydrogen, alkynyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY3Y4 can form a cyclic amine; all the alkyl, alk, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl radicals present in the above radicals are further optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, alkyl, alkoxy radicals , acylamino, (NH-COalk), -C (= 0) OR6, -C (= 0) R6, hydroxyalkyl, car- -854- boxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) n-N (alk) 2, CF3, OCF3, N02, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3Y4 and ?? 3? 4 > these latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more radicals selected from halogen atoms and alkyl radicals, free carboxyl radicals, salified or esterified and acylamino radicals NH-C (0) R5; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound; or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 4.- A compound of formula (Ix) wherein X represents C-R ^ and W, Y and Z, which may be the same or different, represent CH or CR3; or W represents CH, X represents N, Y represents CH or CR3, and Z represents CH or CR3; or W represents N, X represents CH or CR2, Y represents CH and CR3, and Z represents CH or CR3; or 855- W represents N, X represents CH or CR2, Y represents, and Z is CH or CR3; or W represents N, X represents CH or CR2, Y represents CH or CR3, and Z represents N; or W represents N, X represents N, Y represents CH or CR3, and Z represents CH or CR3; A5 represents H or alkyle; R1 is a pyrazolyl radical which R7 hydrogen or alkyl, and R8 and R9 are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) 0R4 -1 ^ 6) ^ = 0 ^ 4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) 0R4 -N (R6) S02R4,. -N (R6) S02NY1Y2, -NY ^ Y2, -OR4, -OC (= 0) R, -OC (= 0) NY Y2, -S (0) NR4 V -S (0) 2NY1Y2; or R8 and R9 together with the carbon atoms to which they are attached form (i) a 5- to 8-membered carbocyclic ring optionally substituted with one or more carbocyclic ring substituents; (I) a phenyl ring optionally substituted with one or more substituents of aryl groups; (iii) a 5- or 6-membered heteroaromatic ring in which one or more ring members is / are nitrogen, oxygen or sulfur and which is optionally substituted with one or more groups selected from haloalkyl, hydroxy, halo, cyano, nitro, R4, -C (= 0) NY ^ Y2, -N (R6) C (= 0) R4 -N (R6) C (= 0) NY1Y2, -N (R6) S02R4, - ?? 1? 2 and -OR5; or (iv) a -856- 5- or 6-membered heterocyclic ring optionally substituted with alkyl or oxo, and containing a group containing heteroatoms selected from O, S, S02 or NY5, where Y5 is hydrogen, R4, -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) OR4 or -SO2R4; R2 and R3 are such that: R2 and R3, which may be the same or different, represent H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4 -C (= 0) NY1Y2, -C (= 0) OR4 - ??? 2, -N (R6) C (= 0) R4, -N (R6) C (= 0) Y1Y2 -N (R6) C (= 0) 0R4 -N ( R6) S02R4, -N (R6) S02NY1Y2, -OR4, -OCF2H, -OCF3, -OC (= 0) R4 -OC (= 0) NYlY2, -S (0) NR4, -S (0) nNYlY2 or -S (0) NOR4; or R2 represents H, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4 -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) OR4, - ???? 2, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N (R6) S02NY1Y, - OR4 -OCF2H, -OCF3, -OC (= 0) R4, -00 (= 0)? 1? 2 -S (0) NR4, -S (0) nNYlY2 or -S (0) NOR4 and R3 represents alkyl; haloalkyl, halogen and OR6; or groups R2 and R3 in adjacent carbon atoms can form a ring based on 5 to 6 member carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, and which may be be optionally substituted with alkyl; R 4 is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, each optionally substituted with one or more substituted -857- and selected from alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, halo, hydroxy, hydroxyalkyl, -C (= 0) NY3Y4, -C (= 0) OR6, -N (R6) C (= 0) NY1Y2, -NY Y2. -OR5 or alkyl substituted with -NY3Y4; R5 is alkyl, alkenyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R6 is chosen from the values of R5; n is zero or an integer 1 or 2; Y1 and Y2 are independently hydrogen, alkenyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or alkyl optionally substituted with one or more groups selected from cyano, aryl, heteroaryl, hydroxy, -C (= 0) OR6, - C (= 0) NY3Y4, -NY3Y4 0 -OR5, or the group _? 1? 2 can form a cyclic amine; Y3 and Y4 are independently hydrogen, alkynyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl; or the group -NY3Y4 can form a cyclic amine; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound; or an N-oxide, prodrug or acid bioisoester of this salt or solvate; with the proviso that the compound is other than 2- (2H-pyrazol-3-yl) -1 H-benzoimidazole; 2- (5-methyl-2H-pyrazol-3-yl) -1H-benzoimidazole; 5-methyl-6- [2- (2H-pyrazol-3-yl) -3H-benzoimidazoI-5-yl] -4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6- [2- (2H-pyrazolo-3-yl) -1 H -benzoimidazol-4-yl] -4,5-dihydro-2H- -858- pyridazin-3-one; 3,5-bis (benzimidazol-2-yl) -1 H-pyrazole; 5,6-dimethyl-2- (5-methy1-1H-pyrazol-3-yl) -1H-benzoimidazole; 6-methyl-2- (5-methyl-1 H-pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dichloro-2- (5-methyl-1 H -pyrazol-3-yl) -1H-benzoimidazole; 5-nitro-2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (5-methyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dimethyl-2- (5-phenyl-1H-pyrazol-3-yl) -1H-benzoimidazole; 5-methyl-2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-chloro-2- (5-methyl-1 H -pyrazol-3-yl) -1H-benzoimidazole; 5-chloro-2- (5-phenyl-1 H-pyrazol-3-yl) -1 H-benzoimidazole; 5,6-dichloro-2- (5-phenyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; N- [2- (5-isoquinolin-4-yl-1 H -indazol-3-yl) -3H-benzoimidazol-5-yl] -methanesulfonamide; 3- (1 H-benzoimidazol-2-yl) -5- (1 H-indazol-4-yl) -1 H-indazole, 3- [3- (1 H-benzoimidazoI-2-yl) -1 H- indazol-5-yl] -2-methoxyphenol; 4- [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-5-yl] isoquinoline; 4-. { 3- [6- (4-Methyl-piperazin-1-yl) -1 H -benzoimidazol-2-yl] -1 H -indazol-5-yl} -isoquinoline; 4- [3- (4-chloro-1 H -benzoimidazol-2-yl) -1 H -indazol-5-yl] -isoquinoline; 4- [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenol; 3- [5- (4-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -1 H-indazoi; 3- [5- (4-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -1 H-indazole; 3- [5- (3-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -1 H-indazole; 3- (1 H-benzoimidazol-2-yl) -5-phenyl-1 H-indazole; 2- (4-bromo-1-methyl-1 H-pyrazol-3-yl) -1 H-benzoimidazole; 2- (5-ert-Butyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 3- (1 H-benzoimidazoI-2-yl) -6- (3-methoxy-phenyl) -1 H -ndazole; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid; 5- methyl acid ester. { [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -amino} -2-hydroxy-benzoic; 5- methyl acid ester. { [3- (1H- benzoimidazol-2-yl) -1H-indazole-6-carbonyl] -amino} -furan-2-carboxylic; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (3-hydroxy-4-methoxy-phenyl) -amide; (3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (5-hydroxy-1H-pyrazol-3-yl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H-indazoI-6-carboxylic acid (1 H-pyrazol-3-yl) -amide; [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] - [4- (2-hydroxy-ethyl) -piperidin-1-yl] -methanone; 3- (1 H -benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (9H-purin-6-yl) -amide; 3- (1 H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid dimethylamide; [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-yl] -morpholin-4-yl-methanone; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid pyrazin-2-ylamide; 3- (1 H-benzoimidazoI-2-yl) -1 H-indazole-6-carboxylic acid cyclohexylamide; (1 H-indazol-5-yl) -amide of acid 3- (1 H-benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid; [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-yl] -pyrrolidin-1-yl-methanone; (1 H-indazol-5-yl) -amide of 3- (1 H -benzoimidazoi-2-yl) -1 H -indazole-6-carboxylic acid; [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] - [4- (furan-2-carbonyl) -piperazin-1-yl] -methanone; [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] - (4-methyl-piperazin-1-yl) -methanone; l-. { 4- [3- (1 H-benzoimidazole-2-ii) -1 H-indazole-6-carbonyl] -piperazin-1-yl} -etanone; (3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (6-methoxy-pyridin-3-yl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (3-hydroxy-phenyl) -amide; 3- (1 H-benzoimidazol-2-yl) -1 H-indazoI-6-carboxylic acid pyridin-4-ylamide; 3- (1 H -benzoimidazoi-2-yl) -1H-indazole-6-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (2-hydroxy-ethyl) -methyl-amide; ethyl ester of acid -860- 3-. { [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -amino} -butyric; 3- (1 H -benzoimidazoi-2-yl) -1 H -indazole-6-carboxylic acid (3-hydroxy-propyl) -amide; 3- (1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid fe-nylamide; 3- (1 H -benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid pyridin-3-ylamide; 3- (6-methoxy-1 H-benzoimidazole-2-yl) -1 H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1 H-benzoimidazoI-2-yl) -6-pyridin-4-yl-1 H-indazole; 3- (5-Chloro-1H-benzoimidazol-2-yl) -1H-indazoI-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-Dimethoxy-1 H-benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5-Fluoro-1 HibenzoimidazoI-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phene) -amide; 3- (6-Trifluoromethyl-1 H-benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (6-C6-Butyl-1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (6,7-Dimethyl-1H-benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-dichloro-1 H-benzoimidazole-2-ii) -1 H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (5,6-difluoro-1 H -benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (3-fluoro-4-hydroxy-phenyl) -amide; 3- (1 H -benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid amide; 3- (1 H -benzoimidazol-2-yl) -1 H -indazole-6-carboxylic acid (4-hydroxy-2,3-dimethyl-phenyl) -amide; 3- (1H-Benzoimidazol-2-yl) -1H-indazole-6-carboxylic acid (4-hydroxy-2-methyl-phenyl) -amide; 3- (1 H -benzoimidazoI-2-yl) -1 H-indazole-6-carboxylic acid (4-hydroxy-phenyl) -amide; 3- (1 H-benzoimidazol-2-yl) -1 H-indazole-6-carboxylic acid cyclopropylamide; acid amide 2- [6- (4- -861- hydroxy-2-methoxy-phenyl) -1 H -indazol-3-yl] -3H-benzoimidazole-5-sulfonic acid; 4- [3- (6-dimethylamino-1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -3-methoxy-phenol; 2- [6- (4-hydroxy-2-methoxy-phenyl) -1H-indazol-3-yl] -3H-benzoimidazoI-5-carboxylic acid methylami-da; 3-methoxy-4-. { 3- [6- (4-Methyl-piperazin-1-yl) -1 H -benzoimidazol-2-yl] -1H-indazol-6-yl} -phenol; 2- [6- (4-Hydroxy-2-methoxy-phenyl) -1 H -indazol-3-yl] -3H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 4- [3- (1 H -imidazo [4,5-c] pyridin-2-yl) -1 H -indazol-6-yl] -3-methoxy-phenol; 3- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -2-methyxy-phenol; 3- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -phenol; 4- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -3,5-dimethyl-phenol; 4- [3- (1 H -benzoimdazol-2-yl) -1 H -indazol-6-ii] -3-phenoxy-phenol; 4- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -benzene-1,3-diol; 4- [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-yl] -3-methoxy-phenol; 4- [3- (1 H -benzoimidazol-2-yl) -1 H -indazol-6-yl] -2-methoxy-phenol; N-. { 3- [3- (1 H-benzoimidazol-2-yl) -1 H -indazol-6-carbonyl] -phenyl} -benzamide; 6- [2- (1, 5-dimethyl-1 H -pyrazol-3-yl) -3H-benzoimidazol-5-yl] -5-methyl-4,5-dihydro-2H-pyridazin-3-one; 5-methyl-6- [2- (1-methyl-1 H -pyrazol-3-yl) -3H-benzoimidazol-5-yl] ^ 4,5-dihydro-2H-pyridazin-3-one; 8- (1, 5-dimethyl-1 H -pyrazol-3-yl) -7H-purine; 2- (1, 5-dimethyl-1 H -pyrazol-3-yl) -1 H -imidazo [4,5-b] pyridine and 2- (5-methyl-1 H -pyrazol-3-y!) - 1 H-imidazo [4,5-b] pyridine. 5. - A compound according to claim 3, wherein R is optionally substituted heteroaryl: 6. A compound according to claim 5, in the. that R1 is dihi-drofuropyrazolyl, imidazolyl, indazolyl, indolyl, isoxazolyl, oxodihydropyridazinyl, oxodihydropyridinopyrazolyl, oxodihydropyridinyl, oxotetrahydropyrrolopyra- -862- optionally substituted zolyl, pyrazolyl, thiazolyl, thienopyrazolyl, tetrahydrocyclopentapyrazolyl, tetrahi-droindazolyl, tetrahydropyranopyrazolyl, tetahydropyridinopyrazolyl, tetrahydropyrrolopyrazolyl or triazolyl. 7 - A compound according to claim 5, wherein heteroaryl is optionally substituted with one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R 4 -C (= 0) R 4, -C ( = 0) NY1Y2 -C (= 0) OR4, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY Y2, -N (R6) C (= 0) OR, - N (R6) S02R4, -N (R6) S02NY Y2, -NY Y2, -OR, -OCF2H, -OCF3, - OC (= 0) R4, -OC (= 0) NY1Y2, -S (0) NR and -S (0) 2NY1 Y2. 8. A compound according to claim 6, wherein dihidrofu-ropirazolilo, midazolilo, indazolyl, indolyl, isoxazolyl, oxodihidropiridazinilo, oxodiliidropiridinopirazoliio, oxodihydropyridinyl, oxotetrahidropirrolopirazolilo, pyrazolyl, thiazolyl, tienopirazolilo, tetrahidrocicíopentapirazolilo, tetrahidroinda-zolilo, tetrahidropiranopirazolilo, tetahidropiridinopirazolilo, tetrahydropyrrolopy-razolyl or triazolyl are optionally substituted with one or more groups selected from carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0 ) OR, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) 0R4, -N (R6) S02R4, -N (R6) ) S02NY1 Y2, -NY ^ Y2, -OR, -OCF2H, -OCF3, -OC (= 0) R4, -OC (= 0) NY1Y2, -S (0) NR4 and -S (0) 2NY1Y2. -863- wherein it is hydrogen or alkyl, and R ^ and R9 are independently selected from hydrogen, carboxy, cyano, halo, haioaikyl, hydroxy, nitro, R4 -C (= 0) R4 -C (= 0) NY1Y2, -C ( = 0) OR4, -N (R6) C (= 0) R4 -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N ( R6) S02NY1Y2, - ???? 2, -OR4, -OC (= 0) R4 -OC (= 0) NY1Y2, -S (0) NR4 and -S (0) 2NY1Y; O ' R8 and R9 together with the carbon atoms to which they are attached form (i) a 5- to 8-membered carbocyclic ring optionally substituted with one or more carbocyclic ring substituents; (ii) a phenyl ring optionally substituted with one or more substituents of aryio groups; (iii) a 5- or 6-membered heteroaromatic ring in which one or more ring members is / are nitrogen, oxygen or sulfur and which is optionally substituted with one or more groups selected from haioaikyl, hydroxy, halo, cyano, nitro, R4, -C (= 0) NY1 Y2, -N (R6) C (= 0) R4 -N (R6) C (= 0) NY1Y2, -N (R6) S02R4, -NY1Y2 and -OR5; or (iv) a 5- or 6-membered heterocyclic ring optionally substituted with alkyl or oxo, and containing a group containing heteroatoms selected from O, S, S02 or NY5, wherein Y5 is hydrogen, R4, -C (= 0 ) R4 -C (= 0) NY1Y2, -C (= 0) OR4 or -S02R4- 10. A compound according to any one of claims 3 to 9, wherein W is CH; X is CR2; And it is CH or CR3; and Z is CH or CR3- -864- 11. - A compound according to any one of claims 3 to 9, wherein W is CH; when X is N; And it is CH or CR3; and Z is CH or CR3. 12. - A compound according to any one of the claims 3 to 9, wherein W is N; X is CH or CR2; And it is CH or CR3; and Z is CH or CR3. 13. - A compound according to any one of the claims 3 to 9 in which W.es N; X is CH or CR2; And it is CH or CR3; and Z is N. 14. - A compound according to claim 3 of formula (Ixa) (Ixa) wherein R7 is hydrogen or alkyl; R8 and R9 are independently selected from hydrogen, carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4, -C (= 0) NY1Y2, -C (= 0) OR4, -N ( R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2 -N (R6) C (= 0) OR4, -N (R6) S02R4, -NY1Y2, -OR4 -OC (= 0) R4 -OC (= 0) NY1Y2, -S (0) NR4 and -S (0) 2NY1Y2; Or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound; or an N-oxide, prodrug or acid bioisoester of this salt or solvate. -865- 15. - A compound according to claim 14, wherein W is CH; X is CH, Y is CH; and Z is CH or C-CH3. 16. - A compound according to claim 14, wherein W represents CH; X represents CH; Z represents CH; and Y represents C-alkyl C-j. 4; C-aryl; C-CN; C-NO2; C-halo; C-haloalkyl; C-heteroaryl; C-OR4; C- C (= 0) R4; C-C = 0) NY1Y2; C-C (= 0) OR4; C-NHC (= 0) R4; C-CH (OH) aryl; C-S (0) 2NY1Y2; O C-S (0) NR4 17. A compound according to claim 16 wherein Y represents C-CH3, C-CH2CH3. C-CH2CH2CH3, C-CH (CH3) 2, -866- C-C (= 0) - I-CH (CH 3) 2 C-C (= 0) -NH-C (CH 3) 2 -CH 2 OH > C-C (= 0) -NH-CH2CH2CN 'C-C ^ -NH-CH ^ IL C ^' C (= 0) OCH3, C-NHC (= 0) CH3, C-NHC (= 0) CH (CH3) 2, or C-S02CH3. 18. A compound according to claim 14, wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-CI, and Z represents CH. 19. A compound according to claim 14, wherein W represents CH; X represents CH; Y represents C-CH3; and Z represents C-CH3. 20. - A compound according to claim 14 in which W represents CH 2; X represents CR; and Y represents CR, wherein R and R form the group -CH2-0-CH2; and Z represents CH. 21. - A compound according to claim 14, wherein W re¬ presents CH; X represents CR ^; And represents CR ^, where R ^ and R3 for¬ man the group -CH2-CH2-CH2-; and Z represents CH. 22. - A compound according to claim 14, wherein it represents hydrogen. 23. - A compound according to claim 14, wherein R8 represents hydrogen, C1.4 alkyl, -SR ^, - Y ^ Y ^ or -OR ^. 24. - A compound according to claim 14 wherein R8 re¬ it presents hydrogen, CH3, CH2CH3, CH (CH3) 2 or CH (CH3) CH2CH3; -868- or -OCH2CH3. 25. - A compound according to claim 14, wherein R re¬ it presents hydrogen, C1-7 alkyl, aryl > -C (= 0) NY Y2, -N (R6) C (= 0) R4, in don¬ of R 4 is alkyl optionally substituted with aryl, cycloalkyl, heteroaryl, heterocycloalkyl, or wherein R4 is NY ^ Y2 or -OR5, O wherein R4 is aryl, or wherein R 4 is cycloalkyl, or wherein R 4 is heteroaryl, or wherein R 4 is heterocycloalkyl; or R9 represents -N (R6) C (= 0) NY1Y2, -NY1Y2, or alkyl substituted with -N (R6) C (= 0) NY1Y2. 26. - A compound according to claim 14, wherein R9 re¬ presents hydrogen, -CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2-CH2-CH (CH3) 2, phenyl, - C (= 0) - H-CH2CH3 > - C (= 0) - H-CH2CH2CH3 = - 0 (= 0) -? -a¾ €? (A? 3) 2, - C (= 0) - H-CH (CH3) 2, - C (= 0) -OTÍ-C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH? - CC ^ HSIH-CH ^ OCE ^ > - C (= 0) -N (CH3) 2 » | C (= 0) -N (C¾CH3) 2 »-C (= 0) - H- ^ | , - C (= 0) - NH-C (= 0) -CH (CH3) 2, - NH-C (= 0) -C (CH3) 3, - NE-C (= 0) -CH2CH (CH3) 2 = - HC (= 0 ) -CH (CH3) CH2CH3 > - NH-C (= 0) -CH2C (CH3) 3 > C (= 0) -CH2 -869- - NH-C (= 0) -NHCH (CH 3) 2 '- NH-C (= 0) -NHCH 2 CH (CH 3) 2' - NH-C (= 0) -NHC (CH 3) 3 '- NH-C ( = 0) -N (CH3) 2 '- NH-C (= 0) -N (CH2CH3) 2, , -870- H3) 2 o. -CI¾-NH-C (== 0) -N O 27. A compound according to claim 14 wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; R8 represents hydrogen, C- | _4 alkyl, -SR4, -? 1? 2; Y R9 represents hydrogen, C-alkyl. , aryl, -C (= 0) NY1Y2, - N (R6) C (= 0) R4, particularly -NHC (= 0) R4, -N (R6) C (= 0) NY Y2, -NY1Y2, or alkyl substituted with -N (R6) C (= 0) NY1Y2. 28. A compound according to claim 14, wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; R ^ represents hydrogen, CH3, CH2CH3, CH (CH3) 2, CH (CH3) CH2CH3], -S-CH3 »-s- a¾a¾ Q -s- OE¾ > - S - CH - - - OCH3 > - S- CH2-CH- v \ -871- , -OCH2CH3; and R9 represents hydrogen, -CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2-CH2-CH (CH3) 2, phenyl, -C (= 0) -NH-CH2CH3, -CÍ ^ -NH-CJ ^ CB ^ CH, > - C (= 0) - H-CH2CH (CH3) 2 > - C (= 0) -NH-CH (CH3) 2, - C ()) - -C (CHj) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) - NH-CH2CH2OCH3 »- C (= 0) -N (CH3) 2» - NH-C (= 0) - C (CH3) 3, - H-C (= 0) - C¾CH (CH3) 2, -872- , -NH2, -CH2-NH-C (= 0) -CH (CH3) 2 or -CH2-NH-C (= 0) -N O. 29. - A compound according to claim 14 wherein W represents CH; X represents CH; Z represents CH; Y represents C-C 1-4 alkyl, C-aryl, C-CN, C-NO 2, C-halo, C-haloalkyl, C-heteroaryl, C-OR 4, C-C (= 0) R 4, C-C = 0) NY 1 Y 2 > C-C (= 0) OR 4 or C-CH (OH) aryl; R8 represents hydrogen, C-j ^ alkyl, -SR4, -NY Y2 or -OR5 and R9 represents hydrogen, alkyl C-, j, aryl, -C (= 0) NY Y2, N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -NY1Y2, or alkyl substituted with N (R6) C (= 0) NY1Y2. -873- 30. - A compound according to claim 14, wherein W represents CH; X represents CH; Z represents CH; And represents C-CH3, r, C-Cl or C-F, C-CF3, c- N, C- / C-OCH, -OCH2CH3 C- C (= 0) -N (CH3) 2, C- CÍ ^ -NH-CELJCBLJ > C-C (= 0) -NH-CH (CH 3) 2 C -C (= 0) -NH-C (CH 3) 2 -CH 2 OH > C- C (= 0) -NH-CH2CH2CN » C-C (= 0) - H-CH2- ^ ^ ^ CH3, C-C ^ -NH-CH.- ^^), -874- C-C (= 0) OCH3, C-NHC (= 0) CH3 or C-NHC (= 0) CH (CH3) 2, C-CH (OH) - > C-SO, - H-CH or C-SO2CH3; R7 repre¬ sat hydrogen; R ^ represents hydrogen, CH3, CH2CH3, CH (CH3) 2, CH (CH3) CH2CH3], -S- CH 3.. -S-CH-CH- or -S-CH; represents hydrogen, -CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2-CH2- CH (CH 3) 2, phenyl, - C (= 0) -NH-CH 2 CH 3. - C (= 0) - H-CH2CH2CH3-C (= 0) -NH-CH2CH (CH3) 2 > - C (= 0) - H-CH (CH 3) 2, - C (= 0) -NH-C (CH 3) 3, - C (= 0) -NH-C (CH 3) 2 CH 2 OH, - C (= 0 ) -NH-CH2C¾OCH3 »- C (= 0) -N (CH3) 2 > -C (= 0) - (CH2CH3) 2. - C (= 0) -NH -C (= 0) -NH-CH, -875- - HC (= 0) -CH3, - NH-C (= 0) - (CH ^ CE ^, - NH-C (= 0) -NH-C (= 0) -C (CH3) 3, - NH- C (= 0) ~ CH2CH (CH3) 2, -NH-C (= 0) -CH (CH3) CH2CH3 > - MÍ-C (= 0) -CH2C (CH3) 3 > -876- -NH-C (= 0) -NHCH (CH3) 2'-NH-C (= 0) -NHCH2CH (CH3) 2 '-NH-C (= 0) -NHC (CH3) 3' - NH-C ( = 0) -N (CH3) 2 '- NH-C (= 0) -N (CH2CH3) 2, -NH-C (= 0) -NH -NH-C (= 0) -NH-CH -NH-C (= 0) -N ^ ' / \ -NH2, -CH2-NH-C (= 0) -CH (CH3) 2 or. -CI¾-NH-C (= 0) -N O 31. - A compound according to claim 14 wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-CI, C-F, Z represents CH; represents hydrogen; R8 represents hydrogen, alkyl C-j.4, -SR4, -NY1Y2, or -OR5; Y R9 represents hydrogen, C- alkyl; _7, aryl, -C (= 0) NY1Y2, - N (R6) C (= 0) R4 -N (R6) C (= 0) NY1Y2, -NY Y2, O alkyl substituted with -N (R6) C (= 0) NY1Y2. 32. - A compound according to claim 14, wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C- CH (CH3) 2, CH (CH3) CH2CH3], -S-CH ^ -S-CH2CH3 or , -CH3, CH2CH2CH3) -CH (CH3) 2, -CH2-CH2-CH (CH3) 2, phenyl, - C (= 0) -NH-CH (CH3) 2, - C (= 0) -NH-C (CH3) 3, - C ^ -OT-CCCH ^ CE ^ OH, - C (= 0) -MÍ -CH2CH2OCH3 »-C (= 0) -N (CH3) 2» -C (= 0) -N (CH2CH3) 2 > - HC (= 0) -CH3, - NH-C (= 0) - (CH2), CH3, - NH-C (= 0) -CH (CH3) 2, - NH-C (= 0) -C ( CH3) 3, - NH-C (= 0) -CH2CH (CH3) 2, - NH-C (= 0) -CH (CH3) CH2CH3 - NE-C (= 0) -CH2C (CH3) 3 || > - H-C (= 0) -CH. -878- -NH-C (= 0) -NHCH (CH3) 2 > - NH-C (= 0) - HCH2CH (CH3) 2 > -NH-C (= 0) ~ NHC (CH3) 3 > - H-C (= 0) -N (CH3) 2 »- HH-C (= 0) - (GH2Ca¾) 2 -NH-C (= 0) -NH- -NH-C (= 0) -NH-CH -NH2, -CH2-NH-C (= 0) -CH (CH3) 2 -CI¾-NH-CX = 0) - O 33. - A compound according to claim 14, wherein W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; R8 represents hydrogen, C1.4 alkyl, -SR4, -NY1Y2 or -OR5; and, R9 represents hydrogen, C_j alkyl, aryl, -C (= 0) NY1Y2; - N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2 -NY1Y2, or alkyl substituted with -N (R6) C (= 0) NY1Y2 34. - A compound according to claim 14, wherein W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; R8 represents hydrogen, CH3, CH2CH3, CH (CH3) 2, CH (CH3) CH2CH3, or S CH3 -S-CH2- < ^ - 8 80- represents hydrogen, -CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2-CH2-CH (CH3) 2j f nilO, -C (= 0) - H-CH2C¾CH3, -C (= 0) ~ MI-C¾CH (CH3) 2 »- C (= 0) -NH-CH (CH3) 2 J - C (= 0) -NH-C (CH3) 3, - C (= 0) -Mí-C (CH3) 2CH20H 5 - C (= 0) -NH-CH2CH2OCH3 »-C (= 0) -N (CH3) 2 > C (= 0) -N (CH2CH3) 2, - C (= 0) C (= 0) -NH -NH-C (= 0) -CH3, - NH-C (= 0) - (CH2) 2CH3, - NH-C (= 0) -CH (CH3) 2, - HC (= 0) -C (CH3 ) 3, - NH-C (= 0) -CH2CH (CH3) 2, -NH-C (= 0) -CH (CH3) C¾CH3 »- NH-C ^ -CH ^ CH ^» - 881- - NH-C (= 0) -NHCH (CH3) 2 > - NH-C (= 0) -NHCH 2 CH (CH 3) 2 '- NH-C (= 0) -NHC (CH 3) 3' - NH-C (= 0) - N (CH 3) 2 '- NH-C ( = 0) -N (CH2CH3) 2, - H-C (= 0) - H- < ^, - H-C (= 0) -NH-CH2 NH-C (= 0) -N 0 = -NH2, -CH2-NH-C (= 0) -CH (CH3) 2 or. - OB-j-NH-C (= 0) -N 35. - A compound according to claim 14 wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; -882- R7 represents hydrogen; R8 represents hydrogen, C1.4 alkyl, -SR4, -NY1Y2, or -OR5; Y R9 represents hydrogen, C-j_7 alkyl, aryl, -0 (= 0)? 