Benzoimidazoles as prolyl hydroxylase inhibitors

FIELD: chemistry.

SUBSTANCE: invention relates to the field of organic chemistry, namely to benzoimidazole derivatives of formula (I), as well as to their enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts, where n equals from 2 to 4, each of R1 substituents is independently selected from H, halogen, -C1-4alkyl, -C1-4pergaloalkyl, trifluoro-C1-4alkoxy, -NO2, -CN, CO2H, -OC1-4alkyl, -SC1-4alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4alkyl, -SO2-C1-4alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one-two Rd, cyanobiphenyl-4-ylmethylsulpfanyl, cyanobiphenyl-4-ylmethanesulphonyl, or -S-(CH2)2-morpholine and two adjacent groups R1 can bind with formation of an aromatic 5-6-membered ring, optionally substituted with one methyl group or two atoms of halogen, optionally containing one or two S or N; Ra and Rb each independently represents C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-Re, C1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Ra and Rb together with a nitrogen atom, which they are bound with, form a monocyclic 5-6- membered heterocycloalkyl ring, optionally containing one heteroatom, selected from O; Rc represents -C3-8cycloalkyl, phenyl, optionally substituted with one-two Rd, benzyl, optionally substituted with one-three Rd; morpholine; Rd independently represents halogen, -OH, -C1-4alkyl or -C1-4perhalogenalkyl, trifluorine C1-4alcoxy, -OC1-4alkyl, or -O-benzyl optionally substituted with halogen, Re represents -C6heterocycloalkyl, optionally containing one or two of O or N atoms, optionally substituted with a methyl group; R2 and R3 both represent H, -CF3 or C1-3alkyl; each of Z represents a C or N atom, on condition that simultaneously not more than two Z represent N. The invention also relates to particular compounds, a pharmaceutical composition, based on formula (I) compound or a particular said compound, a method of treating diseases, mediated by propyl hydroxylase activity.

EFFECT: novel derivatives of benzimidazole, possessing an inhibiting activity with respect to PHD are obtained.

11 cl, 1 tbl, 186 ex

 

The scope of the invention

The present invention relates to certain compounds of benzimidazole containing their pharmaceutical compositions and methods of use thereof for treating diseases, disorders and conditions mediated by the activity of prolylhydroxylase.

Background of invention

Cells respond to hypoxia by activating the read information of genes involved in cell survival, delivery and use of oxygen, the development of blood vessels, cellular metabolism, regulation of blood pressure, hematopoesis and preservation of tissue. Factors (HIF factors, hypoxia-induced) are key transcriptional regulators of these genes (Semenza et al., 1992,Mol Cell Biol., 12(12):5447-54; Wang et al., 1993,J Biol Chem., 268(29):21513-18; Wang et al., 1993,Proc Natl Acad Sci., 90:4304-08; Wang et al., 1995,J Biol Chem., 270(3):1230-37). Described three forms of HIF-α: HIF-1α, HIF-2α and HIF-3α (Scheuermann et al., 2007,Methods Enzymol., 435:3-24). Algae HIFα subunit with HIF-1β forms a functional heterodimeric protein, which, in turn, involves other transcription factors, such as p300 and CBP (Semenza, 2001, Trends Mol Med., 7(8):345-50).

A family of highly conserved oxygen-, iron - and 2-oxoglutarate-dependent enzymes prolylhydroxylase (PHD) are intermediates of the reaction of cells to hypoxia through post-translational modification of HIF(Ivan et al., 2001,Science, 292:464-68; Jaakkola et al., 2001,Science, 292:468-72). In the normal supply of oxygen PHD catalyzes hydroxylation of two conservative groups Proline in HIF. Protein von Hippel-Lindau (VHL) selectively binds to gidroksilirovanii HIF. The binding of VHL turns HIF target for polyubiquitination complex, an E3 ubiquitin ligase and subsequent degradation by the 26S proteasome (Ke et al., 2006,Mol Pharmacol. 70(5):1469-80; Semenza,Sci STKE., 2007, 407(cm8):1-3). Because the affinity PHD to oxygen is in the physiological range of oxygen, and oxygen is a necessary cofactor reaction, PHD inactivated at lower oxygen pressure. Thus, HIF rapidly decomposed under normal conditions of supply of oxygen, but accumulates in the cells under hypoxic conditions or inhibition of PHD.

Describes the four isotope PHD: PHD1, PHD2, PHD3 PHD4 and (Epstein et al., 2001,Cell, 107:43-54; Kaelin, 2005,Annu Rev Biochem., 74:115-28; Schmid et al., 2004,J Cell Mol Med., 8:423-31). Different isotopes are everywhere, but are regulated in different ways and plays a significant physiological role in the response of cells to hypoxia. Obviously, these different isotopes have different selectivity with respect to three different subtypes of HIF is (Epstein et al.,see above). Terms of subcellular localization, PHD1 refers mainly to the nucleus, PHD2 to the cytoplasm, and PHD3, apparently, relates to both the nucleus and the cytoplasm (Metzen E, et al. 2003,J Cell Sci., 116(7):1319-26). PHD2, apparently, is the dominant HIFα by prolylhydroxylase under normal conditions of oxygen supply (Ivan et al., 2002.Proc Natl Acad Sci. USA, 99(21):13459-64; Berra et al., 2003,EMBO J., 22:4082-90). Three isotopes have a high degree of amino acid homology, and the active center of the enzyme is highly conserved.