2; - N (R6) C (= 0) R4, -N (R6) C (= 0) NY Y2, -NY1Y2, or alkyl substituted with -N (R6) C (= 0) NY1Y2. 36. - A compound according to claim 14, wherein W re¬ presents CH; X represents CR2 and Y represents CR ^ where R2 and R ^ for¬ man the group -CH2-O-CH2-; Z represents CH; R7 represents hydrogen; R8 represents hydrogen, CH3, CH2CH3, CH (CH3) 2, , -OCH2CH3; and R9 represents hydrogen, -CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2-CH2-CH (CH3) 2j phenyl, - C (= 0) - H-CH2CH2C¾, - C (= 0) -NE-CH2CH (CH3) 2, - C (= 0) - H-CH (CH3) 2, - C (= 0) -NH-C (CH3) 3, - - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) -NH-CH2CH2OCH3 »- C (= 0) -N (CH3) 2, - C (= 0) -N (C¾CH3) 2. - C (= 0) - II- < ], - C (¾-NH-C] ¼-- <], - NH-C (= 0) -CH3, - NH-C (= 0) - (CH2) 2CH3, - NH-C (= 0) -CH (CH3) 2 -NH-C (= 0) -C ( CH3) 3, - NH ^ C (= 0) -CH2CH (CH3) 2, -883- -NH-C (= 0) -CH (CH3) CH2CH3 »- NH-C (= 0) - CH ^ CH ^ > - NH-C (= 0) - HCH (CH3) 2, - Mi-C (= 0) - HCH2CH (CH3) ¿> - H-C (= 0) -NHC (CH 3) 3, - NH-C (= 0) -N (CH 3) 2, - H-C (= 0) -N (CH 2 CH 3) 2 - H-C (= 0) -NH- < ^, - Mi-C (= 0) -NH-CH2- < ], - 884- - NH-C (= 0) -N ^ O ' -NH2, -CH2-NH-C (= 0) -CH (CH3) 2 or - 37. - A compound according to claim 14 wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R represents hydrogen; R8 represents hydrogen, alkyl -SR4, -NY1 Y2, or -OR5; Y R9 represents hydrogen, alkyl aryl, -C (= 0) NY1Y2, - N (R6) C (= 0) R4, -N (R6) C (= 0) NY Y2, -NY Y2 or alkyl substituted with - N (R6) C (= 0) NY1Y2. 38. - A compound according to claim 14, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; represents hydrogen; -885- represents hydrogen, CH3, CH2CH3, CH (CH3) 2, CH (CH3) CH2CH3, -S-CH3, -S- CH2CH3 -S- C¾ represents hydrogen, -CH3, -CH2CH2CH3, -CH (CH3) 2, -CH2-CH2 - ?? (?? 3) 2, phenyl, - C (= 0) -NH-CH2CH2CH3, - C (= 0) - H-CH2CH (CH3) 2, - C (= 0) -NH-CH (CH3) 2, - C (= 0) - H-C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) -NH-CH2CH2OCH3, - C (= 0) -N (CH3) 2, C (= 0) -N (CH2CH3) 2, -C (= 0) -NH- |; -C (= 0) -NH-C¾ - NH-C (= 0) -CH3, - NH-C (= 0) - (C¾) 2CH3, - NH-C (= 0) -CH (CB3) 2, - MH-C (= 0) -C (CH 3) 3, - NH-C (= 0) -CH 2 CH (CH 3) 2, - NH-C (= 0) ^ CH (CH3) CH2CH3, - H-C (= 0) -CH2C (CH3) 3, , -886- - NH-C (= 0) - HCH (CH3) -MI-C (= 0) -NHCH2CH (CH3) 2. NH-C (= 0) -NHC (CH3) 3 > - NH-C (= 0) -N (CH3) 2. - NH-C (= 0) -N (CH 2 CH 3) 2, - H-C (= 0) - H-NH-C (= 0) -NH-CH; -887 - -NH2, -CH2-NH-C (= 0) -CH (CH3) 2 or -CIL-NH-C (= 0) -N 0 - \ / 39 - A compound according to claim 14, wherein R8 is hydrogen or -CH3; and R9 is -CH2-CH2-CH (CH3) 2, - C (= 0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2CH3, - C (= 0) -NH-CH (CH3) 2, - C (= 0) -NH-C (CH3) 3, - C (= 0) -NH-C (CH3) 2CH2OH, - C (= 0) -NH- - 0 (? 3)? ^ - < ¾ (¾? A¾, - C (= 0) -N (CH3) 2, - C (= 0) -N (CH2CH3) 2, - NH-C (= 0) -CH (CH 3) 2, - NH-C (= 0) -C (CH 3) 3, - I-C (= 0) -C¾CH (CH 3) 2, - NH-C (= 0) - H (CH3) CH2CH3, - NH-C (= 0) -CH2C (CH3) 3, , - NH-C (= 0) -CH2- -NH-C (= 0) -NHCH (CH3) 2. - H-C (= 0) - HC (CH3) 3 · - H-C (= 0) -N (CH3) 2, - NH-C (= 0) -N (CH2CH3) 2, - H-C (= 0) -MÍ ^ ¡, -889- -CH2-NH-C (= 0) -CH (CH3) 2 or _CHr H-C (= 0) -N ^ O · 40. - A compound according to claim 14, wherein it represents hydrogen and represents -CH (CH3) 2, - S - CH3, -S- CH2CH3 ^ - S- CH 41. - A compound according to claim 14, wherein W is CH; X is CH; C-C (= 0) -NH-CH (CH 3) 2, C-C (= 0) -NH-C (CH 3) 2 -CH 2 OH, C- C (= 0) -NH-CH2CH2CN, C-C (= 0) - H-CH2CH2OCH3, -890- C-SO2CH3 or C-SOrNH //; and Z is CH. -891- 42. - A compound according to claim 14, wherein W is CH; X is C-CH3 or C-CH2CH3; And it is 43. - A compound according to claim 14, wherein W is CH; X is C-OCH3; Y is CH, C-CH3, C-CH2CH3, C-CI or C-OCH3; and Z is CH. 44. A compound according to claim 14, wherein W is CH; X is C-OCH2CH3; And it's C-F; and Z is CH. 45.- A compound according to claim 14, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; and Z represents CH. 46. - A compound according to claim 14 wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-0-CH2-; and Z represents CH. 47. - A compound according to claim 14, wherein R8 is hydrogen or -CH3; Y R9 is - C (= 0) -NH-CH2CH3, - C (= 0) -NH-CH2CH2C¾, - C (= 0) - H-CH (CH3) 2, -892- -C (= 0) -NH-CH2CH (CH3) 2, - C (= 0) - H-C (CH3) 3, -C (= 0) -NH-C (CH3) 2CH2OH, -C (= 0) -N (CH2CH3) 2, -C (= 0) - H - NH-C (0) - (CH ^ CHj, -C (= 0) -CH (CH3) 2 -NH-C (= 0) -C (CH3) 3, - NH-CC ^ -CE ^ CHCCHj),, -NH-C (= 0) -CH (CH3) CH2CH3 -NH-CC ^ -CH ^ CCC ^, -NH-C (= 0) -CH2- -893- -NH-C (= 0) -NHCH2CH,, - NB-C (= 0) -NHCH (CH) > - H-C (= 0) - H - MH-C (= 0) -NH-CH: 48. - A compound according to claim 14, wherein W is CH; X is CH; And it is 49. - A compound according to claim 14, wherein W is CH; X is C-OCH2CH3; And it is C-CI or C-F; and Z is CH. 50. - A compound according to claim 14, wherein W is CH, X is C-OCH3; Y is C-CH3, C-CH2CH3, C-Cl, C-F, or C-OCH3; and Z is CH is CH; X is 51. A compound according to claim 14, wherein W C-OCH 2 CH 3; And it is C-Cl or C-F; and Z is CH. 52. - A compound according to claim 14 wherein W represents CH; X represents CR2 and Y represents CR ^ wherein and R3 form the group -CH2-CH2-CH2-; and Z represents CH. 53. - A compound according to claim 14 wherein W repre¬ I felt CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the -CH2-O-CH2- group; and Z represents CH. 54. - A compound according to claim 3, of formula (Ixb) in which -895- R7 is hydrogen or alkyl; R1 ° is carboxy, cyano, halo, haloalkyl, hydroxy, nitro, R4, -C (= 0) R4 -C (= 0) NY''Y2i -C (= 0) OR4, -N (R6) C (= 0) R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -N (R6) S02R4, -N (R6) S02NY1Y2, -NY1Y2, -OR4 -OCF2H, -OCF3, -OC (= 0) R4 -OC (= 0) NY1Y2, -S (0) nR4 or -S (0) 2NY1Y; And p is zero, or an integer 1; and a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 55. A compound according to claim 54, wherein W represents CH; X represents CH; And represents CH; and Z represents CH or C-CH3 56. - A compound according to claim 54, wherein W represents CH; X represents CH; Z represents CH; and Y represents C-alkyl Ci_ 4, C-aryl, - C-CN, C-N02, C-halo, C-haloalkyl, C-heteroaryl, C-OR4 C- C (= 0) R4, C-C = 0) NY1Y2, C-C (= 0) OR4, C-NHC (= 0) R4, C-CH (OH) aryl, C-S (0) 2NY1Y, or C-S (0) nR4. 57. A compound according to claim 54 wherein W represents CH; X represents CH; Z represents CH; and Y represents C-CH3, C-CH2CH3. -896- C- C (= 0) -N (CHj) 2, C-C (= 0) -NH-CH2CH3, C-C (= 0) - H-CH (CH3) 2, C-C (= 0) -TSTH-C (CH3) 2-CH2OH, C-C (= 0) -NH-CH2CH2CN, C-C (= 0) -NH-CH2CH2OCH3, -897- C-S02CH3. -898- 58. - A compound according to claim 54 wherein W represents CH; X represents C-CH 3, C-CH 2 CH 3, C-CH (CH 3) 2, C-OCH 3, C-OCH 2 CH 3, C-Br 0 C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C- and Z represents CH. 59. - A compound according to claim 54, wherein W represents CH; X represents CH; Y represents C-CH3; and Z represents C-CH3 60. - A compound according to claim 54, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 for-man the group -CH2-O-CH2-; and Z represents CH. 61. - A compound according to claim 54 wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; and Z represents CH. 62. - A compound according to claim 54 wherein R? re-presents hydrogen. 63. - A compound according to claim 54 wherein p is zero or one. 64. - A compound according to claim 54 wherein R ^ O represents cyano, halo, alkyl -OR4, O -C (= 0) NY1Y2. -899- 65. - A compound according to claim 54 wherein R ^ 0 represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3, -C (= 0) -NH2, - C (= 0) -NHCH (CH3) 2, or -C (= 0) -N (CH3) 2. 66. - A compound according to claim 54 wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; and represents cyano, halo, C- ^ alkyl, -OR4 or -C (= 0) NY1Y2. 67. - A compound according to claim 54 wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; and represents cyano, chloro, fluoro, methyl, -OCH3 or -OCH2CH3, -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2 . 68. - A compound according to claim 54 wherein W represents CH; X represents CH; Z represents CH; Y represents C-alkyl C- | _4, C-aryl, C-CN, C-NQ2, C-halo, C-haloalkyl, C-OR4, CC (= 0) R4, C-C = 0) NY1Y2, - C (= 0) OR4, C-NHC (= 0) R4, CS (0) 2NY1Y2, or CS (0) NR4; R7 represents hydrogen; p is zero or one; and R ^ O represents cyano, halo, C- | _4 alkyl, -OR4, -C (= 0) NY Y2. 69. - A compound according to claim 54 wherein W represents CH; X represents CH; Z. represents CH; And represents C-CH3, -900- C-C (= 0) -NH-C (CH3) 2-CH2OH, C-C (= 0) - H-CH2CH2CN, - 901- C (= 0) OCH3, C-NHC (= 0) CH3 C-NHC (= 0) CH (CH3) 2, C-SO2CH3; R7 represents hydrogen; p is zero or one; R ^ O represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3, -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2. 70. A compound according to claim 54 wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C- -902- OCH2CH3, C-Br 0 C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C- CI, C-F, Z represents CH; R7 represents hydrogen; p is zero or one; and represents cyano, halo, alkyl C-1.4, OR4, or -C (= 0) NY1Y2. 71. - A compound according to claim 54, wherein W re¬ presents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C- Cl, C-F, c; Z represents CH; R7 represents hydrogen; p is zero or one; R10 represents cyano, halo, chlorine, fluoride or, methyl], -OCH3, -OCH2CH3, -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or - C (= 0) -N (CH3) 2. 72. - A compound according to claim 54, wherein W re¬ presents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; p is zero or one; and R10 represents cyano, halo, alkyl C1-4, -OR4 OR C (= 0) NY1Y2. 73. - A compound according to claim 54, wherein W re¬ presents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; p is zero or one; and R1 0 represents cyano, chloro, fluoro, -903-methyl, -OCH3, -OCH2CH3, -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 0 -C (= 0) -N (CH3) 2. 74. A compound according to claim 54, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; represents hydrogen; p is zero or one; and R "1 0 represents cyano, halo, C1..4 alkyl, -OR4, or -C (= 0) NYly2.75.- A compound according to claim 54, wherein W represents CH; X represents CR2 and Y represents CR3 where R2 and R3 form the group -CH2-O-CH2-, Z represents CH, R7 represents hydrogen, p is zero or one, and R ^ O represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3 , -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2. 76. - A compound according to claim 54, wherein W represents CH, X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-, Z represents CH, R7 represents hydrogen, p is zero or one, and R ^ O represents cyano, halo, alkyl C1-4, -OR ^, or -C (= 0) NY1Y2.77.- A compound according to claim 54, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group - CH2-CH2-CH2-; Z represents CH; P7 represents hydrogen; - 904- is zero or one; and represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3, -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3) 2 . 78 - A compound according to claim 54, wherein R7 represents hydrogen and p is zero. 79. A compound according to claim 54, wherein R7 represents hydrogen; p is one; and R1 ^ represents cyano, chloro, fluoro, methyl, -OCH3, -OCH2CH3, -C (= 0) -NH2, -C (= 0) -NHCH (CH3) 2 or -C (= 0) -N (CH3 ) 2-80 - A compound according to claim 54, wherein W is CH; X is CH; And it's CH, C-CH2CH3, CC (= 0) -NH-CH3, CC (= 0) -NH-CH2CH3, CC (= 0) -NH-CH (CH3) 2 CC (= 0) -NH-C (CH3) 2-CH2OH, CC ^ -NH-CH ^ CE ^ CN -905- it's CH 81. - A compound according to claim 54, wherein W is CH; X is C-CH3 or C-CH2CH3; And it is C-CH3, C-CH2CH3, C-CH (CH3) 2, C-Br, C-CI, C-F, C- // and Z is CH. -906- 82. - A compound according to claim 54, wherein W is CH; X is C-OCH3; Y is CH, C-CH3, C-CH2CH3J C-CI or C-OCH3; and Z is CH. 83. - A compound according to claim 54, wherein W is CH; X is C-OCH2CH3; And it's C-F and Z is CH. 84 - A compound according to claim 54, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; and Z represents CH. 85. A compound according to claim 54, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; and Z represents CH. 86. - A compound according to claim 54, wherein R7 represents hydrogen and p is zero. 87. A compound according to claim 54, wherein R7 represents hydrogen; p is one; and R1 0 represents -OCH3, -OCH2CH3 or -C (= 0) -NHCH (CH3) 2 attached to the 5-position of the indazolyl ring. 88. A compound according to claim 54, wherein W is CH; X is C-CH3 or C-CH2CH3; And it is C-CH3 or C-CH2CH3 and Z is CH. 89. - A compound according to claim 3, of formula (Ixc) -907 - wherein R7 is hydrogen or alkyl; is a C5-8 cycloalkyl ring and R12 is acyl, acylamino, alkoxy, alkoxy, coxycarbonyl, alkylenedioxy, alkylsulphinyl, alkylsulfonyl, alkylthio, aroyl, aroylamino, aryl, arylalkyloxy, arylalkyloxycarbonyl, arylalkylthio, aryloxy, aryloxycarbonyl, arylsulfinyl, arylsulfonyl, arylthio, carboxy, or an acid bioisoyester, cyano, cycloalkyl, halo, heteroaroyl, heteroaryl, heteroarylalkyloxy, heteroarylamino, heteroaryloxy, heterocycloalkyl, hydroxy, nitro, trifluoromethyl, -C (= 0) NY1Y2, -NY1-C (= 0) alkyl, -NY1S02alkyl, -NYY2, -S02NY1Y2 or alkyl, alkenyl or alkynyl; each of which is optionally substituted with aryl, cycloalkyl, heteroaryl, hydroxy, -C (= 0) OR6, -C (= 0) NY1 Y2, -NY ^ Y2 or -OR5; Or a pharmaceutically acceptable N-oxide, prodrug, bioisol, salt or solvate of this compound; or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 90. A compound according to claim 89 wherein W represents CH; X represents CH; And represents CH; and Z represents CH or C-CH3. 91. - A compound according to claim 89, wherein W represents CH; X represents CH; Z represents CH; and Y represents C-alkyl C -] _ 4, C-aryl, C-CN, C-NO2, C-halo; -haloalky, C-heteroaryl, C-OR4, C- , C (= 0) R4 C-C = 0) NY1Y2, C-C (= 0) OR4, C-NHC (= O) R4- C-CH (OH) aryl, C-S (0) 2NYlY2, or C-S (0) nR4. -908 - 92. - A compound according to claim 89, wherein W represents CH; X represents CH; Z represents CH; and Y represents C-CH3, C- r C-OCHF2, C-OCF,, C- 0- (), C-O-CHj C-C (= 0) -NH-CH (CH3) 2, C-C (= 0) - H-C (CH3) 2-CH2OH, C-C (= 0) -NH-CH2CH2CN, C-C (= 0) -NH-CH2CH2OCH3, -909- C (= 0) OCH3, -910- C-SOrNH-C¾- V, C-S02CH3. 93. - A compound according to claim 89, wherein W re¬ presents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; And represents C-CH3, 94. - A compound according to claim 89, wherein W re¬ presents CH; X represents C-CH 3, C-CH 2 CH 3, C-CH (CH 3) 2, C-OCH 3, C-OCH 2 CH 3 1 C-Br 0 C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C- Cl, C-F, C ( { Y and y Z represents CH. -911- 95. - A compound according to claim 89, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; and Z represents CH. 96. A compound according to claim 89, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; and Z represents CH. 97. - A compound according to claim 89 wherein R represents hydrogen. 98. - A compound according to claim 89, wherein represents a cyclopentyl, cyclohexyl or cycloheptyl ring. 99. - A compound according to claim 89, wherein represents a cyclohexyl ring. 100.- A compound according to claim 89, wherein q is zero. 101. A compound according to claim 89, wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; and represents cyclopentyl ring, cyclohexy- lo or cycloheptyl; and q is zero. -912- 102. - A compound according to claim 89, wherein W represents CH; X represents CH; Z represents CH; Y represents C-C4 alkyl, C-aryl, C-CN, C-NO2, C-halo, C-haloalkyl, C-heteroaryl, C-OR4, C- C (= 0) R4 C-C = 0) NY1Y2, -C (= 0) OR4 _C-NHC (= 0) R4, C-CH (OH) aryl0l C-S (0) 2NY1Y2, C-S (0) nR 4, R 7 represents hydrogen; (^^) refers to an anion, cyclopentyl, cyclohexyl or cycloheptyl, and q is zero, 103. A compound according to claim 89, wherein W represents CH, X represents CH, Z represents CH, Y represents C-CH3, C-OCHF2, C-OCF3, C-O - (x), C-O-CH- -913- C-C (= 0) -N (CH 3) 2, C-C (= 0) -NH-CH 2 CH 3, C-C (= 0) -NH-CH (CH 3) 2, C-C (= 0) -NH-C (CH3) 2-CH20H C-C (= 0) -NH-CH2CH2CN, C (= 0) OCH3], C-NHC (= 0) CH3 C-NHC (= 0) CH (CH3) 2, -914- C-SOi-NH-CH; J, C-SO2CH3; R7 represents hydrogen; (^) re " has a cyclopentyl, cyclohexyl or cycloheptyl ring; and q is zero. 105. A compound according to claim 89, wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-; Z represents CH; R7 represents clopentyl, cyclohexyl or cycloheptyl; and q is zero. 106. A compound according to claim 89, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; R7 represents hydrogen; represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and that is ro. 107.- A compound according to claim 89, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R7 represents hydrogen; -915- represents a cyclopentyl, cyclohexyl or cycloheptyl ring; and that is ro. 108. A compound according to claim 89, wherein R7 represents hydrogen and q is zero. 109.- A compound according to claim 89, wherein W is CH; X is C-CH3; And it is C-CH3; and Z is CH. 110.- A compound according to claim 3, of formula (Ixd) where X "! is O, S, S02, or? d, where? 5 is hydrogen, R4 -C (= 0) R4 - C (= 0) NY1 Y2, -C (= 0) OR4 or Y5 is -SO2R4; r is zero or a whole number one or two; R7 is hydrogen or alkyl; and R13 is alkyl or, when two R13 groups are attached to the same carbon atom, they form an oxo group; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound; or an N-oxide, prodrug or acid bioisoester of this salt or solvate. -916- 111. - A compound according to claim 110, wherein W represents CH; X represents CH; And represents CH; and Z represents CH or C-CH3. 12. - A compound according to claim 110, wherein W represents CH; X represents CH; Z represents CH; and Y represents C-alkyl C- | _4, C-aryl, C-CN, C-NO2, C-hala, C-halo, C-heteroaryl, C-OR4, CC (= 0) R4, CC = 0) NY1Y2, CC (= 0 ) OR4, C-NHC (= 0) R4, C-CH (OH) aryl, CS (0) 2 Y1 Y2 or CS (0) NR4. 113. A compound according to claim 110, wherein W represents CH; X represents CH; Z represents CH; and Y represents C-CH3, C- r, -917 - (viii) C-0R4 [p.e. C-OCH3, C-OCELCH,, C-OCHF,, C-OCF, C-C (= 0) -N (CH3) 2, C-C (= 0) -NH-CH2CH3 C-C (= 0) - H-CH (CH3) 2, C-C (= 0) -NB-C (CH3) 2-CH20H C-C (= 0) -NH-CH2CH2CN, C-CC ^ -NH-CH ^ OCHj -918 - 3, C NHC (= 0) CH3, 114. - A compound according to claim 110, wherein W represents CH; X represents C-CH3l C-CH2CH3, C-CH (CH3) 2, C-OCH3, C OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C Cl, C-F, C ( { O; and Z represents CH. -919- 115. - A compound according to claim 110, wherein W represents CH; X represents CH; Y represents C-CH3; and Z represents C-CH3. 116. A compound according to claim 110, wherein W represents CH; X represents CR ^ and Y represents CR ^ wherein R ^ and R3 form the group -CH2-O-CH2-; and Z represents CH. 117. A compound according to claim 110, wherein W represents CH; X represents CR ^ and Y represents CR ^ wherein R ^ and R3 form the group -CH2-CH2-CH2-; and Z represents CH. 118.- A compound according to claim 110, wherein it represents hydrogen. 119. A compound according to claim 110, wherein X ^ O, N-C (= 0) R4, N-C (= 0) NY1Y2, N-C (= 0) OR4, or N-S02R4; and r is ero. 120. - A compound according to claim 10, wherein X1 is O, N-C (= 0) CH3 > N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, N-C (= 0) C (CH3) 3 N- (O0) ^ T, N-C (= 0) N (CH3) 2 > N-C (= 0) NCH (CH3) 2, N- (00) -, N-C (= 0) OCH3, N-C (= 0) OCH2CH3, N-S02CH3 or N-S02CH ('CH3) 2; and r is zero. -920- 121. - A compound according to claim 110, wherein r is zero. 122. A compound according to claim 1, wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents hydrogen; X1 is O, N-C (= 0) R4,? -0 (= 0) ?? 2, N- C (= 0) OR4, N-S02R4; and r is zero. 123. A compound according to claim 1, wherein W represents CH; X represents CH; And represents CH; Z represents CH or C-CH3; R7 represents. hydrogen; X1 is O, N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, N-C (= 0) C (CH3) 3 ? - (? = 0) - < ? ], N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N- (C = 0) -N ? - (? 0) -? N-C (= 0) OCH3, N-C (= 0) OCH2CH3, N-S02CH3 or N- S02CH (CH3) 2; and r is zero. 124. A compound according to claim 110, wherein W represents CH; X represents CH; Z represents CH; Y represents C-alkyl C-j, 4, C-aryl, C-CN, C-NO2, C-halo, C-haloalkyl, C-heteroaryl, C-OR. C- C (= 0) R4, C-C = 0) NY1Y2, -C (= 0) OR4, C-NHC (= 0) R4, C-S (0) 2NY Y2, - 921- C-S (0) nR4; R? represents hydrogen; ? 1 is O, N-C (= 0) R4, N-C (= 0) NY1Y2, N-C (= 0) OR4, or N-S02R4; and r is zero. 125. A compound according to claim 1, wherein W represents CH; X represents CH; Z represents CH; And represents C-CH3, C-CI or C-F], C-CF3, C f (/ ~ \ N, r C-J (, C-OCH3, C-OCH2CH3 CC (= 0) -N (CH3) 2, CC (= 0) -NÉ [-CH 2 CH 3, CC (= 0) -NH-CH (CH 3) 2, CC (= 0) -NH-C (CH 3) 2 -CH2OH, CC ^ C -NH-CH ^ CN, -922- C (= 0) OCH3, W -923- C-SO2CH3; 7 represents hydrogen; ? 1 is O, N-C (= 0) CH3, N- C (= 0) CH2CH (CH3) 2, NC (= 0) CH (CH3) 2, NC (= 0) C (CH3) 3, N- (C = 0) - NC (= 0) N (CH3) 2, NC (= 0) NCH (CH3) 2, NC (= 0) N (CH2CH3) 2 N-C (= 0) OCH3, N-C (= 0) OCH2CH3, N-SO2CH3 or N-S02CH (CH3); and r is zero. 126. A compound according to claim 110, wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C-Cl, C-F, C (o; Z represents CH; R7 represents hydrogen; X1 is O, N-C (= 0) R4, N-C (= 0) NY Y2, IM-C (= 0) OR4 or N-SO2R4; and r is zero. 127. A compound according to claim 110, wherein W represents CH; X represents C-CH3, C-CH2CH3, C-CH (CH3) 2, C-OCH3, C-OCH2CH3, C-Br or C-CI; Y represents C-CH3, C-CH2CH3, C-OCH3, C-Br, C- Cl, C-F,; Z represents CH; R7 represents hydrogen; X "! Is O, -924 - N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2L N-C (= 0) CH (CH3) 2, N-C (= 0) C (CH3) 3 N- (C = 0) N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N- (C = 0) -, N-C (= 0) 0CH3, N-C (= 0) OCH2CH3, N-S02CH3 or N- / S02CH (CH3) 2; and r is zero. 128. - A compound according to claim 110, wherein W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; ? is O, N-C (= 0) R4, N-C (= 0) NY1Y2, N-C (= 0) OR4 or N-S02R4; and r is zero. 129. - A compound according to claim 110, wherein W represents CH; X represents CH; Y represents C-CH3; Z represents C-CH3; R7 represents hydrogen; X1 is O, N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, N-C (= 0) C (CH3) 3 N- (0 = 0) N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, -925- N-S02CH3 or N- S02CH (CH3) 2; and r is zero. 130. A compound according to claim 110, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; represents hydrogen; X1 is O, N-C (= 0) R4 N-C (= 0) NY Y2, N-C (= 0) OR4 OR N-S02R4; and r is zero. 131. A compound according to claim 1, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-O-CH2-; Z represents CH; R7 represents hydrogen; X1 is O, N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2) N-C (= 0) CH (CH3) 2, N-C (= 0) C (CH3) 3 N- (C = 0) N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N_ (C = 0) .NQ0, N-C (= 0) OCH3, N-C (= 0) OCH2CH3, N-S02CH3 or N- S02CH (CH3) 2; and r is zero. 132. - A compound according to claim 110, wherein -926- W represents CH; X represents CR2 and Y represents CR ^ wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R represents hydrogen; X1 is O, N-C (= 0) R4 N-C (= 0) NY Y2, N-C (= 0) OR4 or N-S02R4; and r is zero. 133. - A compound according to claim 110, wherein W represents CH; X represents CR2 and Y represents CR3 wherein R2 and R3 form the group -CH2-CH2-CH2-; Z represents CH; R7 represents hydrogen; X1 is O, N-C (= 0) CH3, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) CH (CH3) 2, N-C (= 0) C (CH3) 3 or N - (C = 0) N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2 N- (C = 0) -N N- (O0) -N, N-C (= 0) OCH3, N-C (= 0) OCH2CH3, N-S02CH3 or N-S02CH (CH3) 2; and r is zero. 134. - A compound according to claim 110 wherein X1 is N-C (= 0) CH (CH3) 2, N-C (= 0) CH2CH (CH3) 2, N-C (= 0) C (CH3) 3; N - (C = 0) -927- N-C (= 0) N (CH3) 2, N-C (= 0) NCH (CH3) 2, N-C (= 0) N (CH2CH3) 2, N - (C = 0) -N. , N-C (= 0) OCH3 or N-C (= 0) OCH2CH3; and r is zero. 135.