Products targeted to HIF gene are involved in several physiological and pathophysiological processes, including, inter alia, the following: Erythro(cyto)of the SEZ, the development of blood vessels, regulation of energy metabolism, vasomotor activity and apoptosis/proliferation of cells. First described as a target for HIF gene was the gene encoding erythropoietin (EPO) (Wang et al., 1993,see above). It was shown that the reduction kislorodoprovody function of blood is perceived by the kidneys and the kidneys and liver are responsible for this development more EPO is a hormone that stimulates the proliferation and maturation of red blood cells. EPO has diverse effects on necrovation cell types and acts as a primary organoprotective cytokine (Arcasoy, 2008,Br J Haematol., 141:14-31). Therefore, EPO is involved in the processes of wound healing and the development of blood vessels, and tissue reaction to ischemic stroke. Most of the enzymes involved what's in anaerobic glycolysis, coded HIF target genes, resulting in glycolysis is enhanced in hypoxic tissues (Shaw, 2006,Curr Opin Cell Biol., 18(6):598-608). Known products targeted to HIF gene in this pathway of metabolism include, inter alia, the following: the vector of glucose, such as GLUT-1 (Ebert et al., 1995,J Biol Chem., 270(49):29083-89), enzymes involved in the conversion of glucose into pyruvate, such as glucokinase and phosphoglucomutase 1 (Firth et al., 1994,Proc Natl Acad Sci. USA, 91:6496-6500), and lactate dehydrogenase (Firth et al.,see above). Products HIF target gene are also involved in the regulation of cellular metabolism. For example, the kinase piruvatdegidrogenazy-1 is a product of HIF target gene and regulates the supply of pyruvate in the Krebs Cycle, reducing the activity of piruvatdegidrogenazy by phosphorylation (Kim et al., 2006,Cell Metab., 3:177-85; Papandreou et al., 2006,Cell Metab., 3:187-197). Products HIF target gene are also involved in the development of blood vessels. For example, vascular endothelial growth factor (VEGF) (Liu et al., 1995,Circ Res., 77(3):638-43) is a well - known regulator of the development of blood vessels, as well as education and development of blood vessels (vasculogenesis). Products HIF target gene also perform certain functions in the regulation of vascular tone and include hemoxygenase-1 (Lee et al., 1997,J Biol Chem., 272(9):5375-81). The number of regulated HIF gene products such as Tr is miitary (PDGF) (Yoshida et al., 2006, J Neurooncol., 76(1):13-21), vascular endothelial growth factor (Breen, 2007,J Cell Biochem., 102(6):1358-67) and EPO (Arcasoy,see above), are also involved in a coordinated response during wound healing.

Scheduled violation of activity of the enzyme prolylhydroxylase (PHD) using small molecules potentially useful for treatment of disorders of perception and distribution of oxygen. Examples include, inter alia, the following: anemia; meniscectomy anemia; peripheral vascular disease; coronary heart disease; heart failure; protection of tissues from ischemic conditions such as myocardial ischemia, myocardial infarction and stroke; the preservation of organs for transplantation; treatment of ischemic tissues by regulating and / or restoring blood flow, oxygen delivery and / or use of energy; acceleration of wound healing, particularly in elderly patients and patients with diabetes; treatment of burns; treatment of infectious diseases; the healing of the fractures and bone growth. In addition, it is assumed that the planned violation of the PHD will be useful for the treatment of metabolic disorders like diabetes, obesity, ulcerative colitis, inflammatory bowel disease, and related diseases, such as Crohn's disease. (Recent Patents on Inflammation &Allergy Drug Discovery, 2009, 3, 1-16).

It is shown that the HIF is the main transcription factor, which leads to increased production of erythropoietin in hypoxia (Wang et al., 1993,see above). Although the use of recombinant human erythropoietin has been shown to be effective in the treatment of anemia, it can be expected that the PHD inhibition by small molecules will have some advantages in comparison with treatment with erythropoietin. In particular, the function of the other gene products required for HIF haematopoiesis, and regulation of these factors increases the efficiency of hemopoiesis. Examples of products HIF target gene critical for hematopoiesis, include transferrin (Rolfs et al., 1997,J Biol Chem., 272(32):20055-62), atransferrinemia receptor (Lok et al., 1999,J Biol Chem., 274(34):24147-52; Tacchini et al., 1999,J Biol Chem., 274(34):24142-46) and ceruloplasmin (Mukhopadhyay et al., 2000,J Biol Chem., 275(28):21048-54). Expression hepcidin also suppressed HIF (Peyssonnaux et al., 2007,J Clin Invest., 117(7):1926-32), and inhibitors of PHD with small molecules has been shown to reduce the production hepcidin (Braliou et al., 2008,J Hepatol., 48:801-10). Hepsidin is a negative factor in regulating the availability of iron required for haematopoiesis, therefore, is expected to reduce the development of hepcidin will positively affect the treatment of anemia. Inhibition of PHD may also be useful in combination with another treatment of anemia, including replenishment of iron and (or) exogenous erythropoietin. Research the Finance natural PHD2 gene mutations in human population provide another basis for use of PHD inhibitors in the treatment of anemia. In two recent studies have shown that patients with dysfunctional mutations in the gene PHD2 increased erythrocytosis and increased level of hemoglobin in the blood (Percy et al., 2007,PNAS, 103(3):654-59; Al-Sheikh et al., 2008,Blood Cells Mol Dis., 40:160-65). In addition, the PHD inhibitor small molecule was tested in healthy volunteers and patients with chronic kidney disease (Patent application U.S. US2006/0276477, 7 December 2006). The content of erythropoietin in the plasma was increased depending on the doses, and in patients with chronic kidney disease increased hemoglobin content in the blood.

Ischemia is a risk for metabolic adaptation and tissue protection. The PHD inhibitors increase the expression of genes, leading to changes in metabolism, beneficial in ischemic conditions (Semenza, 2007,Biochem J., 405:1-9). Many of encoded genes of enzymes involved in anaerobic glycolysis, are regulated by HIF, and glycolysis is increased by inhibiting PHD (Shaw,see above). Known HIF target genes in this pathway of metabolism include, inter alia, the following: GLUT-1 (Ebert et al.,see above), geksokinazou, phosphoglycerides 1, lactate dehydrogenase (Firth et al.,see above), the kinase piruvatdegidrogenazy-1 (Kim et al.,see above; Papandreou et al.,see above). The kinase piruvatdegidrogenazy-1 suppresses the occurrence of pyruvate in qi is l Krebs. HIF plays a role of mediator in the switch expression of cytochromes involved in electron transfer in mitochondria (Fukuda et al., 2007,Cell, 129(1):111-22). This change of the structure of cytochrome optimizes the efficiency of the production of ATP (adenosine triphosphate) in hypoxia and reduces the production of these harmful by-products of oxidative phosphorylation, as hydrogen peroxide and nadterechye. During prolonged exposure to hypoxia HIF stimulates autophagy of mitochondria, resulting in their number decreases (Zhang H et al., 2008,J Biol Chem. 283: 10892-10903). This adaptation to chronic hypoxia decreases the production of hydrogen peroxide and nadterechye, whereas the production of energy by the cell relies on glycolysis. Another adaptive response induced increase in HIF is activated factors in the survival of cells. These factors include the following: insulin-like growth factor (IGF) 2, proteins that bind IGF 2 and 3 (Feldser et al., 1999,Cancer Res. 59:3915-18). The total accumulation of HIF in hypoxia adaptive controls the activation of glycolysis, decreased oxidative phosphorylation, leading to reduced production of hydrogen peroxide and nadterechye, optimization of oxidative phosphorylation, protecting cells from ischemic damage. Thus, it is expected that PHD inhibitors Bud is t useful for preservation of organs and tissues for transplantation (Bernhardt et al., 2007,Methods Enzymol., 435:221-45). Although beneficial effects may be obtained by assigning inhibitors PHD before collection of organs for transplantation, the introduction of the inhibitor into the organ or tissue after harvesting, during storage (for example, cardioplegic solution) or after transplantation, may also have a therapeutic effect.

It is expected that PHD inhibitors will be effective to protect tissues from widespread ischemia and / or hypoxia. Including from ischemia or hypoxia, caused by, inter alia, the following: angina, myocardial ischemia, stroke, ischemia of skeletal muscle. There are a number of experimental evidence that inhibition of PHD and subsequent increase HIF is an appropriate method of conservation of ischemic tissue. Recently it has been shown that ischemic preconditioning is a phenomenon that is dependent on HIF (Cai et al., 2008,Cardiovasc Res., 77(3):463-70). Ischemic preconditioning is a well - known phenomenon whereby brief periods of hypoxia and / or ischemia protects the fabric from the subsequent longer periods of ischemia (Murry et al., 1986,Circulation, 1986 74(5):1124-36; Das et al., 2008,IUBMB Life, 60(4):199-203). It is known that ischemic preconditioning is observed in humans and in experimental animals (Darling et al., 2007,Basic Res Cardiol., 102(3):274-8; Kojima I, et al., 2007,J Am Soc Nephrol., 18:121-26). Despite the fact that the concept of preconditioning is most known for its protective effects in the heart, it also applies to other tissues, including, without limitation, the following: liver, skeletal muscle, lung, kidney, intestine and brain (Pasupathy et al., 2005,Eur J Vasc Endovasc Surg., 29:106-15; Mallick et al., 2004,Dig Dis Sci., 49(9):1359-77). Experimental confirmation timeprocessing effects of inhibition of PHD and increasing HIF obtained in several animal models, including: nokautiroval germline PHD1, which ensured the protection of skeletal muscle from ischemic stroke (Aragonés et al., 2008,Nat Genet., 40(2):170-80), off PHD2 by applying siRNA (short interfering RNA), which protected the heart from ischemic stroke (Natarajan et al., 2006,Circ Res., 98(1):133-40), inhibition of PHD by introducing carbon monoxide, which protected the myocardium from ischemic damage (Chin et al., 2007,Proc Natl Acad Sci. U.S.A., 104(12):5109-14), hypoxia in the brain, which has increased resistance to ischemia (Bernaudin et al., 2002,J Cereb Blood Flow Metab., 22(4):393-403). In addition, the PHD inhibitors small molecule protects the brain in experimental models of stroke (Siddiq et al., 2005,J Biol Chem., 280(50):41732-43). Moreover, it was shown that the activation of HIF protects the heart mouse suffering from diabetes, where the effects are usually worse (Natarajan et al., 2008,J Cardiovasc Pharmacol., 51(2):178-187). Deeprockdrive effects m the should also be observed obliterative obliterans (Buerger's disease), symmetrical gangrene (Raynaud's disease) and acrocyanosis.

Reduced dependence on aerobic metabolism via the Krebs cycle in the mitochondria and increased dependence on anaerobic glycolysis caused by inhibition PHD, may have a beneficial effect on tissue with normal oxygen supply. It is important to note that inhibition of PHD, as shown, increases in HIF conditions of normal oxygen supply. Thus, inhibition of PHD causes pseudogobio, due to the hypoxic response initiated through HIF, but tissue oxygenation remains normal. You can also expect that the restructuring of metabolism, caused by inhibition of PHD will allow you to implement a method of treatment of diabetes, obesity and related disorders, including co-morbidities.

In General, the sum of the changes in gene expression caused by inhibition PHD, reduces the amount of energy produced per unit of glucose, and it will stimulate the body into burning more fat to maintain energy balance. Mechanisms of stimulation of glycolysis discussed above. Other studies have linked hypoxic response from those effects that are, as expected, are beneficial in the treatment of diabetes and obesity. So, it is well known that to reduce the quantity is of body fat are applied training at high altitude (Armellini et al., 1997,Horm Metab Res., 29(9):458-61). It is shown that hypoxia mimic hypoxia substances such as desferrioxamine, prevents the allocation of adipocyte (Lin et al., 2006,J Biol Chem., 281(41):30678-83; Carrière et al., 2004,J Biol Chem., 279(39):40462-69). This effect is reversible upon return to normal conditions oxygen supply. Inhibition of PHD activity in the initial stages of lipogenesis and inhibits the formation of new adipocytes (Floyd et al., 2007,J Cell Biochem., 101:1545-57). Hypoxia, cobalt chloride and desferrioxamine increase HIF and inhibit the transcription of nuclear gamma 2-PPAR (receptors, activating peroxisome proliferation) hormone receptors (Yun et al., 2002,Dev Cell., 2:331-41). Because gamma 2-PPAR - this is an important signal for selecting adipocyte, it should be expected that inhibition of PHD will suppress the secretion of adipocyte. It was shown that these effects should take place with the participation of HIF-regulated gene DEC1/Stra13 (Yun et al.,see above).