- A compound according to claim 110, wherein W is CH; X is CH; And it is CH, C-CH2CH3, C-CH2CH2CH3, C- // W C-C (= 0) - H-CH (CH 3) 2, C-C (= 0) -NH-C (CH 3) 2 -CH 2 OH, C-C (= 0) - H-CH2CH2CN C-C (= 0) -NH-CH2CH2OCH3 > , -928- , C-C (= 0) OCH3 t C-C (= 0) OH, C-SO2CH3 or C-S02-NH-CH2-, and Z is CH. 136.- A compound according to claim 110, wherein W is 137. - A compound according to claim 1, wherein W is CH; X is C-OCH3; Y is CH, C-CH3, C-CH2CH3, C-CI or C-OCH3; and Z is CH. 138.- A compound according to claim 1, wherein W is CH; X is C-OCH2CH3; And it's C-F; and Z is CH. 139. A compound according to claim 1, wherein W represents CH; X represents CR2 and Y represents CR ^ wherein R2 and R3 form the group -CH2-CH2-CH2-; and Z represents CH. -929- 140. - A compound according to claim 110, wherein W represents CH; X represents CR2 and Y represents CR ^ wherein R2 and R3 form the group -CH2-O-CH2-; and Z represents CH. 141. - A compound according to claim 110, wherein X ^ ro. 142. A compound according to claim 110, wherein W represents CH; X represents C-CH3; Y represents C-CH3 or C-CI; and Z represents CH. 143. - A compound according to claim 3, which is 2- (H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid benziamide; 2- (1 H-indazol-3-yl) - H-benzimidazole-5-carboxylic acid N-methylamide; 2- (1 H -indazol-3-yl) -1 H- N-ethylamide benzimidazole-5-carboxylic acid; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-Chloro-5-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; -930- 6-chloro-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1H-benzoimidazole; 2- (5-Methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole; 2- (5-Cyclopropylmethylsulfanyl) -1 H-pyrrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 2- (5-Ethylsulfanyl-1H-pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole; 5,6-dimethy [-2- [5- (pyridin-3-ylmethylsulfanyl) -1 H-pyrrazol-3-yl] -1 H -benzoimidazole; 5- fluoro-2- [5-methylsulfanyl) -1 H-pyrrazol-3-yl] -1 H -benzoimidazole; 5,6-dimethyl-2- (5-phenethylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 4- methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dimethyl-2- (5-benzylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6- chloro-5-methyl-2- (5-morpholin-4-yl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1 H-pyrrazol-3-yl] -1 H -benzoimidazole; 2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methoxy-1 H-benzoimidazole hydrochloride; 5- methyl-2- (5-methylsulfanyl-4-propyl-1 H-pyrrazol-3-yl) -1 H -benzoimidazole; 2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1 H -pyrazol-3-yl) -5-methyl-1H-benzoimidazole; -931- 2- (5-benzylsulfanyl-4-ysopropyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-methylsulfanyl-4-methyl-1 H-pyrrazol-3-yl) -5-methoxy-1 H-benzoimidazole; 2- (5-Methylsulfanyl-4-methyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 3- (5-chloro-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine; 3- (5,6-dichloro-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine; 3- (5,6-dimethyI-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-ylamine; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (6-chloro-5-methioxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-ethoxy-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-ylamine; 3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5-Trifluoromethoxy-1H-benzoamidazo-2-yl) -1H-pyrazol-4-ylamine; 3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-ylamine; 2- (4-amino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester; 3- (1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenyl-methanone; 2- (1H-indazol-3-yl) -3H-benzoimidazol-4-ol; 2-phenyl-1 H -amidazo [4,5-b] pyrazine; -932- 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1 H -ndazol-3-yl) -3H-imydazo [4,5-c] pyridinium 2- (1 H -indazol-3-yl) -3H-imidazo [4,5 -b] pyridine; 2- (1 H-pyrazole-3 I) -1 H-benzoxydazole; 3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole; 3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-fluoro-1 H-indazole; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -6-fluoro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-indazole; 3- (5,6-d.methyl-1 H -benzoimidazol-2-N) -6-methoxy-1 H-indazole; 5,6-dimethyl-2- (4-phenyl-1 H -pyrazol-3-yl) -1H-benzoimidazo !; 3- (5-ethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-isopropyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-bromo-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (3-cyano) phenyl-1 H-benzoimidazoI-2-yl) -1 H-indazole; 3- (5- (pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (6-methyl-5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (2-fluoro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (5,6-methylenedioxy) phenyl-1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (5- (2-methoxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (4-chloro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (4-methy1) phenyl-1 H -benzoimidazole-2-yl) -1 H-indazole; 3- (5-benzyloxy-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-methylenedioxy-1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethoxy-1 H -benzoimidazole-2-yl) -1 H-indazole; 3- (5,6-diethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (4,5-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carbonitrile; 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-ethoxy-1 H-indazole; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -pyrazol-4-carboxylic acid methyl ester; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-pyrazole-4-carboxylic acid methyl ester; cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazole-4-carboxylic acid; 3- (5-methoxy-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidol-2-yl] -1H-indazole; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide; -934 - 3- (5,6-dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazole-4-carboxylic acid propylamide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazoI-5-carbonitrile; 3- (5-difluoromethoxy-1H-benzoimidazoi-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid sopropylamide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile; 2- (5-methy1-1 H -pyrazol-3-yl) -1 H-benzoimidazole; 2- (5-ethoxy-1 H -pyrazol-3-yl) -1H-benzoimidazole; 2- (5-methylsulfanyl-isoxazol-3-yl) -1 H-benzoimidazole; 5-chloro-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dichloro-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; (benzoimidazol-2-yl) -5-methylthio-3-pyrazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-indazole; 2- (5-isopropyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 2- (5-ethyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole; -935- 5,6-dimethyl-2- (1, 4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1 H-benzoimidazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4-fluoro-1 H-indazole; 4- chloro-3- (5,6-dimethyI-1 H-benzoimidazol-2-yl) -1 H -ndazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-chloro-1 H-indazole; 3- (5,6-DimetiI-1 H-benzoimidazol-2-yl) -1 H -indazoI-5-ol; 3- (5-n-propyl-1 H-benzo-rfiidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -1 H-benzoimidazo I-5-sulfonic acid benzylamide; 3- (5-methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -pheni-methanol; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid; [2- (indazol-3-yl) -1H-benzoimidazoI-5-yl] -carboxylic acid methylamide; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid dimethylamide; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid isopropylamide; H-benzoimidazol-5-yl] -carboxylic acid benzylamide; [2- (indazol-3-yl) -1H-benzoimidazoI-5-yl] -carboxylic acid benzamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; -936- 3- (5,6-Dimethyl-1 H-benzoimidazoI-2-yl) -1 H-pyrazole- (2-hydroxy-1, 1-dimethylalkyl) -amide. 4-carboxylic; 2- (4-isopropylcarbamoyl-1 H-pyrrazol-3-yl) -H-benzoimidazo-5-carboxylic acid (pyridin-3-methyl) -amide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 2- (4-Isopropycarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide; 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide; -937 - 2- (1 H-ndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl) -amide of acid; 2- (1 H -ndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1, 1-dimethyl-etl) -amide; (3-imidazol-1-yl-propyl) -amide. 2- (1H-indazol-3-ii) -1H-benzoimidazole-5-carboxylic acid; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutylamide; 3- (5,6-dimethyl-1H-benzoimidazoI-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid cyclopropylmethylamide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 3- (5,6-Dimethyl-1H-benzoimidazoI-2-yl) -1H-indazole-5-carboxylic acid dimethylamide; 2- (4-isobutyriammino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide; [2- (indazoI-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid; 3- (5,6-dimethyl-1H-benzoimidazol-5-yl) -pyrazol-4-carboxylic acid; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; -938- 3- (5,6-Dimethyl-1 H -benzoimidazol-2-y!) - 5-methyl-pyrazole-4-carboxylic acid; - [3- (5,6-d.methyl-1 H -benzoimidazol-2-y!) - 1 H -pyrazol-4-yl] -isobutyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide; N- [3- (5,6-dimethyl-1H-benzoamidazol-2-yl) -1 H -pyrazI-4-yl] -2-phenyl-acetamide; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -afamide of methoxyacetic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopentanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrrazol-4-yl] -amide of trimethylacetic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of tert-butylacetic acid; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-p-arazoyl-4-yl] -amide of butanoic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of isoxazole-5-carboxylic acid; -939- [3- (5,6-Diethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanol co; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-Chloro-5-methoxy-1 H-benzoimidazol-2-yl) -1 H-pyrazol! -4-yl] -amide of piperidin-1-carboxylic acid; 3- [3- (6-chloro-5-methoxy-1 H -benzoimidazoi-2-yl) -1 H -pyrazol-4-yl] -1, 1 -dimethylurea; [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5-Ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-Fluoro-6-methyl-1H-benzomiddazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-Trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; N- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; -940- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of 3,5-dimethyl-isoxazoyl-4-carboxylic acid; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide of furan-3-carboxylic acid; N- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -4-methyl-benzamide; 5,6-dimethyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole; 5-atyl-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-Chloro-5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5-fluoro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole; 2- (4-Nitro-1 H -pyrazol-3-yl) -5-trifluoromethoxy-1 H-benzoimidazole; 2- (4-Nitro-1 H -pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole; 5-chloro-6-methyl-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (4-Nitro-1H-pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methyl ester; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide; cyclopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; isopropyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -metanone; -941- 1 - . 1 - [3- (5,6-dimethyl-1H-benzoimidazol-2-y) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2,2-dimethyl-propan-1-one; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid methyl ester; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H -pyrazolo [4,3-c] pyridine; S-S-chloro-e-methyl-I H-benzoimidazoI ^ -ilH.S.e ^ -tetrahydro-I H-pyrazolo [4,3-c] pyridine; 3- [5- (2-morpholin-4-yl-ethoxy) -1 H -benzoamidazo-2-yl] -4,5,6,7-tetrahydro-1 H-pyrazolo [4,3-c] ] pyridine; 3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H -pyrazolo [4,3-c] pyridine; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester; 5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1H-benzoimidazole; 5-ethoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; . 3- (5-Chloro-6-methyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid tert-butyl ester; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazoI-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] tert-butyl ester ] pyridine-5-carboxylic acid; 3- (5,6-di.methyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole; -942- 3- (5-Triforomethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazole or [4,3-c] pyridino- tert -butyl ester 5-carboxylic; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-morfoin-4-yl-acetamide; 2-dimethylamino-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazI-4-yl] -2- (1 H-1, 2,3,4-tetraazoI-1- il) -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -sonicotinamide; 2-cyclopropyI-N- [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -acetamide; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea; 1-benzyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; acid isopropylamide • 3- (5,6-dimethyl-1 H -benzolamdazoI-2-yl) -1,4,6,7-tetrahydro-pYrazolo [4,3-c] pyridino-5 -carboxy ico; -943- [3- (5-ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazol-4-ylamine; 4-Methylpiperazyl-1-carboxylic acid 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide; 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H -pyrazol-4-yl] -urea; [3- (6-Ethoxy-5-fluoro-1H-benzimidazoI-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-ethoxy-5-fluoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide tetrahydropyran-4-carboxylic acid; [3- (6-Ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] -morpholino-4-carboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazoI-2-yl) -1H-pyrazol-4-yl] -piperidino-4-carboxylic acid amide; 3- [6-ethoxy-5-fluoro-1 H-benzimidazoI-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethylurea; 5-methoxy-2- (4-nitro-1 H -pyrazol-3-yl) -1 H -benzoimidazole; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide of morpholino-4-carboxylic acid; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H-pyrazolo-4-yl] -1, 1-diethyl urea; - 944 - [3- (5-D-Fluoromethoxy-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; [3- (6-Chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-methoxy-1 H -benzoim-dazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1 -yl-methanone; -945- [3- (5,6-dimethyl-1H-benzoimidazol-2-y) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidine- 1-yl-methanone; [3- (5,6-D -methyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-iI] -morpholin-4-l-methanone; 3- (5-chloro-6-methyl-1 H -benzoimidazol-2-ii) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; [3- (5,6-Dimethyl-1H-benzoimitdazol-2-yl) -1H-pyrazolo-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-dimethyl-1 H -benzomidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-diethylamide of tetrahydro-pyrazolo [4,3-c] pyridino-5 -carboxylic; 3- (5-tnfluoromethyl-1H-benzoimidazol-2-yl) -l ^ .ej-tetrahydro-pyrazolo ^. S-cjpyridino-S-carboxylic acid diethylamide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid [2- (2H-tetrazol-5-yl) -ethyl] -amide; 1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-ethyl-6-methyl-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; -946- [3- (5-fluoro-6-methyl-1 H-benzoimidazoI-2-yl) -1 H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 1 - [3- (5-Fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-meitylurea; [3- (5-Fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H-pyridol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; 1-methyl-3- [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea; 1 - [3- (5-Chloro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 4-methyl-piperazin-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; 1-tert-butyl-3- [3- (5,6-d.methyl-1H-benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea; 4-methyl-piperazin-1-carboxylic acid 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; 1-cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; - 947 - 3- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -3-isobutyl-urea; 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -urea; 3- (5-chloro-6-methyl-1 H-benzoimidazol-2-yl) -H-pyrazol-4-ylamine; 3- (5-ethyl-6-methyl-1H-benzoimidazoI-2-yl) -1H-indazole-5-carboxylic acid amide dihydride; 3- (5,6-dimethyl-1 H -benzoimidazoi-2-yl) -1 H -indazole-5-carboxylic acid; 2- (4-Isobutyrylamino-1 H -pyrazol-3-yl) -1 H -benzoimidazo I-5-carboxylic acid; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; 3- (5-nitro-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-etyl) -amide; 2- (1 H-lndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; 2- (1 H-lndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide; N- [2- (1 H-lndazol-3-yl) -1 H-benzoimidazo I-5-yl] -isobutyramide; -948 - N- [3- (5,6-D -methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-piperidin-1-yl-acetamide; 2- (1 H -ndazol-3-yl) -3 H -benzolamdazole-5-amino; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of piperidino-1-carboxylic acid; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound; or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 144. A compound according to claim 14, which is 2- (1 H-indazoI-3-yl) - H-benzimidazo I-5-carboxylic acid N-methylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide; 2- (1 H-indazol-3-yl) -1 H-benzyl-cyanazole-5-carboxylic acid N-phenylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazoi-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-Chloro-5-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-Chloro-2- (5-ethylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; - 949- 2- (5-Methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1 H-benzoimidazole; 2- (5-Cyclopropylmethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole; 2- (5-Ethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 5,6-dimethyl-2- [5- (pyridin-3-ylmethylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole; 5-fluoro-2- [5-methylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole; 5,6-Dimetii-2- (5-phenethylsulfanyl-1 H-pyrazol! -3-yl) -1 H -benzoimidazole; 4-methyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dimethyl-2- (5-benzylsulfanyl ^ 1 H -pyrazol-3-yl) -1 H -benzoimidazole; 5,6-dimethyl-2- [5- (thiophen-2-ylmethylsulfanyl) -1 H -pyrazol-3-yl] -1 H -benzoimidazole; 2- (5-Ethylsulfanyl-1 H -pyrazol-3-yl) -5-methoxy-1 H-benzoimidazole hydrochloride; 5-methyl-2- (5-methylsulfanyl-4-propyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 2- (5- (4-methoxy-benzylsulfanyl) -4-propyl-1 H -pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-benzylsulfanyl-4-isopropyl-1 H -pyrazol-3-yl) -5-meityl-1 H-benzoimidazole; 2- (5-methylsulfanyl-4-methyl-1 H -pyrazol-3-yl) -5-methoxy-1 H-benzoimidazole; - 950 - 2- (5-methylsulfanyl-4-rnethyl-1 H-pyrazol-3-yl) -5-methylene-1 H-benzoimidazole; 3 ^ (5-??? G? -1 H-benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 3- (5,6-dichloro-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-ylamine; 5,6-dimethyl-2- (4-phenyl-1 H -pyrazol-3-yl) -1H-benzoimidazole; cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazole-4-carboxylic acid; 3- (5-methoxy-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide; 3- (5,6-Dimethyl-1 H-benzoimidazoI-2-yl) -1 H-pyrazole-4-carboxylic acid propylamide; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide; 3- (5-difluoromethoxy-1H-benzoimidazole-2-H-pyrazole-4-carboxylic acid isopropylamide; 3- (5-D-fluoromethoxy-1H-benzoimidazol-2-yl) -1 H- cyclopropylamide pyrazole-4-carboxylic acid, 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 2- (5-ethoxy-1H- pyrazol-3-yl) -1 H -benzoimidazole; (benzoimidazol-2-yl) -5-methylthio-3-pyrazole; -951- 2- (5-isopropyl-1 H-pyrrazol-3-yl) -5,6-d-methyl-1H-benzoimidazole; 2- (5-ethyl-1 H-pyrrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 3- (5,6-dithymyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-carboxylic acid (2-hydroxy-1, 1-dimethy-ethyl) -amide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-y [(1-H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide); 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isobutyl-amide; 3- (5,6-dimethyl-1 H -benzoimidazo! -2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 2- (4-isobutyrinamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide; - 952- N- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; N- [3- (5,6-d'metl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -2-phenyl-acetamide; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of methoxyacetic acid; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -cyclopentanecarboxylic acid amide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-p-arazoyl-4-yl] -amide of trimethylacetic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1 H-p-arazoi-4-yl] -amide of urea-butylacetic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of butanoic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of isoxazole-5-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanoic acid; -953- [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ii] -cyclopropanecarboxylic acid amide; [3- (6-Chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (6-chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazI-4-yl] -1, 1-dimethylurea; [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazoM-yl-cyclopropanecarboxylic acid amide; [3- (5-ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ii] -cyclopropanecarboxylic acid amide; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide cyclopropanecarboxylic acid; [3- (5-trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide cyclopropanecarboxylic acid; [3- (5-Trifluoromethyl-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; N- [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of cyclopropanecarboxylic acid; 3,5-Dimethyl-isoxazole-4-carboxylic acid 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; -954 - N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of furan-3-carboxylic acid; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -4-methyl-benzamide; N-p-S S ^ -dimethyl-I H-benzoimidazole ^ -yl ^ l H-pyrazoyl ^ -yl] ^ - morpholin-4-yl-acetamide; 2-dimethylamino-N- [3- (5,6-d-methyl-1 H -benzoimidazol-2-yl) -1-hypirazol-4-yl] -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ii] -2- (1 H-1, 2,3,4-tetraazole- 1 -yl) -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -isonicotinamide; 2-cyclopropyl-N- [3- (5,6-di-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; 1 - . 