Inhibitors PHD small molecules demonstrate a therapeutic effect in animal models of diabetes and obesity (international patent application WO2004/052284, 24 June 2004; WO2004/052285, June 24, 2004). The effects shown for PHD inhibitors in mice with dietary obesity, mice, db/db, and the rats Zucker fa/fa included the reduction of the following: concentration of glucose in the blood, body fat mass, as in abdominal and visceral congestion W the global tissue, hemoglobin A1c, triglycerides, plasma, body weight, and changes in biomarkers of established disease, such as increased levels adrenomedullin and leptin. Leptin is known as a product of the HIF target gene (Grosfeld et al., 2002,J Biol Chem., 277(45):42953-57). The products of the genes involved in the metabolism of fat cells, as has been shown, shall be governed by PHD inhibition depending on HIF (international patent application WO2004/052285,see above). These products are: apolipoprotein A-IV, acyl CoA thioesterase, carnitine acetyl transferase and insulin-like growth factor binding protein (IGFBP)-1.

It is expected that PHD inhibitors should be therapeutically effective as stimulants vasculogenesis, development of blood vessels and arteriogenesis. These processes create or restore blood flow to the tissues and the oxygen saturation in conditions of ischemia and / or hypoxia (Semenza et al., 2007,J Cell Biochem., 102:840-47; Semenza, 2007,Exp Physiol., 92(6):988-91). It has been shown that physical exercise increases HIF-1 and vascular endothelial growth factor in experimental animal models and in humans (Gustafsson et al. 2001,Front Biosci., 6:D75-89) and, accordingly, the number of blood vessels in skeletal muscle. VEGF (growth factor vascular endothelial) - a well known product HIF target gene, which is the main factor in the development of kromanonskogo (Liu et al., supra). Despite the fact that the appointment of different forms of activators of the receptor VEGF is a potent stimulus for the development of blood vessels, blood vessels, the resulting potential treatment method, are leaky. It is believed that this limits the possibility of using VEGF for the treatment of disorders of oxygen delivery. Increased expression of a single angiogenic factor may be insufficient for functional vascularization (new blood vessel formation) (Semenza, 2007,see above). The potential benefits of PHD inhibition in comparison with other similar methods angiogenic therapy are that it stimulates the controlled expression of many angiogenic growth factors depending on HIF, including, without limitation, the following: placenta growth factor (PLGF), angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), beta-platelet-derived growth factor (PDGFB) (Carmeliet, 2004,J Intern Med., 255:538-61; Kelly et al., 2003,Circ Res., 93:1074-81) and growth factor stromal cell-1 (SDF-1) (Ceradini et al., 2004,Nat Med., 10(8):858-64). Expression of angiopoietin-1 in the development of blood vessels leads to the formation of dense blood vessels, unlike blood vessels, resulting in the appointment of only VEGF (Thurston et al., 1999,Science, 286:2511-14; Thurston et al., 2000,Nat Med., 6(4):460-3; Elson et al., 2001,Genes Dev., 15(9):2520-32). It was shown that the growth factor stromal cells 1 (SDF-1) is extremely important for the process flow of the precursors of endothelial cells to sites of tissue damage. The expression of SDF-1 enhances the adhesion, migration, and homing circulating CXCR4-positive progenitor cells to ischemic tissue. Moreover, inhibition of SDF-1 in ischemic tissue or blockade of CXCR4 in cells circulating in the peripheral blood, prevents the involvement of progenitor cells to sites of damage (Ceradini et al., 2004,see above; Ceradini et al., 2005,Trends Cardiovasc Med., 15(2):57-63). It is important that the involvement of precursors of endothelial cells to sites of damage in adult mice is reduced, and this is compensated by interventions that increase HIF at the wound site (Chang et al., 2007,Circulation, 116(24):2818-29). Inhibition of PHD provides benefits not only by increasing the expression of a number of angiogenic factors, but also by coordinating their expression during development of the blood vessels and attract precursors of endothelial cells to ischemic tissue.

The proof of the applicability of PHD inhibitors in Pro-angiogenic therapy are presented in the following studies. Surgentes HIF with the participation of adenovirus has been shown to cause the development of blood vessels in noiselessly tissue of adult animals (Kelly et al., 2003,Cir Res ., 93(11):1074-81) and suggests that the treatment that increases HIF, such as inhibition of PHD, will cause the development of blood vessels. It was shown that placenta growth factor (PLGF), a target gene of HIF plays an important role in the development of blood vessels in ischemic tissue (Carmeliet, 2004,J Intern Med., 255(5):538-61; Luttun et al., 2002,Ann N Y Acad Sci., 979:80-93). Demonstrated effective Pro-angiogenic effects of treatment, which increases HIF through sverginate HIF, in skeletal muscle (Pajusola et al., 2005,FASEB J., 19(10):1365-7; Vincent et al., 2000,Circulation, 102:2255-61) and in the myocardium (Shyu et al., 2002,Cardiovasc Res., 54:576-83). It was also shown the involvement of precursors of endothelial cells to ischemic myocardium target gene of HIF SDF-1 (Abbott et al., 2004,Circulation, 110(21):3300-05). These results confirm the overall concept, the essence of which is that the PHD inhibitors will be effective to stimulate the growth of blood vessels in the regulation of tissue ischemia, particularly myocardial ischemia of the muscles. It is assumed that therapeutic development of blood vessels caused by inhibitors PHD, will be useful for restoring blood flow to tissues and, consequently, for the treatment of diseases including, but not limited to, the following: angina, ischemia and myocardial infarction, peripheral ischemic disease, alternating lameness, ulcer of stomach and duodenum to the loud, ulcerative colitis and inflammatory bowel disease.

PHD and HIF plays a Central role in wound healing and tissue regeneration, including the healing of wounds and ulcers. Recent studies have shown increased expression of all three PHD on the field ran in adult mice and, as a result, a reduction in the accumulation of HIF (Chang et al.,supra). Thus, the increase of HIF in adult mice by assigning desferrioxamine increases the degree of healing to the level observed in young mice. Similarly, in mice with diabetes, increased HIF was weakened in comparison with mice of the same litter without diabetes (Mace et al., 2007,Wound Repair Regen., 15(5):636-45). Local application of cobalt chloride, simulator hypoxia or surgentes murine HIF, which limits the scope of the decomposition dependent on oxygen, and, thus, provides a constantly active form of HIF leads to increased HIF in the wound, increased expression of HIF target genes, such as VEGF, Nos2 and Hmox1, and to accelerate wound healing. Recently, it was shown that the beneficial effect of inhibiting PHD is not limited to the skin and that PHD inhibitors small molecule give a positive result in mice with colitis (Robinson et al., 2008,Gastroenterology, 134(1):145-55).

It is assumed that the inhibition PHD, leading to accumulation of HIF, has at least even the d mechanism of action, each of which contributes to faster and more complete healing of wounds and ulcers: 1) fabric protector susceptible to hypoxia and / or ischemia, 2) encouraging the development of blood vessels to create or restore adequate blood flow to the site of lesion, 3) engaging the precursors of endothelial cells to the lesion, 4) stimulating the production of those growth factors that specifically stimulate healing and regeneration.

Recombinant human platelet-derived growth factor (PDGF) is present on the market in the form of becaplermin (trade name Regranex™) and approved by the Department of sanitary inspection behind quality of foodstuff and medicines of the USA for the treatment of diabetic neuropathic ulcers of the lower extremities that extend into the subcutaneous or next, and supplied with blood enough". It was shown that becaplermin effective in accelerating wound healing in patients with diabetes (Steed, 2006,Plast Reconstr Surg., 117(7 Suppl):143S-149S; Nagai et al., 2002,Expert Opin Biol Ther., 2(2):211-8). Since PDGF is a target gene of HIF (Schultz et al., 2006,Am J Physiol Heart Circ Physiol., 290(6):H2528-34; Yoshida et al., 2006,J Neurooncol., 76(1):13-21), it is assumed that the inhibition of PHD will increase the production of endogenous PDGF and will provide similar or more favorable effect on those that are produced only backup what Ermin. Animal studies have shown that topical application of PDGF increases the amount of DNA, protein and hydroxyproline formation of a thicker layer of granulation and epidermal tissue, increased cellular secondary colonization of faults. PDGF activates the local effect of intensifying the formation of a new connective tissue. It is assumed that the efficiency of inhibition of PHD will be higher than the efficiency of inhibition caused by becaplermin because of the additional timeprocessing and Pro-angiogenic effects mediated HIF.

It is expected that the beneficial effects of inhibition of PHD will apply not only to the acceleration of wound healing in the skin and the colon, but also on healing other damage to the tissue, including, but not limited to, the following: gastrointestinal ulcers, replantation transplant, burns, chronic ulcers and frostbite.

Stem cells and precursor cells found in hypoxic niches inside the body, and hypoxia regulates their differentiation and metabolic pathway cells (Simon et al., 2008,Nat Rev Mol Cell Biol., 9:285-96). Thus, inhibitors of PHD may be suitable for the maintenance of stem cells and precursor cells in a pluripotent state and promote differentiation towards the desired cell type. Stem the cells may be useful for the cultivation and growth of populations of stem cells and can hold cells in a pluripotent state, while hormones and other factors are introduced into cells in order to affect the differentiation and metabolic pathway of the cell.

Continued use of PHD inhibitors in the treatment of stem cells and cells-precursors associated with the use of PHD inhibitors for the conditioning of these cells so that they can support the process of implantation in the body and in order to generate the appropriate response of the body, resulting in the implantation of stem cells and the cells of the predecessor will be feasible (Hu et al., 2008,J Thorac Cardiovasc Surg., 135(4):799-808). More specifically, the PHD inhibitors can contribute to the integration of stem cells and the involvement of the appropriate blood flow to support stem cells after injection. This formation of the blood vessel will also be a transfer of hormones and other factors released by these cells for the rest of the body.

The PHD inhibitors may also be useful in the treatment of infections (Peyssonnaux et al., 2005,J Invest Dermatol.,115(7):1806-15; Peyssonnaux et al., 2008J Invest Dermatol.,August 2008; 128(8):1964-8). It was shown that the increase in HIF enhances the innate immune response to infection in phagocytes and keratinocytes. Phagocytes with increased HIF demonstrate higher bactericidal activity, increased secretion of nitric oxide and increased the th production of antibacterial peptide cathelicidin. These effects can be also useful for the treatment of burn infections.

It was also shown that HIF is involved in the process of bone growth and fusion of the fracture (Pfander D, et al., 2003J Cell Sci.,116(Pt 9):1819-26., Wang et al., 2007J Clin Invest.,17(6):1616-26.) and, therefore, can be used for treatment or prevention of fractures. HIF stimulates glycolysis, which power the synthesis of extracellular matrix of epiphyseal chondrocytes in hypoxia. HIF also plays an important role in the stimulation of VEGF and the development of blood vessels in the process of accretion of the fracture. The growth of blood vessels in the growing or non-Union of bone may be a factor limiting the speed of the process.

The literature describes some molecules of small size c antagonistic activity against prolylhydroxylase. These molecules are among some of imidazo[1,2-a]pyridine derivatives (Warshakoon et al., 2006,Bioorg Med Chem Lett., 16(21):5598-601), substituted pyridine derivatives (Warshakoon et al., 2006,Bioorg Med Chem Lett., 16(21):5616-20), some pyrazolopyrimidine (Warshakoon et al., 2006,Bioorg Med Chem Lett., 16(21):5687-90), some bicyclic heteroaromatic N-substituted derivatives of glycine (international patent application WO2007/103905, September 13, 2007), compounds based on quinoline (international patent application WO2007/070359, June 21, 2007), some of the barbiturate-N-substituted the s derivative of glycine (international patent application WO2007/150011, December 27, 2007) and substituted aryl and heteroaryl-amide (U.S. patent application number US 2007/0299086, 27 December 2007).