1 - . 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 1- [3- (5,6-Dimetyl! -1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea; -955- 1-benzl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ii] -urea;. [3- (5-Ethoxy-6-etl-1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] cyclopropanecarboxylic acid amide; 4-methyl-piperazine-1-carboxylic acid [3- (5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] amide; 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H -pyrazol-4-yl-urea; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-y1) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide tetrahydropyran-4-carboxylic acid; [3- (6-ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] morpholino-4-carboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -idene of piperidino-4-carboxylic acid; 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethylurea; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazl-4-methylmethyl] -amido morpholine-4-carboxylic acid; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; -956- [3- (5-difluoromethoxy-1 H-b'enzoimidazol-2-yl) -1H-pyrazol-4-yl] -arnide of piperidino-1-carboxylic acid; [3- (6-chloro-5-methoxy-1H-benzpimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; Cyclopropanecarboxylic acid [3- (1, 5,6,7-tetrahydro-1,3-diaza-s -ndacen-2-yl) -1H-pyrazol-4-yl] -amide; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea; • [3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of piperidino-1-carboxylic acid; S-tS-S-fluoro-e-methyl-I H-benzoimidazole ^ -i-I H-pirazoM-ilj-I-dimethyl-urea; [3- (5-Trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-D-methyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; -957 - 1 - . 1 - . 1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; [3- (5-Fluoro-6-methyl-1-H-benzoimidazo-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 1 - [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-Fluoro-6-methyl-1-H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; 4-methyl-piperazin-1-carboxylic acid [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide; 1-methyl-3- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ii] -urea; 1 - [3- (5-Chloro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 4-Methyl-p-piperazino-1-carboxylic acid [3- (5-chloro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazolo-4-yl] -amide; 1-tert-butyl-3- [3- (5,6-dimethyI-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; -|958 - 1 - [3- (5,6-Dimetyl | -1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea; 4-methyl-piperazin-1-carboxylic acid 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; 1-Cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-diethyl urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-ii] -3-isobutyl-urea; 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -dimethyl-urea; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-piperdin-1-yl-ethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; N- [2- (1 H -indazol-3-yl) -1 H -benzoimidazol-5-yl] -sobutramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-y) -1 H -pyrazol! -4-yl] -2-piperidin-1-y-acetamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-morphoiinoamide; -959- N- (N'-methylpiperazino) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; N- (isobutyl) 2- (1 H-indazoI-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; N- (cyclohexylmethyl) 2- (1H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; N- (2-furfuryl) 2- (1 H -indazol-3-yl) -H-benzamidozol-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl; 5,6-dimethyl-2- (1 H -indazol-3-yl) -1 H-benzimidazole; 2- (1 H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid; 2- (5-ethoxy-2H-pyrazol-3-yl) -1 H -benzimidazole-4-carboxylic acid; 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1 H -benzimidazole; 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1 H -benzimidazole; 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzimidazole; 2- (5-ethyl-2H-pi-razol-3-yl) -5,6-d-methyl-1H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1 H-benzimidazole -960- 2- (5-etl-2H-p¡razol-3-yl) -5-bromo-1 H-benzimidazole; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or ste of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or ste. 145. A compound according to claim 14, which is benzylamide of 2- (1 H -ndazol-3-yl) -1 H-benzimidazole-5-carboxylic acid; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-methylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2- (1 H-indazol-3-yl) -H-benzimidazole-5-carboxylic acid N-isopropylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide; 5,6-dimethyl-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -1 H -benzoimidazole; 6-chloro-2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-methyl-1 H -benzoimidazole; 6-chloro-2- (5-ethylsulfanyl-H-pyrazol-3-yl) -5-methyl-1 H-benzoimidazole; 2- (5-methylsulfanyl-1 H -pyrazol-3-yl) -5-trifluoromethyl-1H-benzoimidazole; 2- (5-cyclopropylmethylsulfanyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1H-benzoimidazole; -961- 2- (5-ethylsulfanyl-1 H-pyrazol-v3-yl) -5,6-d-methyl-1 H -benzolamdazole; cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazole-4-carboxylic acid; 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid sopropylamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-methoxy-ethyl) -amide; S-^. S-dimethyl-I H-benzoimidazole ^ -i-H-pyrazole-4-carboxylic acid propylamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide; 3- (5-d.fluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5-D-fluoro-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 2- (5-isopropyl-1 H -pyrazol-3-yl) -5,6-dimethyl-1 H-benzoimidazole; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; -962- 2- (4-Isopropylcarbamoyl-1 H -pyrazol-3-yl) -1 H -benzoimidazoi-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide; 2- (4-Isopropylcarbamoyl-1H-pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isobutyl-amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H7-pyrazoyl-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 2- (4-isobutyrylamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isobutyramide; N- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of N- [3- (5,6-dimethyl-1H-benzoimidazole- 2-yl) -1 H-pyrazol-4-yl] -2-phene-acetamide; -963- [3- (5,6-Dimethyl-1H-benzomiddazol-2-yl) -1 H-pyrrazol-4-yl] -amide cyclopropanecarboxylic acid; [3- (5,6-dimethyl-1 H -benzoimidazoi-2-yl) -1 H-pyrazol-4-yl] -amidoxyacetic acid amide; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopentanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of trimethylacetic acid; [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyraz [4-yl] -amide of ferricbutylacetic acid; [3- (5,6-Dimethyl-1H-benzo.imidazol-2-yl) -1H-pyrazol-4-yl] -amide of butanoic acid; [3- (5,6-Dimethyl-1 H -benzoimidazo! -2-yl) -1H-pyrazol-4-yl] -amide of isoxazole-5-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methylbutanoic acid; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-ii) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (6-Chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (6-chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -dimethylurea; -964- [3- (5-methoxy-1H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5-Ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5-Trifluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-trifluoromethyl] -1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of cyclopropanecarboxylic acid; N- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-ii) -1 H -pyrazol-4-yl] -isobutyramide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 3,5-dimethyl-isoxazole-4-carboxylic acid; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -acetamide; [3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of furan-3-carboxylic acid; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -4-methyl-benzamide; - 965- N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-morpholin-4-yl-acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2- (1 H-1, 2,3,4-tetraazole-1 - il) -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] - sonicotinamide; 2-Cyclopropyl-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazole-2-ii) -1 H -pyrazol-4-yl] -3-isopropyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-phenyl-urea; 1-benzyl-3- [3- (5,6-dimethyl-1 H -benzoimidazo [-2-yl] -1 H-pyrrazol-4-yl] -urea; [3- (5-Ethoxy-6-ethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; 4-methyl-piperazino-1-carboxylic acid 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide; 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H-pyrazol-4-yl-urea; - 966- [3- (6-Ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-Ethoxy-5-fiuoro-1H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide tetrahydropyran-4-carboxylic acid; [3- (6-ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] morpholino-4-carboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-4-carboxylic acid amide; 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -diethylurea; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-ylmethyl] -amide of morpholino-4-carboxylic acid; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -diethyl-urea; [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide; [3- (6-chloro-5-methoxy-1H-benzoimidazoI-2-yl) -H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl-amide of cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; -967 - [3- (5-Methoxy-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; [3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-p-arazoI-4-yl] -amido of piperidino-1-carboxylic acid; 3- [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H-p-arazoI-4-yl] -1,1-dimethyl-urea; [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido morpholino-4-carboxylic acid; [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid; 1-Cyclopropyl-3- [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5-eti [-6-meth] -1-H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 4-methyl-piperazine-1-carboxylic acid [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; [3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; -968- 1 - . 1 - [3- (5-fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [S-1S-fluoro-e-methyl-1H-benzoimidazole] -iO-1 H-pyrazole-1-yl-morpholino-4-carboxylic acid amide; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; 1-methyl-3- [3- (5-trifluoromethyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazi-4-yl] -urea; 1 - [3- (5-Chloro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 4-methyl-piperazin-1-carboxylic acid 3- (5-duro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide; 1-tert-butyl-3- [3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4 ' L] -urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; 1-cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyiurea; -969- 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H ~ pyrazol-4-yl] -3-isobutyl-urea; 1-cyclopropylmethyl-3- [3- (5,6-d-methyl-1-H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1,1-dimethyl-urea; 2- (1 H-lndazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-piperidin-1-yl-ethyl) -amide; (2- (1 H-indazol-3-yl) -1-hybenzoimidazole-5-carboxylic acid (pyridin-2-ylmethi) -amide; N- [3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-piperidin-1-yl-acetamide; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 146 - A compound according to claim 14, which is cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazole-4-carboxylic acid; 3- (5-methoxy-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazole-4-carboxylic acid; -970- 3- (5-methoxy-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazoi-4-carboxylic acid (2-methoxy-ethyl) -amide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid propylamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-ii) -1 H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide; 3- (5-difluoromethoxy-1H-benzoimidazoI-2-yl) -1H-pyrazole-4-carboxylic acid isopropiiamide; 3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid cyclopropylamide; 3- (6-ethyl-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isopropiiamide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazoyl-4-carboxylic acid isopropiiamide; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; (2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid cyclopropylamide; -971- 2- (4-isopropylcarbamoyl-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenylmethyl-amide; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide; 3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H -benzoimidazoi-2-yl) -1 H-pyrazole-4-carboxylic acid cyclopropylmethyl-amide; 5,6-Dimethyl-1 H-benzoimidazol-2-yl) -5-methyl-1 H-pyrazole-4-carboxylic acid tert-butylamide; 2- (4-Isobutyrylamino-1 H -pyrazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzylamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazi-4-yl] -isobutyramide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-butyramide; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-yl] -amide of methoxyacetic acid; [3- (5,6-dimethyl-1 H -benzoimidazole-2-ii) -1 H-pyrazole-4-ii] -cyclopentanecarboxylic acid amide; -972- [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of trimethylacetic acid; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of fer-butylacetic acid; [3- (5,6-D-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of butanoic acid; [3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H-pyrazolo-4-yl] -amide of 5-oxo-5-carboxylic acid; [3- (5,6-dimethy! -1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of S (+) - 2-methyIbutanoic acid; [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-Chloro-5-methoxy-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 3- [3- (6-chloro-5-methoxy-1-t-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethylurea; [3- (5-methoxy-1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5-Ethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of cyclopropanecarboxylic acid; [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; - 973- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; N- [3- (5-Trifluoromethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-y!] - isobutyramide; [3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 3,5-dimethyl-isoxazole-4-carboxylic acid; [3- (5-chloro-6-methyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of furan-3-carboxylic acid; N- [3- (5,6-Dimethyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2-morpholin-4-yl-acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -2- (1 H-1, 2,3,4-tetraazole- 1-l) -acetamide; N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -isonicotinamide; 2-cyclopropyl-N- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -acetamide; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-isopropyl-urea; - 974 - 1 - . 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl-3-phenyl-urea; 1-Benzyl-3- [3- (5,6-dimethyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -urea; [3- (5-ethoxy-6-ethyl-1H-benzoimidazoi-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid amide; 4-methyl-piperazino-1-carboxylic acid [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H -pyrazol-4-yl] -amide; 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-yl) -1 H -pyrazol-4-yl] -urea; [3- (6-Ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1H-pyrazolo-4-yl] -cyclopropanecarboxylic acid amide; [3- (6-ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-ii] tetrahydropyran-4-carboxylic acid amide; [3- (6-ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] morpholino-4-carboxylic acid amide; [3- (6-Ethoxy-5-fluoro-1 H -benzimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-4-carboxylic acid; 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -diethylurea; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -diethyl-urea; -975- [3- (5-D-fluoro-methoxy-1H-benzolamdazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; [3- (6-chloro-5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1, 3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -cyclopropanecarboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5-methoxy-1H-benzoamidazol-2-yl) -1H-p-arazoI-4-ii] -piperidino-1-carboxylic acid amide; 3- [3- (5-methoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; [3- (5-ethyl-6-methyl-1 H-benzoimidazoI-2-yl) -1H-pyrazol-4-yl] -piperidino-1-carboxylic acid amide; 3- [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; [3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-y!] - morpholino-4-carboxylic acid amide; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of morpholino-4-carboxylic acid; [3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; -97 6- 1 - . 1 - . 1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1H-benzoimidazol-2-yl) -1 Hp -razol-4-yl] -urea] 1 - [3- (5-et L-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-etl-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1 -amide carboxylic; [3- (5-fluoro-6-methyl-1-H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido of piperidino-1-carboxylic acid; 1 - [3- (5-Fluoro-6-methyl-1 H-benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-fluoro-6-methyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amido morpholine-4-carboxylic acid; 1-methyl-3- [3- (5-trifluoromethyl-1 H -benzoimidazol-2-I) -1 H -pyrazol-4-ii] -urea; 1 - [3- (5-Chloro-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-methyl-urea; [3- (5-Chloro-6-methyl-1H-benzo-midezol-2-yl) -1H-pyrazol-4-yl] -amide of 4-methyl-piperazin-1-carboxylic acid; 1-tert-butyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -3-ethyl-urea; - 977- 4-Methyl-piperazine-1-carboxylic acid [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazl-4-yl] -amide; 1-cyclopropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-d.methyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrrazole-4-yl] -3-isobutyl-urea; 1-cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazo! -2-yl) -1 H -pyrazol-4-yl] -urea; or 3- [3- (5,6-dimeti [-1 H -benzoimidazol-2-ii) -1 H -pyrazol-4-yl] -1, 1-dimethyl-urea; or an N-oxide, prodrug, acid bioisoester, pharmaceutically acceptable salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 147. - A compound according to claim 14, which is 3- (5-methoxy-6-methyl-1 H-benzoimidazol-2-yl) -1 H-pyrazole-4-carboxylic acid isopropylamide; cyclopropylamide of 3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1 H-pyrazole-4-carboxylic acid; 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -H-pyrazole-4-carboxylic acid (tetrahydro-pyrano-4-yl) -amide; 3- (5,6-dimethyl-H-benzoimidazol-2-yl) -1H-pyrazole-4-carboxylic acid isobutyl-amide; - 978 - Cyclopropanecarboxylic acid [3- (5-ethoxy-6-etyl] -1H-benzoimidazol-2-yl) -1 H-pyrrazol-4-yl] -amide; 1,1-dimethyl-3- [3- (1, 5,6,7-tetrahydro-s-indacen-2-y!) - 1 H -pyrazol-4-yl] -urea; [3- (6-Ethoxy-5-fluoro-1 H-benzyldazol-2-yl) -1H-pyrazol-4-yl] -idene of piperidino-4-carboxylic acid; 3- [6-ethoxy-5-fluoro-1 H-benzimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethylurea; 3- [3- (5-difluoromethoxy-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-diethyl urea; [3- (5-difluoromethoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; [3- (1, 5,6,7-tetrahydro-1,3-diaza-s-indacen-2-yl) -1H-pyrazol-4-yl-amide of cyclopropanecarboxylic acid; [3- (5-methoxy-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazolo-4-yl] -amide of piperidino-1-carboxylic acid; 1-cyclopropyl-3- [3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; -979- [3- (5-Fluoro-6-methyl-1H-benzoimidazol-2-yl) -1H-pyrazol-4-yl] -amide of piperidino-1-carboxylic acid; 1-tert-butyl-3- [3- (5,6-d.methyl-1 H -benzoimidazoI-2-yl) -1 H -pyrazol-4-yl] -urea; 1-cyc! Opropyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-pyrazol-4-yl] -urea; 3- [3- (5,6-d.methyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1-dethyl-urea; 1-Cyclopropylmethyl-3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -urea; 3- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H -pyrazol-4-yl] -1, 1 -dimethyl-urea; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 148. A compound according to claim 54, which is 3- (1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-methoxy-1 H-benzoimidazoI-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenyl-methanone; 2- (1 H-indazol-3-ii) -3H-benzoimidazoI-4-ol; 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -3H-imidazo [4,5-c] pyridine; 2- (1 H-indazol-3-yl) -3H-imidazo [4,5-b] pyridine; -980- - (5,6-dimethyl-1 H-benzoimidazoi-2-yl) -5-methoxy-1 H-indazo !; - (5,6-dimethyl-1H-benzoimidazol-2-yl) -5-fluoro-1 H-indazole; - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-fluoro-1 H-indazole; - (5,6-d.methyl-1 H -benzoim- dazoyl-2-yl) -5-methyl-1 H-indazole; - (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-methoxy-1 H-indazole; - (5-ethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-etl-6-methyl-1 H -benzoimidazol-2-yl) -1 H-indazole; - (5-isopropyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-bromo-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (3-cyano) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H-indazole; - (6-methyl-5-phenyl-1 H-benzoimidazol-2-yl) -1 H -indazole; - (5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (2-fluoro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (5,6-methylenedioxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazoI; - (5- (2-methoxy) phenyl-1 H-benzoimidazole-2-yl) -1 H-indazole; - (5- (4-chloro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5- (4-methyl) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5-benzyloxy-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5,6-methylenedioxy-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5,6-dimethoxy-1 H-benzoimidazol-2-yl) -1 H-indazole; - (5,6-diethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; -981- 2- (1 H-indazol-3-y!) - 1 H-benzoimidazole-5-carbonitrile; 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-ethoxy-1 H-indazoI; -3- [5- (2-morpholin-4-yl-ethoxy) -i H-benzoimidazole -2-il] -1 H-indazole; 3- (5-ethyl-6-methyl-1 H -benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile; 3- (5,6-dimethyl-H-benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4-fluoro-1 H-indazoI; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-chloro-1 H-indazole; 3- (5-n-propyl-1 H-benzoimidazoI-2-yl) -1 H-indazole; 2- (1 H-indazol-3-ii) -1 H-benzoimidazole-5-suphonic acid benzylamide; : · 3- (5-methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazoi-3-yl) -1 H -benzoimidazoi-5-yl] -phenyl-methanol; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid; [2- (indazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid, methylamide: [2- (ndazol-3-ii) -1 H -benzoimidazol-5-yl] - carboxylic acid, dimethylamide; [2- (indazol-3-ii) -1 H-benzoimidazol-5-yl] -carboxylic acid, sopropi-lamide; [2- (indazol-3-yl) -1 H-b8nzoimidazol-5-yl] -carboxylic acid, benzylamide; -982- [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid, benza-mida; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole-5-carboxylic acid dimethylamide; ^ 983- or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoiser, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 149. A compound according to claim 54, which is 3- (5-methoxy-1 H-benzoimidazol-2-yl) -1 H-indazole; '3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-methoxy-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-fluoro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-fluoro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-meth i-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -6-methoxy-1 H-indazole; 3- (5-ethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-isopropyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-bromo-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-bromo-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (3-cyano) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (pyrid-3-yl) -1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (6-methyl-5-phenyl-1 H-benzoimidazoI-2-yl) -1 H-indazole; 3- (5-phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole, (compound designated A60-B63), Example 235 (q); 3- (5- (2-fluoro) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5- (3,4-methylenedioxy) phenyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5-benzyloxy-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-methylenedioxy-1 H -benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethoxy-1 H-benzoimidazoI-2-yl) -1 H-indazole; 3- (5,6-diethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carbonitrile; 3- (5-methoxycarbonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-ethoxy-1 H-indazole; 3- [5- (2-morpholin-4-yl-ethoxy) -1 H -benzoimidazol-2-yl] -1 H -indazole; 3- (5-ethyl-6 ~ methyl-1 H -benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile; 3- (5,6-dirnethyl-1 H -benzoimidazol-2-yl) -1 H -indazol-5-carbonitrile; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4-fluoro-1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5-chloro-1 H-indazole; 3- (5-n-propyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-suphonic acid benzyl amide; 3- (5-methanesulfonyl-1 H-benzoimidazol-2-yl) -1 H-indazole; [2- (indazol-3-yl) -1 H -benzoimidazol-5-yl] -phenyl-methanol; [2- (indazol-3-yl) -1 H -benzoimidazoi-5-yl] -carboxylic acid, ethylamide; [2- (indazol-3-yl) -1 H-benzoimidazol-5-jl] -carboxylic acid, methylamide; [2- (indazol-3-yl) -1 H -benzoimidazoI-5-yl] -carboxylic acid, isopropyl-lamide; -985- [2- (ndazol-3-yl) -1H-benzoimidazol-5-yl] -carboxylic acid, benzylamide; [2- (ndazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid, benza-mida; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H-indazoi-3-yl) -1 H-be.nzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (2-oxo-pyrrolidin-1-yl) -propyl] -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid (2-morpholin-4-yl-ethyl) -amide; 2- (1 H -indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-cyano-ethyl) -amide; 2- (1H-IndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide; -986- 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1H-indazole-5-carboxylic acid dimethylamide; [2- (Ndazol-3-yl) -1 H -benzoimidazol-5-yl] -carboxylic acid; amide dihydrochloride 3- (5-ethyl-6-methyl-1 H-2-¡I benzo¡midazol-acid) -1 H-indazol-5-carboxíIico; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 150. A compound according to claim 54, which is 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -5-methoxy-1 H-indazole; 3- (5-ethyl-6-methyl-1 H-benzoimidazol-2-yl) -1 H-indazole; or 3- (5,6-diethyl-1 H-benzoimidazol-2-yl) -1 H-indazole; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1 H-indazole-5-carboxylic acid dimethylamide; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 151- A compound according to claim 89, which is 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-indazole; S.e-dimethyl ^ -yl ^^. E-tetrahydro-cyclopentapyrazol-S-iO-IH-benzoimidazole; -987- 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,5,6,7,8-hexahydro-cycloheptapyrazole; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 152. A compound according to claim 89, which is 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -4,5,6,7-tetrahydro-1 H-indazole; or 5,6-dimethyl-2- (1, 4,5,6-tetrahydro-cyclopentapyrazol-3-yl) -1 H-benzoimidazole; or an N-oxide, prodrug, bioisoéster acid, pharmaceutically acceptable salt or solvate of this compound, or an N-oxide, prodrug or bioisoéster acid of this salt or solvate. 153. - A compound according to claim 110, which is sopropilamida 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) - 1, 4,6,7-tetrahydro-p¡razolo [4, 3-c] pyridine-5-carboxylic acid; cyclopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; isopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydropyridolo [4,3-c] pyridin-5-yl] -methanone; 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -ethanone; 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2-methyl -propan-1-one; -988 - 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester co; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -3-methyl -butan-1-one; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2.2 -dimethyl-propan-1-one; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-arazoo [4,3-c] pyridin-5-carboxylic acid methyl ester co; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid isopropylamide; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -, 4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-p¡razolo [4,3-c] pyridin-5-yl] -pyrrolidin -1-l-methanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1 -yl-methanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4- il-methanone; 3- (5-chloro-6-methyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid diethylamide; -989- 3- [5- (2-morfoin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3] diethylamide -c] pyridine-5-carboxylic acid; 3- (5-trifluoromethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2 , 2-dimethyl-propan-1-one; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -5- (propane-2-sulfonyl) -4,5,6,7-tetrahydro-1 H-pyrazolo [4,3-c] pyridine; or 3- (5,6-dimethyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrano [4,3-c] pyrazole or an N-oxide, prodrug, acid bioisoester pharmaceutically acceptable salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 154. A compound according to claim 110, which is isopropylamide of 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3- c] pyridino-5-carboxylic acid; Cyclopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; isopropyl- [3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-. pyrazolo [4,3-c] pyridin-5-yl] -methanone; 1 - [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2 , 2-dimethyl-propan-1-one; -990- 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester; 3- (5,6-Dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid isopropylamide; 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1-yl -metanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-y!] - piperidin- 1-l-methanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -morpholin-4 -yl-methanone; 3- (5-Chloro-6-methyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid diethylamide; 3- [5- (2-morpholin-4-yl-ethoxy) -1H-benzoimidazol-2-yl] -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino diethylamide -5-carboxylic acid; 3- (5-trifluoromethyl-H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-carboxylic acid diethylamide; 3- (5,6-dimethyl-1H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide; 1 - [3- (5,6-D -methyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2 -methyl-propan-1-one; -991- 3- (5,6-Dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid methyl ester; 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -3-methyl -butan-1 -one; or 1- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -2, 2-dimethyl-propan-1-one; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 155. A compound according to claim 110, which is isopropylamide of 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-] c] pyridine-5-carboxylic acid; cyclopropyl- [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -methanone; 3- (5,6-Dimethyl-1H-benzoimidazoI-2-yl) -1 ^. SJ-tetrahydro-pyrazolo-S-c-pyridine-S-carboxylic acid isopropylamide; prepared 3- (5,6-dimethyl-H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino-5-carboxylic acid diethylamide; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -pyrrolidin-1 -yl-methanone; [3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridin-5-yl] -piperidin-1-yl -metanone; - 992- 3- (5-Chloro-6-methyl-1 H-benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridino- diethylamide 5-carboxylic; or 3- (5,6-dimethyl-1 H -benzoimidazol-2-yl) -1,4,6,7-tetrahydro-pyrazolo [4,3-c] pyridine-5-carboxylic acid dimethylamide; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 156. A compound according to claim 3, which is benzylamide of 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-meitylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2- (1 H-indazol-3-y!) - 1 H-benzimidazole-5-carboxylic acid N-isopropylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenethylamide; 2- (1 H -ndazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-morpholinoamide; N- (N'-methyl-piperazin) -2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; N- (isobutyl) 2- (1H-indazol-3-yl) -1H-benzamidazole-5-carboxylic acid amide; N- (cyclohexylmethyl) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-benzyl-N-methylamide; 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl ester; 5,6-dimethyl-2- (1 H -indazol-3-yl) -1 H-benzimidazole; 5-methoxy-2- (1 H -indazol-3-yl) -1 H-benzimidazole; 2- (1 H-indazol-3-yl) -3H-benzimidazole-4-carboxylic acid; 2- (5-ethoxy-2H-pyrazol-3-yl) -1H-benzimidazole-4-carboxylic acid; 5,6-dimethyl-2- (5-methyl-2H-pyrazol-3-yl) -1 H -benzimidazole; 5,6-dimethyl-2- (5-thiophen-2-yl-2H-pyrazol-3-yl) -1 H -benzimidazole; 2- (4-Bromo-2H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzimidazo I; 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-d-methyl-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -4,5-ethylenedioxy-1 H-benzimidazole; 2- (5-ethyl-2H-pyrazol-3-yl) -5-methoxy-1 H-benzimidazole; - 994- 2- (5-ethyl-2H-pyrazol-3-yl) -4-hydroxy-1 H-benzimidazole 2- (5-ethyl-2H-pyrazol-3-yl) -5-bromo-1 H-benzimidazole; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 4-methanesulfonyl-benzylamide of 2- (1 H-indazol-3-yl) -1-hibenzoimidazole-5-carboxylic acid; 2- (1 H-indazol-3-yl) -1 H-benzoimidazoi-5-carboxylic acid (2- (1 H-indazol-3-yl) -1 H-benzoimidazoi-5-carboxylic acid (4-trifluoromethyl-benzylamide of 2- (1 H-indazole- 3-yl) -1 H-benzoimidazole-5-carboxylic acid 2- (1 H -ndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid dimethylamino-benzylamide: tert-butyl ester of 4- ( { [2- (1 H-indazol-3 -yl) -1 H-benzoimidazole-5-carbonyl] -amino.} - methyl) -piperidin-1-carboxylic acid; 4-nitro-benzylamide of 2- (1 H-indazol-3-yl) acid -1 H-benzoimidazole-5-carboxylic acid; - 995- 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (pyridin-3-ylmethyl) -amide; 3- (1H-indazol-3-i)) - 1 H-benzoimidazole-5-carboxylic acid bromo-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylamide; (2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [1,3] dioxol-5-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (1,3-dimethyl-1 H -pyrazol-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methyl-benzylamide; 2- (1 H-indazoyl-3-yl) -1H-benzoimidazoi-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 4- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid phenoxy-benzylamide; -996- 3- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H -indazo! -3-yl) -1H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (1-metii-1 H-pyrazol-4-ylmethyl) -amide; 4- (1 H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid isopropyl-benzylamide; 2- (1 H-indazol-3-yl) -0 1 H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-furan-3-ylnnetyl) -annide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-2-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid [3- (3-acetylamino-phenoxy) -propyl] -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; (p ^ 'L-phenyl-phenyl-S-ilmethyl 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-methyl) - 2- (1 H-indazol-G 3-yl) -1 H-benzoimidazole-5-carboxylic acid amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole 4-cyano-benzylamide -5-carboxylic acid; - 997 - 2- (1 H-indazoI-3-yl) -1 H-benzoimidazoi-5-carboxylic acid (5-chloro-benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzyamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; (benzo [b] thiophen-3-ylmethyl) -amide of 2- (1 H -indazol-3-ii) -1 H-benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyrano-4-ylmethyl) -amide; 2,3-dihydro-benzo [1,4] dioxin-2-ymethyl) -amide of 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; . 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-nitro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (thiophen-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (1-methyl-1 H-benzoimidazol-2-ylmethyl) -amide; - 998 - 3-methyl-benzylamide of 2- (1H-indazol-3-yl) -1 H -benzolamdazole-5-carboxylic acid; 3- 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid chloro-benzylamide; 4- 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid sulfamoyl-benzylamide; (3-ethoxy-propy!) - 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid amide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-bromo-benzylamide; (2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (naphthalene-1-ylmethyl) -amide); 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-dimethylamino-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-nitro-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3-bromo-benzylamide; - 999- 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3-methoxy-benzylamide; (2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1H-IndazoI-3-yl) -3H-benzoimidazole-4-carboxylic acid 4-phenoxy-benzylamide; 3- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3-ylfluoromethoxy-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (2,3-dihydro-benzofuran-5-methyl) -amide; 2- (1 H -indazol-3-ii) -3H-benzoimidazo I-4-carboxylic acid trifluoromethyl-benzylamide; 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (furan-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 2-nitro-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide; |1000- 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3-chloro-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid phenylamide; 2- (1 H-indazoyl-3-yl) -3H-benzoimidazole-4-carboxylic acid benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazo-4-carboxylic acid phenethyl-amide; 3- (6-phenyl-1 H-benzoimidazoi-2-yl) -2H-indazole; 3- [6- (2,4-dichloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-naphthalen-1-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (4-fluoro-phenyl) -1 H -benzoim.idazol-2-yl] -2H-indazole; 3- [6- (4-chloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-methoxy-phenyl] -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-chloro-4-fluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3,5-dichloro-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- (6-thiantren-1-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-biphenyl-4-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-p-tolyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-m-tolyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-o-tolyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-thiophen-3-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (3-trifluoromethyl-phene) -1H-benzoimidazoI-2-yl] -2H-indazole; -1001- 3- [6- (4-Trifluoromethyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-chloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-methoxy-phen) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3,5-dimethy1-pheny1) -1H-benzoimidazoi-2-yl] -2H-indazole; 3- [6- (3,4-dimethy1-pheny1) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-Benzo [1, 3] d -oxol-5-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (4-tert-Butyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- (6-hex-1-ene-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (3,4-D-methoxy-phenyl] -1H-benzoimidazol-2-yl] -2H-indazole; 3- [2- (2H-indazol-3-yl) -3H-benzoxydazol-5-yl] -phenol; 4- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenol; 3- [6- (3,4-dichloro-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-trifluoromethoxy-phenyl) -1H-benzoimidazol-2-yl] -2H-ndazole; 1-. { 4- [2- (2 H -ndazol-3-yl) -3 H -benzoimidazol-5-yl] -phenyl} -etanone; 3- (6-benzo [b] iiophen-2-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (3,4,5-trimethoxy-pheny] -1H-benzoimidazol-2-yl] -2H-indazole; 1-. { 5- [2- (2H-indazol-3-yl) -3H-benzoamidazoI-5-yl] -thiophen-2-yl} - 1-. { 3- [2- (2H-indazol-3-yl) -3H-benzoimidazoI-5-yl] -phenyl} -etanone; 3- [6- (4-benzyloxy-pheny] -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (2-fluoro-bipheni! -4-yl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-benzo [b] thiophen-3-yl-1 H-benzoimidazol-2-y!) - 2H-indazole; . { 3- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenyl} -methanol; -1002- 3- [6- (4-ethylsulfanyl-phenyl] -1 H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (2,4-difluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-trifluoromethoxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-fluoro-2-methyl-phenyl] -1 H -benzoimidazol-2-yl] -2H-indazole; 3-. { 6- [2- (4-fluoro-phenyl) -vin] -1-H-benzoimidazol-2-yl} -2H-indazoI; 3-. { 6- [2- (4-chloro-phenyl) -vinyl] -1H-benzoimidazoI-2-yl} -2H-indazole; acid 3-. { 4- [2- (2H-indazol-3-yl) -3H-benzoamidazol-5-yl] -phenyl} -propionic; . { 4- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenI} -methanol; 3- (6-furan-2-yl-1 H-benzoimidazol-2-yl) -2H-indazoI; 3- [6- (3-benzyloxy-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-isopropyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-methanesulfonyl-phenyl) -1H-benzoamidazol-2-yl] -2H-indazole; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyrano-4-ylmethyl) -amide; 4- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid acetylamino-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid methylamide; 2- (1 H-indazoyl-3-yl) -1 H-benzoimidazole-5-carboxylic acid isopropylamide; [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl-morpholin-4-yl-methanone; -1003- [2- (1 H-indazol-3-yl) -1 H -b'enzoimidazol-5-yl] - (4-methyl-piperazin-1-yl) -methanone; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid benzyl-methyl-amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3-n-benzylamide; 2-Fluoro-benzylamide 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-2-fluoro-benzylamide; "2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2- (1 H-indazole) 3,4-difluoro-benzylamide -3-yl) -1 H-benzoimidazoi-5-carboxylic acid, 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 3,4,5-trifluoro-benzylamide; -1004- 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (4'-doro-biphenyl-4-ylmethyl) -amide; (3 ', 5'-dichloro-biphenyl-4-ylmethyl) -amide of 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (4'-fluoro-biphenyl-4-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2- (1 H -ndazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzyl amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-fluoro-benzamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl) -amide; 2- (1 H-indazoyl-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -annide; -1005- 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (5-pyridin-2-yl-thiophen-2-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazo I-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide; 4- [2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carbonyl] -piperazino-1-carboxylic acid tert-butyl ester; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) acid amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-cyclo-6-methyl-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide; 2- [5- (benzyloxy) -2H-pyrazol-3-yl] -1H-benzo-imidazole; 2- [5- (3-phenyl-allyloxy) 2 H -pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (2-methyl-allyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazoI; 2- [5- (3,7-dimethyl-octa-2,6-dienyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (3-bromo-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 3- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxymethyl] -benzonitrile; -1006- 2- [5- (4-trifluoromethyl-benzyloxy) -2H-pyrazol-3-ii] -1H-benzoimidazole; 2- [5- (3,4-dichloro-benzyloxy) -2H-pyrazol-3-y!] - 1 H -benzoimidazole; 2- [5-pentafluorophenylmethoxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (4-tert-Butyl-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (2-benzenesulfonylmethyl-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 4- [5- (1 H-benzoimidazol-2-y1) -1 H -pyrazol-3-yloxymeth N] -benzonitrile; 2- [5- (biphenyl-4-ylmethoxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of 2-dichioro-benzenesulfonic acid; 2- [5- (2-morpholin-4-yl-ethoxy) -2H-pyrazol-3-yl] -1 H-benzoimidazo I; 2- [5- (2-piperidin-1-yl-ethoxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (3-methoxy-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1-p-tolyl-ethanone; 1 - [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -3,3,4,4,4-pentafluoro-butan-2-one; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1-biphenyl-4-yl-ethanone; 1 - [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -butan-2-one; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1- (4-dimethylamino-phenyl) -ethanone; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1- (3-phenyl-isoxazol-5-yl) -ethanone; -1007- 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -N-phenyl-acetamide; 1 - [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3 -oxy] -3,3-dimethyl-buían-2-one; 1 -adamantan-1 -yl-2- [5- (1 H-benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -ethanone; 2- [5- (1 H-benzoimidazoI-2-yl) -1 H -pyrazol-3-yloxy] -1-naphthalen-2-yl-ethanone; 4-. { 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -acetyl} -benzonitrile; 6- { 2- [5- (1 H-benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -acet [} -3,4-dihydro-1 H-quinolin-2-one; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3 -oxy] -1- (4-trifluoromethoxy-phenyl) -ethanone; 5-. { 2- [5- (1 H-benzoimidazol-2-yl) -1 H-pyrazol-3-yloxy] -acetyl} -2-chloro-benzenesulfonamide; 2- [5- (1 H-benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1- (4-methoxy-phenyl) -ethanone; 2- [5- (1 H -benzoimidazol-2-yl) -1 H -pyrazol-3-yloxy] -1-c'clopropyl-ethanone; 5- (1 H-benzoimidazol-2-yl) -1 H-pyrazol-3-yl ester of isonico-tínico acid; -1008- 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of 2,2-dimethyl-propionic acid ester; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of benzyloxy-acetic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of 4-methoxy-benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of fenii-acetic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl acid 