Some derivatives of benzimidazole described in the literature. For example, LeCount et al.,Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry(1972-1999) (1974), (2):297-301, Senga et al.,Journal of Heterocyclic Chemistry(1975), 12(5):899-901, Kandeel et al.,Polish Journal of Chemistry(1983), 57(1-3), 327-31, Povstyanoi et al.,Ukrainskii Khimicheskii Zhurnal(Russian Edition) (1990), 56(10):1089-92, Singh et al.,Indian Journal of Chemistry, Section B: Organic Chemistry Including Medicinal Chemistry, (1993) 32B(2):262-5, Lipunova et al.,Mendeleev Communications(1996), (1):15-17, Lipunova et al.,Russian Journal of Organic Chemistry(Translation of Zhurnal Organicheskoi, Khimii) (1997), 33(10):1476-86, benzoimidazol-pyrazoles as intermediate compounds for inhibitors of NHE-1 (WO9943663), N-heteroaromatic as drugs that act on the psyche (DE3824658). In addition, 1-(1H-benzoimidazol-2-yl)-5-methyl-1H-pyrazole-4-carboxylic acid (CAS No. 1017666-26-0), ethyl ester of 1-(1H-benzoimidazol-2-yl)-5-hydroxy-1H-pyrazole-4-carboxylic acid (CAS No. 1006582-96-2), 1-(1H-benzoimidazol-2-yl-5-pyrrol-1-yl-1H-pyrazole-4-carboxylic acid (CAS No. 1017666-37-3) and 1-(1H-benzoimidazol-2-yl)-5-(2,5-dimethylpyrrole-1-yl)-1H-pyrazole-4-carboxylic acid (CAS No. 1017666-50-0) available on market.

However, still there remains a need for potent modulators of prolylhydroxylase with desirable pharmaceutical properties. Notwithstanding the above, the present invention is the meet the purpose of new derivatives of benzimidazole, suitable for this purpose.

Brief description of the invention

The aim of the present invention, in General, are compounds representing a PHD inhibitors of formula (I),

where

nis from 2 to 4

R1independently selected from H, halogen, -C1-4of alkyl, -C3-8cycloalkyl-C1-4pergolla, trifter-C1-4alkoxy-OH, -NO2, -CN, CO2H, -OC1-4of alkyl, -SC1-4of alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rd, -O-Rc, -CH2-O-Rc, -C(O)NH-Rc, -NRaRb, benzyloxy, optionally substituted Rd, phenyl or monocyclic heteroaryl, optionally substituted Rd, -C3-8cycloalkyl, optionally containing O, S or N, and referred-C3-8cycloalkyl optionally substituted Rdand two adjacent R1groupcan be connected with the formation of optionally substituted 3-8-membered ring, optionally containing one or more atoms O, S or N;

Raand Rbeach independently represents H, C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-ReC1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, f the Nile, optionally substituted Rd, benzyl, optionally substituted by Rdor monocyclic heteroaryl ring, optionally substituted by Rd; or Raand Rbtogether with the nitrogen atom to which they are joined, can form an optionally substituted monocyclic geteroseksualnoe ring, optionally containing one or more atoms O, S or N;

Rcrepresents a C3-8cycloalkyl, phenyl, optionally substituted by Rd, benzyl, optionally substituted by Rdor monocyclic heteroaryl ring, optionally substituted by Rd;

Rdindependently represents-H, halogen, -OH, -C1-4alkyl or C1-4perhalogenated, trifter C1-4alkoxy, -OC1-4alkyl, -O-phenyl or O-benzyl;

Rerepresents a C3-8heteroseksualci, optionally containing one or more atoms O, S or N;

R2and R3both represent H, -CF3or-CH3; and

each Z is an atom C or N, provided that no more than two Z can be N; and

enantiomer, the diastereomers, the racemates of these compounds, or pharmaceutically acceptable salts of these compounds.

The present invention includes isomeric forms of the compounds of formula (I) and their pharmaceutically acceptable salts, and link here at the bottom of such isomeric forms indicates a reference to at least one of such isomeric forms. The person skilled in the art recognizes that the compounds in accordance with this invention can be, for example, in a single isomeric form, while other compounds may exist in the form of a regioisomeric mixture.

The present invention also relates to pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of compounds of formula (I). In certain preferred embodiments, the implementation of compound of formula (I) is a compound selected from the species described or illustrated in the following detailed description.

The following General aspect, the invention relates to drugs, each of which includes: (a) an effective amount of the compounds of formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite; and (b) pharmaceutically acceptable filler.

In another General aspect the invention is directed to a method of treatment of a subject with an existing or diagnosed disease, disorder, or a disorder caused by the activity of the enzyme prolylhydroxylase. The method consists in assigning to a patient in need of such treatment, an effective amount of the compounds of formula (I) or farmacevtichesky acceptable salt, pharmaceutically acceptable prodrug or pharmaceutically active metabolite.

In certain preferred embodiments, the application of the method of the invention, the disease, disorder or condition is selected from the following: anemia, vascular disorders, metabolic disorders and wound healing.

Additional embodiments, features and advantages of the invention will be apparent from the following detailed description and the practical implementation of the invention.

Detailed description

The present invention can be more fully appreciated from the following description, including a Glossary of terms and the final examples. For brevity cited publications, including patents, are included in the present description by reference.

The terms "including", "containing", "comprising" are used herein in their open, unlimited value.

The term "alkyl" refers to alkyl group with straight or branched chain, containing from 1 to 12 carbon atoms. Examples of alkyl groups include methyl (Me, which also may be structurally marked with this symbol "/"), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl (tBu), phenyl, isopentyl, tert-phenyl, hexyl, isohexyl, and groups that in light of the common knowledge and teachings, PR is stavlennik here will be considered equivalent to one of the above examples.

The term "bergalli" refers to an alkyl group with straight or branched chain, having from 1 to 12 atoms in the chain and hydrogen atoms, optionally substituted with halogen atoms. Examples perilously groups include trifluoromethyl (CF3), deformity (CF2H), MonitorMaster (CH2F), pentaborate (CF2CF3), tetraborates (CHFCF3), triptorelin (CH2CF3and groups that in light of the common knowledge and the information presented in this document can be considered equivalent to one of the above examples.

Used in this application, the term "cycloalkyl" means a saturated or partially saturated monocyclic, condensed polycyclic or Spiro-polycyclic carbocycle containing from 3 to 12 ring atoms carbocycle. Illustrative examples cycloalkyl groups include the following objects, in the form of appropriately related components:

"Heteroseksualci" means a saturated or partially saturated monocyclic ring structure containing from 4 to 7 atoms in the ring structure selected from carbon atoms and up to two heteroatoms selected from nitrogen, oxygen and sulfur. The ring structure may need is certainly to contain up to two oxoprop, attached to the sulfur heteroatoms. Illustrative objects in the form of appropriately related components include:

Used in this application, the term "heteroaryl" means a monocyclic, condensed bicyclic or condensed polycyclic aromatic heterocycle (ring structure having ring atoms selected from carbon atoms and up to four heteroatoms selected from nitrogen, oxygen and sulfur), containing from 3 to 12 ring atoms on the heterocycle. Illustrative examples of heteroaryl groups include the following objects in the form of appropriately related components:

The specialists will determine that listed or illustrated above examples cycloalkyl, geterotsiklicheskikh and heteroaryl groups are not exhaustive and that under certain conditions the present invention can be selected and other groups of the specified type.