2,3,4,5,6-pentafluorobenzoic acid ester; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of cyclopropanecarboxylic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl acid ester 2,2,3,3,4,4,4-heptafluoro-butyric; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of cyclo-pentanecarboxylic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl-3-phenyl-propionic acid ester; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of biphenyl-4-carboxylic acid; -1009- 5- (1 H -benzoimidazol-2-yl) -1 H-pyrrazol-3-yl ester of 3,5-bis-trifluoromethyl-benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of 4-trifluoromethyl-benzoic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazoic-3-yl ester of thiophene-2-carboxylic acid; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 157. A compound according to claim 14, which is 2- (5-ethyl-2H-pyrazol-3-yl) -5,6-dimethyl-1 H-benzimidazole; or 2- (5-methyl-2H-p -razol-3-yl) -5,6-dimethyl-1H-benzimidazole; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 158. A compound according to claim 54, which is 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-methylamide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-ethylamide; 2- (H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-isopropylamide; -1010- 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-phenylamide; 2- (lH-indazol-3-yl) -H-benzimidazole-5-carboxylic acid N-phenethylamide; 2- (1 H-indazol-3-yl) -1 H-benzimidazoy-5-carboxylic acid N-morpholinoamide; N- (N'-methylpiperazino) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; 2- (1 H-indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-pyrrolidinoamide; N- (isobutyl) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; N- (cyclohexylmethyl) 2- (1 H-indazoI-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N- (2-furfuryl) amide; 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid N-benzyi-N-methylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (3-ethoxy-propyl) -amide; -1011- 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 4-methanesulfonyl-benzylamide of 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (naphthalene-l-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1 H -indazol-3-ii) -1-hybenzoimidazole-5-carboxylic acid (thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-dimethylamino-benzylamide; 4- ( { [2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carbonyl] -amino} -methyl) -piperidino-1-tert-butyl ester carboxylic; 2- (1 H-indazol-3-Ib) -1 H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; (2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-3-ymethyl) -amide of acid; 2- (1 H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid 3-bromo-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 3-methoxy-benzylamide; -1012- (2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [1,3] d, oxo-5-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (1,3-dimethyl-1 H-pyrazol-4-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-trifluoromethoxy-benzylamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 2-methylbenzylamide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (3-methyl-thiophen-2-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethyl-benzylamide; 2- (1 H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-phenoxy-benzylamide; 3- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid trifluoromethoxy-benzylamide; 2- (1 H -ndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (3-isopropoxy-propyl) -amide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (1-methyl-1 H -pyrazol-4-ylmethyl) -amide; -1013- 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-isopropyl-benzylamide; 2- (1 H -indazol-3-ii) -1 H-benzoimidazole-5-carboxylic acid (2,5-dimethyl-furan-3-ylmethyl) -amide; 5- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (benzo [b] thiophen-2-ylmethyl) -amide; [3- (3-Acetylamino-phenoxy) -propyl] -amide of 2- (1 H -indazol-3-H-benzoimidazole-5-carboxylic acid; (6-cyclo-pyridin-3-ylmethyl) -amide] 2- (1 H-indazol-3-yl) -1-hyl or benzoimidazole-5-carboxylic acid; 2- (1 H-indazoI-3 (2- [2 '] -thiopiophenyl-5-ylmethyl) -amide) -yl) -1 H- benzoimidazole-5-carboxylic acid (2,3-dihydro-benzofuran-5-ylmethyl) -amide of 2- (1 H-indazol-3-yl) -1 H -benzoimidazole -5-carboxylic acid; 4-cyano-benzylamide of 2 ~ (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid; (5-chloro-benzo [b] thiophen-3-ylmethyl) 2- (1 H-indazol-3-yl) -H-benzoamidazole-5-carboxylic acid amide: 2- (1 H-indazol-3-yl) -1 H- 3-trifluoromethyl-benzylamide 0-benzoimidazole-5-carboxylic acid 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; -1014- 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid benzo [b] thiophen-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (tetrahydro-pyrn-4-ylmethyl) -amide; (2,3-Dihydro-benzo [1,4] dioxin-2-ylmethyl) -amide of 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (furan-3-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid nitrobenzamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid thiophen-3-methylmethyl -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 3,5-dimethyl-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (1-methyl-1H-benzoimidazol-2-ylmethyl) -amide; 3- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methylbenzamide; 3- 2- (1H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid chloro-benzylamide; 4- 2- (1H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid sulfamoyl-benzylamide; -1015- 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (pyridin-3-ylmethyl) -amide; 2- (1 H-indazoI-3-yl) -3H-benzoimidazo I-4-carboxylic acid 3-methoxy-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid (furan-3-ylmethyl) -amide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid nitro-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 3,5-dimethyl-benzylamide; 2- (1 H-indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid phenylamide; 3- [6- (4-fluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-chloro-4-fluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- (6-m-tolyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-o-tolyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-thiophen-3-yl-1 H-benzoimidazol-2-y [(2)] -2H-indazole; 3- [6- (3-chloro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3-methoxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (3,5-dimethyl-phene) -1 H -benzoimidazol-2-yl] -2H-indazole; -1016- 3- (6-benzo [1,3] dioxol-5-yl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- (6-hex-1-enyl-1 H-benzoimidazol-2-yl) -2H-indazole; 3- [6- (3,4-dimethoxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [2- (2H-indazo [-3-yl] -3H-benzoimidazol-5-yl] -phenol; 4- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenol; 3- [6- (3,4,5-trimethoxy-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 1-. { 5- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -thiophen-2-yl} -etanone; . { 3- [2- (2H-indazo [-3-yl] -3H-benzoimidazol-5-yl] -phenyl} -metahol; 3- [6- (2,4-difluoro-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazole; 3- [6- (4-fluoro-2-methyl-phenyl) -1H-benzoimidazol-2-yl] -2H-indazole; . { 4- [2- (2H-indazol-3-yl) -3H-benzoimidazol-5-yl] -phenyl} -methanol; 3- (6-furan-2-yl-1 H-benzoimidazol-2-yl) -2H-indazoi; 3- [6- (4-isopropyl-phenyl) -1 H -benzoimidazol-2-yl] -2H-indazoI; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid tetrahydro-pyrn-4-ylmethyl) -amide; 4- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid acetylamino-benzylamide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid methylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid isopropylamide; -1017- [2- (1 H -ndazol-3-yl) -1 H -benzoimidazoI-5-yl] -morfoin-4-yl-methanone; [2- (1 H-indazol-3-yl) -1 H -benzoimidazol-5-yl] - (4-methyl-piperazin-1-yl) -methanone; benzyl-methyl-amide of 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid; 3- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid nitro-benzylamide; 2- (1 H-indazol-3-yl) -1H-β-benzoimidazole-5-carboxylic acid 2-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-difluoro-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 2,6-difluoro-benzylamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-b6-cyl-amide; 4- (1 H-indazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid chloro-2-fluoro-benzylamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-bromo-2-f! Uoro-benzylamide; 3,4-difluoro-benzylamide of 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; -1018 - 3,4,5-trifluoro-benzylamide of 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; 2- (1 H-indazoI-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,6-difluoro-3-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide *; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-chloro-benzylamide; 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-chloro-2-methyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-fluoro-benzamide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2'-chloro-biphenyl-4-ylmethyl) -amide; 2- (1H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-trifluoromethyl-pyridin-3-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (5-pyridin-2-yl-iiophen-2-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (3-imidazol-1-yl-propyl) -amide; 4- [2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carbonyl] -piperazine-1-carboxylic acid tert-butyl ester; -1019- 2- (1H-IndazoI-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,6-d, fluoro-4-chloro-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) acid amide; 2- (1 H -indazoI-3-yl) -1 H -benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2-fluoro-4-chloro-6-methyl-benzyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide; 2- [5- (benzyloxy) -2H-pyrazole-3-ii] -1 H-benzoimidazole; 2- [5- (3-phenyl-allyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (3,7-dimethyl-octa-2,6-dienyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (3-bromo-benzyloxy) -2H-pyrazol-3-yl] -1 H-benzoimidazole; 2- [5- (3,4-dichloro-benzyloxy) -2H-pyrazol-3-yl] -1 H -benzoimidazole; 2- [5- (2-benzenesulfonylmethyl-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 2- [5- (biphenyl-4-ylmethoxy) -2H-pyrazol-3-yl] -1 H -benzoimidazo I; 2- [5- (3-methoxy-benzyloxy) -2H-pyrazol-3-yl] -1H-benzoimidazole; 5- (1H-benzoimidazol-2-yl) -1H-pyrazol-3-yl ester of isonicotinic acid; 5- (1H-benzoimidazol-2-yl) -1H-pyrazole-3-yl ester of benzoic acid; -1020- 5- (1 H-benzoimidazol-2-yl) -1 H-pyrrazol-3-ylco ester of 3-phenyl-propionic acid; 2- (1 H-indazol-3-yl) -3H-benzimidazole-5-carboxylic acid methyl ester; 5-methoxy-2- (1 H -indazol-3-yl) -1 H-benzimidazole; 5-bromo-2- (1 H-indazol-3-yl) -3H-benzimidazole, or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 159. A compound according to claim 54, which is N- (cyclohexylmethyl) amide of 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid; N- (2-furfuryl) 2- (1 H -indazol-3-yl) -1 H-benzimidazole-5-carboxylic acid amide; 2,4-dic! 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-bromo-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-methanesulfonyl-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-nitro-benzylamide; 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methylbenzylamide; -1021- 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-chloro-pyridin-3-ylmethyl) -amide; (2,3-dihydro-benzofurandr-5-ymeleyl) -amide of 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 2-methylsulfanyl-benzylamide; (benzo [b] thiophen-3-ylmethi) -amide of 2- (1 H -indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid; 2- (1 H-indazol-3-yl) -1-hibenzoimidazole-5-carboxylic acid 3-methyl-benzylamide; 3- 2- (1 H-indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid chloro-benzylamide; 2- (1 H -indazol-3-yl) -3H-benzoimidazole-4-carboxylic acid 2-methylsulfanyl-benzylamide; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid 4-bromo-2-fluoro-benzylamide; 2- (1 H -.indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 2,4-dichloro-benzylamide; 4- chloro-benzylamide of 2- (1 H-indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid 4-cyclo-2-methyl-benzylamide; -1022- 2- (1 H -indazol-3-yl) -1 H -benzolamdazole-5-carboxylic acid (2,6-difluoro-4-chloro-benzyl) -amide; 2 ~ (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (2,4-dichloro-6-fluoro-benzyl) acid; 2- (1 H -indazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (3-fluoro-4-chloro-benzyl) acid amide; 2- (1 H-indazol-3-yl) -1 H -benzoimidazole-5-carboxylic acid (2-fIuoro-4-chloro-6-methyl-benzyl) acid amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid (6-methoxy-pyridin-3-ylmethyl) -amide; or a pharmaceutically acceptable N-oxide, prodrug, acid bioisoester, salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. 160. A compound according to claim 3, which is 2- (1 H-lndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (2-pyridin-1-yl-ethyl) -amide.; (2- (1 H-lndazol-3-yl) -1 H-benzoimidazole-5-carboxylic acid (pyridin-2-ylmethyl) -amide; 2- (1 H -indazol-3-yl) -1H-benzoimidazole-5-carboxylic acid [3- (4-methyl-piperazin-1-yl) -propyl] -amide; N- [2- (1 H-lndazol-3-yl) -1 H -benzoimidazol-5-yl] -isobutyramide, Example 246 (ae) N- [3- (5,6-Dimethyl-1 H-benzoimidazole- 2-yl) -1 H -pyrazol-4-yl] -2-piperidin-1-yl-acetamide, -1023- or an N-oxide, prodrug, acid bioisoester, pharmaceutically acceptable salt or solvate of this compound, or an N-oxide, prodrug or acid bioisoester of this salt or solvate. wherein: X represents C-R2 and V, Y and Z, which may be the same or different, represent CH or CR3; R1 represents aryl or heteroaryl selected from pyrazolyl radicals, triazolyl, imidazolyl, indolyl, indazolyl, tienopirazolilo, tetrahidroin-dazolilo, tetrahidrociclopentapirazolilo, dihidrofuropirazolilo, oxodihidropiridazi-nile tetrahidropirrolopirazolilo, oxotetrahidropirrolopirazolilo, tetrahidropiranopi-razolilo, tetrahidropiridinopirazolilo and oxodihidropiridinopirazolilo being op-tionally all these radicals substituted with one or more radicals X1, X2 or X3 selected from H, halogen, haloalkyl, OH, R4, N02, CN, S (0) nR4, OR4, NY1Y2, COR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, -N (R6) C (= 0) R4, - -1024- N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY Y2, -OC (= 0 ) NY1Y2, -OS (0) nR4, -OC (= 0) R4 and optionally substituted thienyl, R2 and R3 are such that: any of R2 and R3, - which may be the same or different, re-present H, R4, halogen, haloalkyl, OH, N02, CN, OR4, COR4, S (0) nR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, -NY1Y2, -N ( R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -SCOJnNYV, -OC (= 0) NY1Y2 and -OC (= 0) R4 or R2 represents H, R4, halogen, haloalkyl, OH, N02, CN, OR4, COR4, S (0) nR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, -NY Y2, -N (R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2 , -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2 and -OC (= 0) R4 and R3 represents alkyl, haloalkyl, halogen and OR6, or R2 and R3 together form a ring based on 5 to 6 membered carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and S , R4 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl, all of these radicals being optionally substituted with one or more radicals chosen from optionally substituted aryl, halogen, alkyl, hydroxyalkyl, OH, OR5, C (= 0) NY3Y4; NY3Y4, alk-NY3Y4 and C (= 0) OR6 ,; -1025- R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkyl-quinilyl. Y1 and Y2 are such that: any of Y1 and Y2, which may be the same or different, represents H and optionally substituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or Y1 and Y2 form, together with the nitrogen atom to which they are attached, a cyclic radical, Y3 and Y4 are such that: any of Y3 and Y4, which may be the same or different, represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y3 and Y4 form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical, A5 represents H or alkyl, R6 is chosen from the values of R5, all the alkyl or alk radicals, which represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl present in the above radicals are further optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH-COalk), -C (= 0) OR6, acyl -C (= 0) Rs, hydroxyalkyl, carboxyalkyl, S (0) radicals ) n-alk, S (0) n-NH2 (S (0) n-NH (alk), -1026- S (0) nN (alk) 2, CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3Y4 and NY3Y4, these latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more radicals selected from halogen atoms and alkyl radicals, free, salified or esterified carboxyl radicals and acylamino radicals NH-C (0) R5, the phenyl radicals are further optionally substituted with a dioxol radical , n represents an integer from 0 to 2, with the proviso that when R 1 represents an indazolyl radical to provide the compounds of formula (F) below: wherein X represents H, R2 or R3 as defined above, then W of formula (F) necessarily represents H or unsubstituted alkyl; or the racemic isomeric enantiomeric or diastereomeric form of this -1027- compound, or an addition salt of a mineral or organic acid or a mineral base of this compound. 162 - A compound according to claim 160, of formula (la) TO 5 (the) wherein Xa represents C-R2a and Wa, Ya and Za, which may be equal or different, represent CH or CR3a; . R-a represents aryl or heteroaryl selected from pyrazolyl, triazolyl and indazolyl radicals, and all these radicals are optionally substituted with one or more X a, X 2 a or X 3 a radicals selected from H, halogen, OH, R 4a, OR a, NY 1 a and 2 a , S (0) nR4a, -C (= 0) NY1aY2a,. -C (= 0) OR a, - N (R6a) C (= 0) R4a, -N (R6a) S02R4a, -N (R6a) C (= 0) NY1aY2a, -N (R6a) C (= 0) OR4a, -OC (= 0) NY1aY2a, -OC (= 0) R4a, -OS (0) nR4a and thienyl optionally substituted with an alkyl radical, R2a and R3a are such that: any of R2a and R3a, which may be equal or different, represent H, R4a, halogen, OH, OR4a, C (= 0) NY1aY2a, -C (= 0) OR4a and -1028- -C (= 0) OH, and R3a represents alkyl, halogen and OR6a, or R2a represents H, R4a, halogen, OH, OR4a, C (= 0) NY1aY2a, -C (= 0) OR4a and -C (= 0 ) OH, and R3a represents alkyl, halogen and OR6a, 'or R2a and R3a together form a ring -0-CH2-0- or -O-CH2-CH2-O-, R4a represents alkyl, alkenyl, cycloalkyl, aryl, heteroaryl , cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl, all of these radicals being optionally substituted with one or more radicals selected from aryl (optionally substituted), halogen, alkyl, hydroxyalkyl, OH, OR5a, C (= 0) NY3aY4a, NY3aY4a, alk-NY3aY4a and C (= 0) OR6a, R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, and all of these radicals are optionally substituted, Y1a and Y2a are such that: any of Y and Y2a, which may be identical or different, represent H, alkyl, alkoxyalkyl, aryloxyalkyl, arylal chyl, heteroarylalkyl, heterocycloalkylalkyl, cycloalkyl, aryl and heteroaryl, and all of these radicals are optionally substituted, or Y1a and Y2a form, together with the nitrogen atom to which they are attached, an optionally substituted amino radical, Y3a and Y4a are such: of Y3a and Y4a, which may be the same or different, represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, -1029- or Y3a and Y4a form, together with the nitrogen atom to which they are attached, a cyclic amino radical, A5 represents H or alkyl, all alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl present in the above radicals are further optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, acylamino (NH-C (0) R6a), -C (= 0) OR6a radicals , acyl -C (= 0) R6a, hydroxyalkyl, carboxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n -NH (alk), S (0) nN (alk) 2 , CF3, OCF3, NO2, arylalkoxy, aryl, heteroaryl, aryloxy, aryloxyalkyl, -C (= 0) -NY3aY4a and NY3aY4a, these latter radicals containing alkyl, aryl and heteroaryl are themselves optionally substituted with one or more chosen radicals between halogen atoms and alkyl radicals, alkoxy radicals, free carboxyl radicals, salified or esterified radicals and acylamino NH radicals -C (0) R6a, the phenyl radicals are further optionally substituted with a dioxol radical, R6a is chosen from the values of R5a, n represents an integer from 0 to 2, or the racemic isomeric enantiomeric or diastereomeric form of this compound, or an addition salt of a mineral or organic acid or a mineral base of this compound. -1030- A compound of formula (I) TO. O) in which: X represents C-R2 and V, Y and Z, which may be the same or different, represent CH or CR3; R1 represents aryl or eteroarilo chosen from pyrazolyl radicals, triazolyl, imidazolyl, indoliio, indazolyl, tienopirazolilo, tetrahidroin-dazolilo, tetrahidrociclopentapirazolilo, dihidrofuropirazolilo, oxodihidropiridazi-nile tetrahidropirrolopirazolilo, oxotetrahidropirrolopirazolilo, tetrahidropiranopi-razolilo, tetrahidropiridinopirazolilo and oxodihidropiridinopirazolilo being op-tionally all these radicals substituted with one or more radicals X1, X2 or X3 selected from H, halogen, haloalkyl, OH, R4, N02, CN, S (0) nR4, OR4, NY Y2, COR4, -C (= 0) NY1Y2; -C (= 0) OR4, -C (= 0) OH, -N (R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N ( R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2, -OS (0) nR4, -OC (= 0) R4 and optionally substituted thienyl, R2 and R3 are such that: any of R2 and R3, which may be the same or different, represent H, R4, halogen, haloalkyl, OH, N02, CN, OR4, COR4, S (0) nR4, C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, -NY1Y2, -N (R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2 and -OC (= 0) R4 or R2 represents H, R4, halogen, haloalkyl, OH, N02, CN, OR4, COR4, S (0) nR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, - NY1Y2, -N (R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2 and -OC (= 0) R4 and R3 represent alkyl, haloalkyl, halogen and OR6, or R2 and R3 together form a ring based on carbon atoms of to 6 members containing one or more heteroatoms, which may be the same or different, chosen from O, N and S, R 4 represents alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, cycloalkylalkyl, heterocycloalkyl, heteroarylalkyl and arylalkyl, optionally substituted all these radicals with one or more radicals selected from aryl (optionally substituted), halogen, alkyl, hydroxyalkyl, OH, OR5, C (= 0) NY3Y4, NY3Y4, alk-NY3Y4 and C (= 0) OR 6; R5 represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl; R6 represents H and C1-C4 alkyl; n represents an integer from 0 to 2; Y1 and Y2 are such that: any of Y1 and Y2, which may be equal or different, represents H and optionally substituted alkyl, alkenyl -1032- lo, cycloalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, or Y1 and Y2 form, together with the nitrogen atom to which they are attached, a radical! cyclic, Y3 and Y4 are such that: any of Y3 and Y4, which can be Equal or different, they represent hydrogen, alkenyl, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl or Y3 and Y4 form, together with the nitrogen atom to which they are attached, an optionally substituted cyclic amino radical, A5 represents H or alkyl, with the proviso that when R1 represents an indazoyl radical to provide the following compound of formula (F): (F) where X represents H, R2 or R3 as defined above, then W of formula (F) necessarily represents H or unsubstituted alkyl; or the racemic isomeric enantiomeric or diastereomeric form of this compound, or an addition salt of