The term "halogen" refers to chlorine, fluorine, bromine or iodine. The term "halo" means chlorine, fluorine, bromine or iodine.

The term "substituted" means that the specified functional group or component has one or more substituents. The term "unsubstituted" means that the specified group does not have substituents. Use the th in this application, the term "possibly substituted" means, that the group either does not have substituents, or bears one or more substituents. If the term "substituted" is used to describe the structural system, this means that the substitution occurs at any position of the system where it is allowed by valence. In cases where for a particular component or group explicitly stated that she is optionally substituted or substituted with any particular Vice, it is assumed that such component or group is unsubstituted.

Each of these in this application of the formulas is as connections with the structures illustrated in this structural formula, and some variations or forms of such structures. In particular, the compounds of any information provided in this document formulas can have asymmetric centers and therefore exist in different enantiomeric forms. All optical isomers and stereoisomers of the compounds of the General formula, as well as mixtures thereof, are within the scope of this formula. Thus, any given here the formula is intended to denote a racemate, one or more enantiomeric forms, one or more diastereomeric forms, one or more atropisomers forms and mixtures mentioned. In addition, some patterns may exist in the form of the geometric isomero is (for example, CIS-andTRANSisomers), in the form of tautomers, or in the form of atropisomers. In addition, any given here, the formula includes a hydrate, solvate and polymorphs of such compounds, and mixtures specified.

In addition, each given in this application formula, in addition to the compounds, including their hydrates, solvate and polymorphs, and mixtures thereof, even if such forms are not specified explicitly. Some compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I) can be obtained in the form of a solvate. The solvate include a shape formed as a result of interaction or complexation of the compounds that are the subject of the present invention, one or more solvent, and the obtained either in the form of a solution or in the form of a solid or crystalline form. In some embodiments mentioned solvent is a water, and the solvate is a hydrate. In addition, some of the crystalline forms of the compounds of formula (I) or pharmaceutically acceptable salts of compounds of formula (I) can be obtained in the form of co-crystals. In some embodiments, implementation of the present invention the compounds of formula (I) were obtained in crystalline form. In other embodiments, implementation of the crystalline forms of the compounds of formula (I) were cubic in nature. Other variants of implementation of the pharmaceutically acceptable salts of compounds of formula (I) were obtained in crystalline form. In other embodiments, implementation of the compounds of formula (I) were obtained in the form of one of several polymorphic forms, in the form of a mixture of crystalline forms, in the form of polymorphic forms or amorphous form. In other embodiments, implementation of the compounds of formula (I) in solution are transferred from a single crystal and (or) polymorphic form to another and back again.

For a more concise description of the number given in this application of quantitative expressions are given without the modifier "about". Assume that regardless of whether you specify whether the modifier "about" explicitly or not, each given in this application is the numerical value refers to a specific given value, and approaching this shows the value that can be reasonably estimated by any specialist, including equivalents and approaches associated with the conditions of the experiment and (or) to measure such values. When specifying connection output in percent driven output refers to the weight of structural units, for which you specify the output, relative to the maximum achievable number of this unit in particular stoichiometric conditions. Unless otherwise noted, given in percent concentrations are related to mass ratios.

Women is the chemical structural unit in the present application means a reference to any of the following: (a) literally, the above form of this chemical structural units; and (b) any form mentioned chemical structural units in the environment where the connection is at the time mentioned. For example, the reference in the present application of such compounds, as R-COOH, includes a reference to any of, for example, the following forms: R-COOH(s)R-COOH(sol)and R-COO-(sol). In the above example, R-COOH(s)refers to the solid compound, for example, in the form of tablets or other solid pharmaceutical form or composition; R-COOH(sol)refers to medicationabana form compounds in a solvent; and R-COO-(sol)refers to the dissociated form of the compound in a solvent, such as dissociated form compounds in the aquatic environment, regardless if this dissociated form of R-COOH, salts thereof or of any other structural units, which give R-COO - by dissociation in the considered environment. In another example, such an expression as "action at a structural unit of a compound according to the formula R-COOH" means action on the aforementioned structural unit form or forms of the compounds R-COOH, which exist, or which exist in the environment in which the described effect. In another example, such an expression as "the introduction of the structural unit in the reaction with the compound according to the formula R-COOH, refers to the reaction (a) is similar to the structural unit is s in the appropriate chemical form or forms, which exist, or which exist in the environment in which the described reaction, (b) the appropriate chemical form or forms of the compounds R-COOH, which exist, or which exist in the environment in which the described reaction. In this regard, if such a structural unit is, for example, in the aquatic environment, it is understood that the above-mentioned compound R-COOH is in the same environment, and so on mentioned structural unit are such reagents as R-COOH(aq)and (or) R-COO-(aq)where the subscript "(aq)" means "water" in accordance with its accepted meaning in chemistry and biochemistry. In the above examples used the item applies carboxyl functional group, however, this choice is by no means a restriction was made for illustration purposes only. Assumes that similar examples can be given for other functional groups, including, without limitation, groups such as hydroxyl group, nitrogen-major group, for example, amines have had, as well as any other groups that are known to interact or rebuilt in containing the connection environment. Such interaction and adjustment include, among other things, dissociation, Association, tautomerism, solvolysis, including hydrolysis, with whom lately, including hydration, protonation and deprotonation.