a mineral or organic acid or a mineral base of this compound. -1033- 164. - A compound according to claim 161 of formula (la) (la) in which: Xa represents C-R2a and Wa, Ya and Za, which may be the same or different, represent CH or CR3a; R a represents aryl or heteroaryl selected from pyrazolyl, triazolyl or indazolyl radicals, and all these radicals are optionally substituted with one or more radicals X 1 a, X 2 a or X 3 a selected from H, halogen, OH, R4a, OR4a, NY1aY2a, S (0) nR4a, -C (= 0) NY1aY2a, -C (= 0) OR a, --N (R6a) C (= 0) R4a, -N (R6a) S02R4a, -N (R6a) C (= 0) NY1aY2a, -N (R6a) C (= 0) OR4a, -OC (= 0) NY aY2a and -OC (= 0) R4a, -OS (0) nR ay thienyl optionally replaced with a radica! alkyl, R2a and R3a are such that: any of R2a and R3a, which may be the same or different, represents H, R4a, halogen, OH, OR4a, C (= 0) NY1aY2a, -C (= 0) OR a, -C (= 0) OH and R3a represents alkyl, halogen and OR6a, or R2a represents H, -1034- R4a, halogen, OH, OR4a, C (= 0)! \! Y1aY2a, -C (= 0) OR4a, -C (= 0) OH and R3a represent alkyl, halogen and OR6, or R2a and R3a together form a ring an -O-CH2-O or -O-CH2-CH2-0-, R a represents alkyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, heteroarylalkyl or arylalkyl, and all these radicals are optionally substituted with one or more radicals chosen from aryl, OH, OR5a, C (= 0) NY3aY4a, NY3aY4a and C (= 0) OR6a, R5a represents alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, cycloalkylalkyl, heteroarylalkyl and heterocycloalkylalkyl, R6a represents H and Ci-C4 alkyl, n represents an integer from 0 to 2, Y1a and Y2a are such that: any of Y1a and Y2a, which may be the same or different, represents H, alkyl, cycloalkyl, aryl and heteroaryl, and all of these radicals are optionally substituted with one or more radicals selected from hydroxyl, -C (= 0) -NY3Y4, -C (= 0) OR6 and NY3Y4, or Y1a and Y2a form, together with the nitrogen atom to which they are attached, a cyclic amino radical, Y3a and Y4a are such: any of Y3a and Y4a , which may be identical or different, represents hydrogen, alkyl, aryl, arylalkyl, cycloalkyl, heteroaryl or heteroarylalkyl, or Y3a and Y4a form, together with the nitrogen atom to which they are attached, a cyclic amino radical, -1035- A5 represents H or alkyl, or the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 165. - A compound according to claim 161, of formula IA (IA) in which A represents a saturated heterocyclic radical which is a 5- or 6-membered monocyclic radical or a bicyclic radical having no more than 0 members, and these members are such that at least two of them represent a nitrogen atom and the others, which may be the same or different, they represent a carbon atom or a heteroatom selected from O, N and S, and this heterocycle A is optionally substituted with one or more X-rays, XA2 or XA3 selected from H, halogen, haloalkyl, OH, R4, N02, CN, S (0) nR4, OR4, NY1Y2, COR4, -C (= 0) NY1Y2, -C (= 0) OR4, -C (= 0) OH, --N (R6) C (= 0) R4, -N (R6) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2 , -OS (0) nR 4, -OC (= 0) R 4 and optionally substituted thienyl; -1036- Ai, A2, A3 and A4, which may be the same or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, aryl, heteroaryl and aryloxy radicals, a carboxyl radical. boxyl which is free, salified, esterified with an alkyl radical or amidated with a radical NA6A7 such that any of A6 and A7, which may be the same or different, is chosen from optionally substituted alkyl, alkoxyalkyl, phenoxyalkyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycloalkylalkyl and heteroarylalkyl radicals, or A6 and A7 form, together with the nitrogen atom to which they are attached, an optionally substituted 5 or 6-membered cyclic radical, it being understood that two consecutive radicals between Ai, A2, A3 and A4 can form, with the benzimidazole radical to which they are attached, a ring based on 5 to 6 membered carbon atoms containing one or more heteroatoms, which can be n being the same or different, chosen from O, N and s, A5 represents a hydrogen atom or an alkyl radical, R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl, all the alkyl, alkenyl, aryl, heteroaryl, aryloxy, cycloalkyl and heterocycloalkyl present in the above radicals are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH) radicals -COR6), -C (= 0) OR6b, -1037- acyl -C (= 0) R6b, hydroxyalkyl, carboxyalkyl, phenoxy-cyclic, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, N02, CN, phenyle, substituted in itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2, all the above alkyl, alkenyl, alkoxy and alkylthio radicals are linear or branched and contain not more than 4 carbon atoms, all the phenyl radicals of the above radicals are also optionally substituted with a dioxol radical, n represents an integer from 0 to 2, the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 166.- A compound according to claim 161, of formula (the A) (the A) wherein Aa represents a pyrazolyl, triazolyl or indazolyl radical, and this heterocycle Aa is optionally substituted with one or more radicals XA1, XA2 or XA3 selected from H, halogen, haloalkyl, OH, R4, N02, -1038- CN, S (0) nR4, OR4, NY1Y2, COR4, -C (= 0) NY Y2, -C (= 0) OR4, -C (= 0) OH, -N (R6) C (= 0) R4 , -N (R5) S02R4, -N (R6) C (= 0) NY1Y2, -N (R6) C (= 0) OR4, -S (0) nOR4, -S (0) nNY1Y2, -OC (= 0) NY1Y2, -OS (0) nR4, -OC (= 0) R4 and optionally substituted thienyl; A-ia, A2a, Asa and A4a, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, akoxy, nitro, cyano, phenyl and phenoxy radicals, and a carboxyl radical that is free, salified or esterified with an alkyl radical or amidated with a radical NA6aA7a such that any of A6a and A7a, which may be the same or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, thienylalkyl and pyridylalkyl radicals, or A6a and A7a form, together with the nitrogen atom to which they are attached , a pyrrolidinyl, pyrazolydinyl, pyrazolinyl, piperidyl, morpholino or piperazinyl radical, optionally substituted on the second nitrogen atom with an alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals between A-ia, A2a , A3a and A-va can form, with the benzimidazole radical to which they are attached, a ring based on carbon atoms of 5 to 6 members optionally substituted which contains one or two oxygen atoms, A5a represents a hydrogen atom or an alkyl radical, and the above phenyl and phenoxy radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy radicals , alkyl, akoxy, amino, -1039- alkylamino, dialkylamino, phenylamino, phenylalkylamino, free, salified or esterified carboxyl and dioxole, and all the above alkyl, alkoxy and alkylthio radicals are linear or branched and contain not more than 6 carbon atoms, the racemic, enantiomeric isomeric form or diastereoisomer of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 167.- A compound according to claim 161, of formula IA wherein A represents a saturated heterocyclic radical which is a 5- or 6-membered monocyclic radical or a bicyclic radical having not more than 10 members, and these members are such that at least two of them represent a nitrogen atom and the others, which may be the same or different, represent a carbon member or a heteroatom member selected from O, N and S, and this heterocycle A is optionally substituted with one or more XA1, XA2 or XA3 radicals selected from halogen atoms, radicals alkyl, alkoxy or alkylthio or thionyl radicals optionally substituted with an alkyl radical, -1040- Ai, A2, A3 and A4, which may be the same or different, are chosen from a hydrogen atom, halogen atoms and hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals, a carboxy radical that is free, salified or esterified with an alkyl or amidated radical with a radical NA6A7 so that A6 and A7, which may be the same or different, are chosen from a hydrogen atom and alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and heteroanalkyl radicals, or A6 and A7 form, together with the nitrogen atom to which they are attached, a cyclic radical of 5 or 6 members, it being understood that two consecutive radicals between Ai, A2, A3 and A4 can form, with the benzimidazole radical to which they are attached, a ring based on 5-6 membered carbon atoms containing one or more heteroatoms, which may be the same or different, chosen from O, N and s, A5 represents a hydrogen atom or an alkyl radical, all residues the phenyl, phenoxy, cycloalkyl and heteroanalkyl are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluorome-toxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, carboxyl radicals free, salified or esterified and dioxole, and all the above alkyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 6 carbon atoms, -1041- the racemic, enantiomeric or diastereomeric isomeric form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 168.- A compound according to claim 161, of formula lAb wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or two radicals selected from halogen atoms and OH, alkyl, alkynyl, -OR6b including alkoxy, -COR6b, -0-COR6b, -OS (0) nR¾ radicals, -0 (CH2) n-CO-R6b, phenyl, phenylalkyl, CF3, OCF3, N02, CN, NY1bY2b, -NH-C (= 0) NY bY2b, acylamino (NH-CO-R6b), S (0) n -alk, S (0) n-NY1bY2b, -C (= 0) -NY1bY2b, -C (= 0) OR%, -NH-C (= 0) R6b, -NH-S (0) nR¾, -NH -C (= 0) OR6b, -N (R6b) C (= 0) NY1bY2b, -OC (= 0) NY1bY2b and thienyl, and all these radicals are optionally substituted, NY1bY2b is such that either of Y1b and Yb, which they can be the same or different, hydrogen is chosen from optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl or Y 1b and Y 2b form, together with the nitro -1042- geno to which they are attached, a piperidyl, hexahydrofuran, morpholinyl or morpholinyl alkyl radical, Aib, A2b, A3b and A4b, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl radicals, alkyl , alkenyl, -OR6b including alkoxy, -CO-R6b, -0-COR6b, -OS (0) nR6b, -0 (CH2) n-CO-R5b, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thianthrenyl, phenyl and phenoxy and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA6bA7b so that A6b and A7b, which may be identical or different, are chosen from hydrogen and radi-cal alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthyl, thienylalkyl, piperidyl, pyridyl, benzotienilalquilo, pyrazolylalkyl, dihidrobenzofuranoilalquilo, hexa-hidropiranilalquilo, etilendioxifenilalquilo and bencimidazolilalquilo, and these radicals are optionally substituted, or ¾ and A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl radical, morfoli-not or piperazinyl, and piperazinyl radical is optionally substituted on the second nitrogen atom with an alkyl radical which are themselves optionally substituted, it being understood that between two consecutive radical A b, A2b, A3b and A4b may form, with the radical benzimidazole to which they are attached, an optionally substituted-4,5 etilendioxibencimidazol radical or a 4,5-metilendioxibencimidazol optionally substituted, represents A5b a hydrogen atom, -1043- and all the above radicals containing aikyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidium, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH-COR6b), -C (= 0) OR¾, acyl -C (= 0) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (0) n- alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, N02, CN, phenyl, optionally substituted by itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2, n represents an integer of 0 to 2, and R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihydroquinoline, -NH-phenyl, phenylalkyl and cycloalkylalkyl, and all of these radicals are optionally substituted two with a morpholino, piperidiio or phenyl radical optionally substituted with one or more radicals selected from halogen atoms and the cyano radical, CF3, OCF3, alkyl, phenyl-S (0) n-alk-phenyl, alkoxy, NH2, NHalk, N (alk) 2, S02NH2) S02Nalk or S02N (alk) 2, and all the above alkyl, alkenyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 10 carbon atoms, and all phenyl radicals of the radicals above are also optionally substituted with a dioxol radical, -1044- the racemic, enantiomeric or diastereomeric isomeric form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 169.- A compound according to claim 161, of formula lAb wherein Ab represents a radical] pyrazolyl or indazolyl optionally substituted with one or two radicals selected from halogen atoms and OH, alkyl, alkynyl, alkoxy, phenyl, phenylalkyl, CF3, OCF3, NO2, CN, NY bY2b, -NH radicals -C (= 0) NY bY2b, acylamino (NH-CO-R6b), S (0) n-alk, S (0) n-NY1bY2b, -C (= 0) -NY1bY2b, -C (= 0) OR6b , -NH-C (= 0) R6b, -NH-S (0) nR6b, -NH-C (= 0) OR6b, -N (R6b) C (= 0) NY1bY2b, -OC (= 0) NY bY2b and thienyl which are optionally substituted, and NY bY2b is such that any of Y1 and Y2b, which may be the same or different, are selected from hydrogen and alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl optionally substituted or Y be Y2b form, together with the nitrogen atom to which they are attached, a radical to piperidyl, hexahydrofuran, morpholiniyl or morpholinyl alkyl, -1045- A-ib, A2b, A3b and A_b, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkenyl, alkoxy, nitro, cyano, furyl, thienyl, benzothienyl, naphthyl, thienyl-nyl, phenyl and phenoxy and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidified with a radical NA6bA7b so that A6b and A7b, which may be identical or different, are chosen from hydrogen and alkyl radicals , alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthyl, thienylalkyl, piperidyl, pyridyl, benzotienilalquilo, pyrazolylalkyl, dihidrobenzofuranoilalquilo, hexahidropirani-lalquilo, etilendioxifenilalquilo and bencimidazolilalquilo, and these radicals are optionally substituted, or A6b and A7b form , together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical which is optionally substituted on the second nitrogen atom with an alkyl radical which is itself optionally substituted, it being understood that two consecutive radicals between A1b, A2b, A3b and A b can form, with the benzimidazole radical to which they are attached, a radical Optionally substituted 4,5-ethylenedioxybenzimidazole or an optionally substituted 4,5-methylenedioxybenzimidazole radical, A5b represents a hydrogen atom, and all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl, thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkyl, -1046- quilamino, phenylamino, phenylalkylamino, acylamino (NH-COR6b), -C (= 0) OR6b, acyl -C (= 0) R6b, hydroxyalkyl, carboxyalkyl, phenoxyalkyl, S (0) n-alk, S (0 ) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2j CF3, OCF3, N02, CN, phenyl, optionally substituted in itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) -N (alk) 2) n represents an integer from 0 to 2, and R6b represents hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, phenylalkyl and cycloalkylalkyl, and all the above alkyl, alkenyl, alkoxy and alkylthio radicals are. linear or branched and contain no more than 10 carbon atoms, and all the phenyl radicals of the above radicals are further optionally substituted with a dioxole radical, or the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt thereof. a mineral or organic acid or a mineral base of this compound. 170.- A compound according to claim 161, of formula lAb wherein Ab represents a pyrazolyl radical substituted with one or two radicals such that one is selected from hydrogen, halogen atoms and -1047- alkyl, alkynyl, -COR6b, phenyl, phenylalkyl, CF3, N02, CN, NY1bY2b, -NH-C (= 0) NY bY2b, NH-CO-R6b, S (0) "- alk, S ( 0) n-NY1bY2b, -C (= 0) -NY1bY2b, -C (= 0) OR6b, -NH-C (= 0) R6b, -NH, and all these radicals are optionally substituted, and the other is chosen from OH radicals, -OR6b, -0-CORsb, -OS (0) nR6b, -0 (CH2) n-CO-R6b and -OC (= 0) NY1bY2b, and these radicals are optionally substituted, NY1bY2b is such that Y1b Y2b, which may be the same or different, are chosen from hydrogen and optionally substituted alkyl, cycloalkyl, cycloalkylalkyl, phenyl, naphthyl, phenoxy, phenylalkyl, phenylalkylthio and naphthylalkyl, or Y1b and Y2b form, together with the nitrogen atom to which they are attached , a radical to piperidyl, hexahydrofuran, morpholinyl or morpholinyl-chyl, A-ib, A2b, A3b and A4, which may be the same or different, are such that two of them represent hydrogen and the other two, which may be the same or different , are chosen among an atom d and hydrogen, halogen atoms, hydroxyl, alkyl, alkenyl, -OR6b (including alkoxy), -CO-R6b, -0-COR6b, -OS (0) nR6b, -0 (CH2) n-CO-R6b, nitro , cyano, furyl, thienyl, benzothienyl, naphthyl, thiantrenyl, phenyl and phenoxy and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidated with a radical NA6bA7b so that any of A6b and A7b, which may be the same or different, are chosen from hydrogen and alkyl, alkoxyalkyl, phenoxyalkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl, naphthylalkyl, -1048-thienylalkyl, piperidylalkyl, pyridylamino, benzothienylalkyl, pyrazolylalkyl, dihydrobenzofuranoylalkyl, hexahydropyranylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl, and all of these radicals are optionally substituted, or A6b and A7b form, together with the nitrogen atom to which they are attached, a radical pyrrolidinyl, morpholino or piperazinyl which is optionally substituted on the second nitrogen atom with an alkyl radical which is itself optionally substituted, A5b represents a hydrogen atom, and all the above radicals containing alkyl, alkenyl, phenyl, phenoxy, furyl , thienyl, piperidyl, pyridyl, pyrazolyl and benzimidazolyl are optionally substituted with one or more radicals selected from halogen atoms and hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, acylamino (NH-COR6b) radicals ), -C (= 0) OR6b, acyl -C (= 0) R6b, hydroxyalkyl , carboxyalkyl, phenoxyalkyl, S (0) n-alk, S (0) n-NH2, S (0) n-NH (alk), S (0) nN (alk) 2, CF3, OCF3, N02, CN, phenyl, which is optionally substituted by itself with one or more halogen atoms, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk) and C (= 0) - N (alk) 2, n represents an integer from 0 to 2, and R6b representing hydrogen, alkyl, alkenyl, cycloalkyl, phenyl, pyridyl, thienyl, naphthyl, isoxazole, adamentyl, quinoline, quinolone, dihi-droquinolone, -NH phenyl, phenylalkyl and cycloalkylalkyl, and all these radicals are optionally substituted with a morpholino, piperidyl or phenyl radical optionally substituted by itself with one or more radicals selected from -104- of halogen atoms and the cyano radical, CF3, OCF3, alkyl, phenyl-S (0) n-alk-phenyl, alkoxy, NH2, NHalk, N (alk) 2, S02NH2, S02Nalk or S02N (alk) 2, and all the above alkyl, alkenyl, alkoxy and alkylthio radicals are linear or branched and contain no more than 10 carbon atoms, and all the phenyl radicals of the above radicals are further optionally substituted with a dioxol radical, or the isomeric form racemic, enantiomeric or diastereomeric of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 71.- A compound according to claim 61, of formula lab (IAb) wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals selected from halogen atoms and alkyl, alkoxy and thienyl radicals, -1050- Aib, A2b, A3b and A b, which may be the same or different, are chosen from a hydrogen atom; halogen atoms; radicals of the following types: hydroxyl, alkyl, alkenyl optionally substituted with fe-nyl itself optionally substituted by one or more halogen atoms, alkoxy, nitro, cyano, furyl, thienyl optionally substituted by acyl COalk, benzothienyl, naphthyl , tiantrenyl, phenyl and phenoxy which are optionally substituted; and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidified with a radical NA6bA7b so that any of A6b and A7b, which may be the same or different, is chosen from hydrogen and radicals of the following types: alkyl, alkoxyalkyl containing no more than 6 carbon atoms, phenoxyalkyl optionally substituted with acylamino, NH-C (0) alk, phenyl, optionally substituted phenylalkyl, cycloalkylalkyl, cycloalkyl, furylalkyl optionally substituted with one or more alkyl, naphthylalkyl radicals, thienylalkyl optionally substituted with alkyl or thienyl, pyridylalkyl optionally substituted with a carboxyl radical that is free, salified or esterified with an alkyl, pyridylalkyl radical optionally substituted with one or more radicals chosen from halogen and CF3, benzothienylalkyl, optionally substituted pyrazolylalkyl with one or more alkyl radicals, dihydrobenzofuranylalkyl, hexahydropyra nylalkyl, ethylenedioxyphenylalkyl and benzimidazolylalkyl optionally substituted with one or more alkyl radicals, or A6b and A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical, and the radical -1051- piperazinyl is optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals between A-ib, A2b, Asb and * b can form, with the benzimidazole radical to which they are attached, a radical 4 , Optionally substituted 5-ethylenedioxybenzimidazole or an optionally substituted 4,5-methylenedioxybenzimidazole radical, Asa represents a hydrogen atom, and the above phenyl, phenoxy and phenylalkyl radicals are optionally substituted with one or more radicals selected from halogen atoms, hydroxyl radicals, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and NH-COalk, a carboxyl radical that is free, salified or esterified with an alkyl radical and hydroxyalkyl, carboxyalkyl, phenoxyalkyl, alkylthio, S02alk radicals, S02NH2, S02-NH (alk), S02-N (alk) 2, CF3, OCF3, N02, CN, phenyl, optionally substituted by itself with one or more halogen atoms genos, thienyl, phenoxy, phenylalkoxy, -C (= 0) -NH2, -C (= 0) -NH (alk), C (= 0) -N (alk) 2 and C (0) CH3, and all Alkyl or alk, alkenyl, alkoxy and alkylthio radicals above are linear or branched and contain no more than 4 carbon atoms, and all phenyl radicals of the above radicals are further optionally substituted with a dioxol radical, or the racemic, enantiomeric or diastereomeric isomeric form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 172. A compound according to any one of claims 168, 169, 170 or 171, wherein when one of A1b, A2b, A3b and A4b represents a carboxy-lo radical amidated with a radical NA6bA7b, then either of A6b and A7b represents a hydrogen atom or an alkyl radical and the other of A6b and A7b is chosen from the values defined for A6b and A7b, or A¾ and A7b form, together with the nitrogen atom to which they are attached, a cyclic radical of 5 or 6 members; or the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 173. - A compound according to claim 161, wherein X, W, Y and Z are such that two or three of them represent CH and the others are chosen between the values of CR2 or CR3 and, if appropriate, ie when two of them represent CH and CR2 and CR3 are adjacent to each other, they can form a dioxol radical, or the racemic, enantiomeric or diastereomeric form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 174. A compound according to claim 165 or claim 167, wherein A-i, A2, A3 and A4 are such that two or three of them represent -ios: so a hydrogen atom and, when two of them represent a hydrogen atom and the other two are in adjacent carbon atoms, they can form a dioxol radical; or the racemic, enantiomeric or diastereoisomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 175 - A compound according to claim 161, of formula (the A) wherein Aa represents a pyrazolyl, triazolyl or indazolyl radical, and this heterocycle Aa is optionally substituted with one or more radicals XA1, XA2 or XA3 selected from halogen atoms, alkyl, alkoxy or alkylthio radicals and thienyl radicals optionally substituted with a radical alkyl, Aia, A2a, A3a and A a, which may be the same or different, are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl, alkoxy, nitro, cyano, phenyl and phenoxy radicals and a carboxyl radical which is free, salified, esterified with an alkyl radical or amidated with a radical NA6aA7a so that any of A6a and A7a, which may be identical or different, is chosen from a hydrogen atom and alkyl, phenyl, phenol radicals. Alkyl, cycloalkylalkyl, cycloalkyo, furylalkyl, thienylalkyl and pyridylalkyl, or A6a and A7a form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, pyrazolidinyl, pyrazolinyl, piperidyl, morpholino or piperazinyl radical optionally substituted on the second atom of nitrogen with an alkyl or phenyl radical, which are themselves optionally substituted, it being understood that two consecutive radicals between Aia, A2a, A3a and A4a can form, with the benzimidazole radical; to which an optionally substituted 5 to 6-membered carbon atom ring containing one or two oxygen atoms is attached, A5a represents a hydrogen atom or an alkyl radical, the above phenyl and phenoxy radicals are optionally substituted with one or more radicals chosen from halogen atoms and hydroxyl, cyano, trifluoromethyl, trifluoromethoxy, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino, free carboxyl, salified or esterified and dioxole radicals, all alkyl, alkoxy and alkylthio radicals The above are branched linear and contain no more than 6 carbon atoms, or the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 176. A compound according to claim 161, wherein R represents a pyrazolyl or indazolyl radical. -1055- 177. A compound according to claim 166 or claim 175, wherein Aa represents an optionally substituted pyrazolyl radical or optionally substituted indazolyl, Aia, A2a, Asa and A4a is chosen from the following values: A-a represents hydrogen or carboxyl or a ring with the adjacent member A2a; A4a represents hydrogen or carboxyl or forms a ring with the adjacent member Asa; A2a represents a carboxyl radical that is free, salified, esterified with an optionally substituted alkyl radical or an amidated carboxyl; A2a and Asa represent two optionally substituted alkyl radicals; - Asa represents hydrogen; or the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 178. - A compound according to claim 161, of formula (lAb): -1056- (lAb) wherein Ab represents a pyrazolyl or indazolyl radical optionally substituted with one or more radicals selected from halogen atoms and alkyl, alkoxy and thienyl radicals, A-ib, A2b, A3b and A4b, which may be the same or different, they are chosen from a hydrogen atom, halogen atoms, hydroxyl, alkyl and alkoxy, nitro, cyano, phenyl and phenoxy radicals and a carboxyl radical that is free, salified, esterified with an alkyl radical or amidated with a radical NA6bA7b so that any of A6b and A7b, which may be the same or different, is chosen from alkyl, phenyl, phenylalkyl, cycloalkylalkyl, cycloalkyl and furylalkyl radicals, or A6b and A7b form, together with the nitrogen atom to which they are attached, a pyrrolidinyl, morpholino or piperazinyl radical optionally substituted on the second nitrogen atom with an alkyl radical, it being understood that two consecutive radicals between Aib, A2b, A3b and A4b can form, with the benzimidazole radical to which they are linked -1057- two, an optionally substituted 4,5-ethylendioxybenzimidazole radical or a 4,5-methylenedioxybenzimidazole radical, A5b represents a hydrogen atom, and the above phenyl and phenoxy radicals are optionally substituted with one or more radicals chosen from halogen atoms and free, salified or esterified hydroxyl, cyano, alkyl, alkoxy, amino, alkylamino, dialkylamino, phenylamino, phenylalkylamino and carboxyl radicals, and all the above alkyl, alkoxy and alkylthio radicals are straight or branched and contain no more than 4 carbon atoms , or the racemic, enantiomeric or diastereomeric isomer form of this compound, or the addition salt of a mineral or organic acid or a mineral base of this compound. 179. A pharmaceutical composition, comprising a pharmaceutically effective amount of a compound according to any one of claims 3 to 178, together with one or more pharmaceutically acceptable carriers or excipients. 180. - A method for treating a patient suffering from or undergoing conditions which can be improved by administering an inhibitor of the Syk catalytic activity, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 181. - A method for treating a patient suffering from or being subjected to conditions that can be improved by administering a -1058- inhibitor of the catalytic activity of SyK, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 182. - A method for treating a patient suffering from or undergoing to states that can be improved by administration of a KDR catalytic activity inhibitor, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 183. - A method for treating a A patient suffering from or undergoing conditions that can be improved by administering a KDR catalytic activity inhibitor, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 20, 179. - A method to treat a patient who suffers from or is subject to conditions that can be improved by administering an inhibitor of the catalytic activity of tie2, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 185. - A method for treating a patient suffering from or undergoing to states that can be improved by administering an inhibitor of the catalytic activity of tie2, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. - 1059- 186. A method for treating a patient suffering from or subject to conditions that can be improved by administering an inhibitor of ITK catalytic activity, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of the claims 3 to 178. 187. A method for treating a patient suffering from or undergoing conditions which can be improved by administration of an inhibitor of ITK catalytic activity, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 79. 188. - A method for treating an inflammatory disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 189.- A method to treat an inflammatory disease in a patient who need, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 190. A method for treating cancer in a patient in need thereof, comprising administering said patient. a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. -1060- 191. A method for treating cancer in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 192.- A method for treating chronic pulmonary obstruction disease. in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 193. - A method for treating chronic pulmonary obstruction disease in a patient in need thereof, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 194. - A method for treating asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic lung obstructive disease , Syndrome of respiratory failure in adults, silicosis, pulmonary sarcoidosis, arthritis reu matoid, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubeila arthritis, psoriatic arthritis, acute and chronic urticaria, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram-negative sepsis, diabetes, multiple sclerosis , systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft versus host disease, rejection in organ transplantation, reperfusion injury, Crohn's disease or ulcerative colitis in a patient who needs it, which comprises administering said patient an amount -1061- Pharmaceutically effective of a compound according to any one of claims 3 to 178. 195. - A method for treating asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, chronic lung obstructive disease, respiratory insufficiency syndrome in adults. , silicosis, pulmonary sarcoidosis, rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubeila arthritis, psoriatic arthritis, acute and chronic urticaria, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram sepsis -negative, diabetes, multiple sclerosis, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft versus host disease, rejection in organ transplantation, reperfusion injury, Crohn's disease or ulcerative colitis in a patient who it needs it, which comprises administering a pharmaceutical amount to said patient Effective of a compound according to any one of claims 1, 2 or 179. 196. - A method for treating cancers, atherosclerosis, degenerative muscle diseases, obesity, congestive heart failure, Parkinson's depression, schizophrenia, stroke, cranial trauma, wound of the spinal cord, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis or fibrotic diseases of the viscera in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. -1062- 197. - A method to treat cancers, atherosclerosis, degenerative muscle diseases, obesity, congestive heart failure, Parkinson's depression, schizophrenia, stroke, cranial trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis , cachexia, osteoporosis or fibrotic diseases of the viscera in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 198. A method for treating asthma, atopic dermatitis, psoriasis, eczema herpetiformis, necrotizing and cutaneous vasculitis, bullous disease, acute urticaria and chronic allergic rhinitis or allergic conjunctivitis, arthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and west-arthritis, chronic lung obstruction disease, adult respiratory distress syndrome, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram-negative sepsis, diabetes, multiple sclerosis, restenosis, myocarditis, B-cell lymphomas, systemic lupus erythematosus Viral infections, bacterial infections, parasitic infections, graft versus host disease and other rejection events associated with transplants, reperfusion injury, Crohn's disease, ulcerative colitis, cancers, tumors, atherosclerosis, degenerative muscle diseases vas, obesity, congestive heart failure, Parkinson's disease, depression, schizophrenia, stroke, cranial trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, fibrotic diseases of the viscera or inflammatory bowel disease, in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 199.- A method for treating asthma, atopic dermatitis, psoriasis, eczema herpetiform, necrotizing and cutaneous vasculitis, bullous disease, acute and chronic urticaria, allergic rhinitis or allergic conjunctivitis, arthritis, rheumatoid arthritis, rheumatoid spondylitis, gouty arthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis and west-arthritis, chronic lung obstruction disease, respiratory failure in adults, silicosis, pulmonary sarcoidosis, acute synovitis, autoimmune diabetes, autoimmune encephalomyelitis, colitis, atherosclerosis, peripheral vascular disease, cardiovascular disease, cutaneous and systemic anaphylaxis, endotoxemia, sepsis, septic shock, endotoxic shock, gram-negative sepsis, diabetes, multiple sclerosis, restenosis, myocarditis, B-cell lymphomas, systemic lupus erythematosus, viral infections, bacterial infections, parasitic infections, graft-versus-host disease and other rejection events associated with transplants, reperfusion injury, Crohn's disease, ulcerative colitis, cancers, tumors, atherosclerosis, degenerative muscle diseases, obesity, congestive heart failure, Parkinson's disease, depress -1064 - schizophrenia, stroke, cranial trauma, spinal cord injury, Alzheimer's disease, neuropathic pain syndrome, amyotrophic lateral sclerosis, cachexia, osteoporosis, fibrotic diseases of the viscera or intestinal inflammation disease, in a patient who it is needed, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 200. A method for inhibiting angiogenesis in a patient in need thereof, comprising administering said patient A pharmaceutically effective amount of a compound, according to any one of claims 3 to 178. 201. - A method for inhibiting angiogenesis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to a any of claims 1, 2 or 179. 202.- A method according to claim 190 or the reinvidication 191, in which the cancer being treated is colon-rectal, prostate, breast, thyroid, skin, colon or lung cancer. 203. - A method for treating asthma in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. 204. - A method for treating asthma in a patient. patient who needs it, which comprises administering to said patient a pharmaceutical amount- The method for treating psoriasis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound of a compound according to any one of claims 1, 2 or 179. according to any one of claims 1 to 178. 206. - A method for treating psoriasis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 207. - A method for treating joint inflammation in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1 to 178. 208.- A method for treating inflammation of the joints in a patient who needs it, which comprises administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 209 - A method for treating intestinal inflammation disease in a patient in need, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 3 to 178. -1066- 210. A method for treating intestinal inflammation disease in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to any one of claims 1, 2 or 179. 211. A method for preparing the compound of formula (I) according to claim 161, characterized in that an acid of formula (D): Rl'-COOH (D) in which R1 'has the meaning given in claim 161 for R, in which the possible reactive functions are optionally protected with protecting groups, is subjected to an esterification reaction to provide an ester of acid of formula (II) Rl'-COOalk | (II) in which R1 'has the meaning given above and alk represents an alkyl radical, is subjected to a reduction reaction to provide the alcohol of formula (III): R1 '-CH20H (III) wherein R1' has the meaning given above, which is oxidized to the aldehyde of formula (IV): Rl'-CHO (IV) wherein R1 'has the meaning given above, and the compound of Formula (D) or compound of formula (IV) as defined above is reacted with a diamine of formula (V) -1067- wherein W \ X ', Y' and Z 'have the meanings provided in claim 161, respectively, for W, X, Y and Z, in which the possible reactive functions are optionally protected with protecting groups, to provide a compound of formula (G) wherein A5 'has the meaning provided in claim 61 for A5, in which the possible reactive functions are optionally protected with protecting groups, and R-i', W \ X 'and Z' have the meanings given above , and the compound of formula (G) is a compound which can be a compound of formula (I) and which, in order to obtain a compound or other compound of formula (I), can be subjected, if desired and if necessary, to one or more of the following conversion reactions, in any order: a) an esterification reaction of an acid function, b) a saponification reaction of an ester function to an acid function, -1068- c) an oxidation reaction of an alkytithium group to the corresponding sulfoxide or sulfone, d) a conversion reaction of a ketone function to an oxime function. e) a reduction reaction of the free or esterified carboxyl function in an alcohol function, f) a reaction for the conversion of the alkoxy function to a hydroxyl function or, alternatively, of the hydroxyl function in an alkoxy function, g) a reaction for the oxidation of an alcohol function in an aldehyde, acid or ketone function, h) a reaction for the conversion of a nitrite radical to tetra-zolyl, i) a reaction for the separation of the protective groups that can be carried by protected reactive functions, j) a salification reaction with a mineral or organic acid p with a base to provide the corresponding salt, k) a reaction for the resolution of the racemic forms in resolved products, and said compound of formula (I) thus obtained is any possible racemic, enantiomeric or diastereomeric isomeric form. 212. A process for preparing the compound of formula (I) according to claim 1, corresponding to formula (IA) according to any 1069- any of claims 165, 167 or 174, characterized in that an acid of formula (D): A'-COOH (D) wherein A 'has the meaning provided in any one of claims 165, 167 or 174 for A, in which the possible reactive functions are optionally protected with protecting groups, it is subjected to an esterification reaction to provide an acid ester of formula (II) A'-COOalk (II) in which A 'has the meaning given above and alk represents a radical-alkyl, is subjected to a reduction reaction to provide the alcohol of formula (III): A'-CH20H (III) wherein A 'has the meaning given above, which is oxidized to the aldehyde of formula (IV): A'-CBO (IV) wherein A 'has the meaning given above, and the compound of formula (D) or compound of formula (IV) as defined above are reacted with a diamine of formula (V): -1070- wherein? -? ',? 2', A3 'and A4' have the meanings provided in any one of claims 165, 167 or 174, respectively, for Ai, A2, A3 and A4, in which the possible functions reactants are optionally protected with protecting groups, to provide a compound of formula (?? '): wherein A5 'has the meaning provided in any one of claims 165, 167 or 75 for A5, in which the possible reactive functions are optionally protected with protecting groups, and? \' 2 ', A3' and A4 have the meanings given above, and the compound of formula (?? ') is a compound which can be a compound of formula (IA) and which, in order to obtain a compound or other compound of formula (IA), can be subjected to , if desired and if necessary, in any order, to one or more conversion reactions chosen among the reactions of paragraphs a) to k) defined in claim 211, and said compound of formula (IA) thus obtained is in any isomeric possible racemic, enantiomeric or diastereomeric form. 213. As medicinal compounds, the compounds of formula (I) as defined in any one of claims 161 to 178, and -1071- also the salts by adding pharmaceutically acceptable mineral and organic acids, or pharmaceutically acceptable organic and mineral bases, of said compounds of formula (I). 214. As medicinal compounds, the compounds of formula (I) as defined in any one of claims 156 to 159, and also the addition salts of pharmaceutically acceptable mineral and organic acids, or of pharmaceutically acceptable mineral and organic bases, of said compounds of formula (I). 215. - Pharmaceutical compositions containing, as active ingredient, at least one of the compounds of formula (I) as defined in any one of claims 161 to 178, or a pharmaceutically acceptable salt of this product or a prodrug of this compound and a pharmaceutically acceptable carrier. 216. Use of the compounds of formula (I) as defined in any one of claims 156 to 159 or claims 161 to 178, or of pharmaceutically acceptable salts of these compounds, for the preparation of a medicinal product intended to inhibit the activity of a protein kinase. 217. - Use of a compound of formula (I) as defined in any one of claims 156 to 159 or claims 161 to 78, for the preparation of a medicinal product for treating or preventing a disease characterized by a dysregulation of the activity of a protein kinase. -1072- 218. - Use according to claim 216, wherein the qui-nase protein is a protein tyrosine kinase. 219. Use as defined in claim 216, wherein the protein kinase is chosen from the following group: FGFR1, FGFR2, FGFR3, FGFR4, FGFR5, flt-1, IGF-1R, KDR, PDGFR, tie2 and VEGFR. 220. Use as defined in claim 216, wherein the protein kinase is KDR. 221. - Use as defined in claim 216, wherein the protein kinase is tie2. 222.- Use as defined in claim 216, wherein the protein kinase is a cell culture. 223. - Use as defined in claim 216, wherein the protein kinase is in a mammal. 224. - Use of a compound of formula (I) as defined in any one of claims 156 to 159 or claims 161 a 178, for the preparation of a medicinal product to treat or prevent a disease chosen from the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, metabolic disorders, allergies, asthma, thrombosis , diseases of the nervous system, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers. 225. - Use of a product of formula (I) as defined in any one of claims 156 to 159 or claims 161 to 178, -1073- for the preparation of a medicinal product for treating or preventing a disease chosen from the following group: disorders of blood vessel proliferation, fibrotic disorders, disorders of mesangial cell proliferation, retinopathy, psoriasis, rheumatoid arthritis, diabetes, muscle degeneration and cancers.; 226.- Use of a compound of formula (I) as defined in any one of claims 156 to 159 or claims 161 to 178, for the preparation of a medicinal product for preventing or treating diseases associated with uncontrolled angiogenesis. 227.- Use of a compound of formula (1) as defined in any of claims 156 to 159 or claims 161 to 178, for the preparation of a medicinal product for treating diseases in oncology. 228. - Use of a compound of formula (I) as defined in any one of claims 156 to 159 or claims 161 to 178, for the preparation of a medicinal product to treat cancers. 229. - Use according to claim 227, for the treatment of solid tumors. 230. - Use according to claim 228 or 229, for the treatment of cancers that are resistant to cytotoxic agents. 231. - Use according to claim 228 or 229, for the treatment of breast cancer, stomach cancer, ovarian cancer, colon cancer, lung cancer, brain cancer, laryngeal cancer, cancer of the system. -1074- " lymphatic issue, cancer of the genito-urinary tract that includes the bladder and prostate, bone cancer and pancreatic cancer. 232. Use according to claim 228 or 229, for the treatment of breast cancer, colon cancer or lung cancer. 233. Use of the compounds of formula (I) as defined in claims 156 to 159 or claims 161 to 178, for the preparation of medicinal products intended for cancer chemotherapy. 234. - Use of the compounds of formula (I) as defined in claims 156 to 159 or claims 161 to 178, for the preparation of medicinal products intended for cancer chemotherapy alone or in combination. 235. Use of the compounds of formula (I) as defined in claims 156 to 159 or claims 161 to 178, as inhibitors of kinase. 236.- Use of the compounds of formula (I) as defined in claims 156 to 159 or claims 161 to 178, ·· as KDR inhibitors. 237. Use of the compounds of formula (I) as defined in claims 156 to 159 or claims 161 to 178, as inhibitors of tie2. 238. - A method according to claim 190 or 191, wherein the cancer being treated is breast cancer, stomach cancer, ovarian cancer, colon cancer, lung cancer, brain cancer, -1076- SUMMARY The invention is directed to physiologically active compounds of general formula (Ix) and compositions, which contain these compounds, and their prodrugs, and the pharmaceutically acceptable salts and solvates of these compounds and their prodrugs, as well as new compounds within the scope of formula (lx), and to processes for their preparation; These compounds and compositions have useful pharmaceutical properties, in particular the ability to inhibit kinases.
MXPA04003954A 2001-10-26 2002-10-24 Benzimidazoles and analogues and their use as protein kinases inhibitors. MXPA04003954A (en)

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GB0206893A GB0206893D0 (en) 2002-03-22 2002-03-22 Chemical compounds
US39515102P 2002-07-11 2002-07-11
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