In another example, zwitterion connection in this application is incorporated by reference to the compound, which can form zwitterion, even if it is not explicitly mentioned in its zwitterionic form. The terms "zwitterion", "zwitterion", and their synonyms "zwitterion connection" and "zwitterion connections are standard recommended by IUPAC terms that are well known and included in the standard set of certain scientific terms. In this regard, the term "zwitterion assigned a unique ID, CHEBI:27369 in the Dictionary chemical entities of biological interest (ChEBI). As is generally well known, zwitterion or zwitterion connection is a generally neutral compound having a single formal charges of opposite signs. Sometimes such connections also used the term "internal salt". In a number of sources such compounds are called "dipolar ions, although other sources latter term is incorrect. As a concrete example, aminoethanol acid (the amino acid glycine has the formula H2NCH2COOH and in some environments (in this case in a neutral environment) exists in the form zwitterion+H3NCH2COO-. Zwitterion, zwitterion with the unity, internal salt and dipolar ions in the well-known and well-documented values of the above terms apply to the scope of the present invention, as will easily be defined by experts. Since there is no need to call each individual variant implementation of the present invention, which can be determined by a specialist in this application are not given explicitly patterns zwitterionic compounds related to the compounds constituting the subject matter of the present invention. However, all such structures are part of the embodiments of the present invention. In this application does not provide further examples in this regard because of possible interactions and alterations in a given environment, leading to different forms of each specific connection.

Each of these in this application of the formulas is also as its and isotope-labeled forms of the corresponding compounds. Isotope-labeled compounds have structures that correspond presented in this application formulas, except that one or more atoms in them are replaced by an atom having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen is, oxygen, phosphorus, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,15N18O,17O,31P,32P,35S18F,36Cl125I, respectively. Such labeled with isotopes compound suitable for studies of metabolism (preferably14C)studies of the kinetics of reactions (for example, with2H or3H), methods of detecting or receiving images [such as tomography, based on the method of positron emission (PET)or single photon emission computed tomography (SPECT)], including quantitative analyses of drug or substrate tissue, or radiation therapy patients. In particular, compounds labeled18F or11C may be particularly preferred for research methods PET or SPECT. In addition, the substitution of heavier isotopes such as deuterium (i.e.2H), may provide some therapeutic benefits as a result of a greater metabolic stability of compounds, for example, increased half-life ofin vivoor decrease the required dosage. Compounds of the present invention labeled with isotopes, and prodrugs thereof can generally be prepared by carrying out the procedures according to the schemes or examples and methods of preparation described below, by replacing the reagent is, not containing labeled atoms, readily available reagent labeled with atoms.

When discussing any given in this application of the formula the choice of a specific fragment from a list of possible options for a specific chemical variable does not fix such a choice of the fragment for the given variable in the other formulas. In other words, if some chemical variable is present in the formula in more than one place, with the option for it from a list of possible in one place does not depend on the choice for the same variable in another place in the formula, unless otherwise noted.

As a first example used to denote substituents terminology, if the Deputy S1examplerepresents one of the S1and S2and Deputy S2examplerepresents one of the S3and S4these options indicate substituents include embodiments of the present invention in accordance with the following sets: S1examplerepresents the S1and S2examplerepresents the S3; S1examplerepresents the S1and S2examplerepresents the S4; S1examplerepresents the S2and S2exampleis S 3; S1examplerepresents the S2and S2examplerepresents the S4; and is equivalent to each of the following sets of deputies. Therefore, for brevity without loss of generality in this application uses the abbreviated terminology: "S1examplerepresents one of the S1and S2and S2examplerepresents one of the S3and S4". Above is the first example used to denote substituents terminology given in General terms, illustrates different ways to denote substituents described in this application. The above-mentioned condition of the substituents extends, when applicable, on such groups as R1, R2, R3, A, X4X5X6X7, Ra, Rb, Rc, Rdand Reand any other General symbolic notation of the substituents used in the present document.

In addition, if any member of the chemical structure or Deputy is more than one option, embodiments of the present invention include various independent combinations of options from the list of possible substitutes, and their equivalents. As a second example used to refer to cover the oil terminology, if this application States that the Deputy Sexamplerepresents one of the S1, S2and S3this list includes embodiments of the present invention, in which Sexamplerepresents the S1; Sexamplerepresents the S2; Sexamplerepresents the S3; Sexamplerepresents one of the S1and S2; Sexamplerepresents one of the S1and S3; Sexamplerepresents one of the S2and S3; Sexamplerepresents one of the S1, S2and S3; and Sexampleis any equivalent of each of these options. Therefore, for brevity without loss of generality in this application uses the abbreviated terminology: "Sexamplerepresents one of the S1, S2and S3". Above the second example is used to denote substituents terminology given in General terms, illustrates different ways to denote substituents described in this application. The above-mentioned condition of the substituents extends, when applicable, on such groups as R1, R2, R3, A, X4X5X6X7, Ra, Rb, Rc, Rdand Reand any other is bsie symbolic signs substituents, used in this document.

Item Ci-j"where j>i that is used in this application to denote the class of substituents, includes embodiments of the present invention, for which individually implemented each and every possible number of carbon atoms from i to j, including i and j. As an example, the term C1-3applies independently to variants of implementation, in which there is one atom of carbon (C1), variants of implementation, which has two carbon atoms (C2), and options for implementation, in which there are three atoms of carbon (C3).

Used in this application, the term Cn-malkyl means a linear or branched aliphatic chain with a complete number N of carbon centers in the chain, satisfying the condition n≤N≤m, where m>n.

Any reference in this application devalentino Deputy involves different ways of joining mentioned Deputy, if there is more than one such possibility. For example, the reference devalentino Vice-A-B-a, where A≠B, the present invention relates to such divalentin Vice-A-B-, where A fragment is attached to the first replaceable center and fragment B is attached to the second replaced the center, and to such divalentin Vice-A-B-, where A fragment is attached to the second is replacing the center and fragment B is attached to the first replaced the center.

In accordance with the above considerations in the designation of Vice and used the item it is understood that in this application there is no explicit mention of a certain set of capabilities means, in the presence of a chemical sense, and unless otherwise specified, an independent reference for all possible options for the implementation of this set, as well as a reference to all and every possible variant of the implementation of subsets explicitly specified set of options.

Images of chemical structures are designed to provide a detailed exposition of those parts of the compounds described herein which contain orientation.

The aim of the present invention, in General, are the compounds of formula (I),

the use of compounds of formula (I) and pharmaceutical compositions containing such compounds of formulas to treat patients (humans or other mammals)having a disease associated with the modulation of the enzyme prolylhydroxylase. The current invention also includes methods of making such compounds, pharmaceutical compositions, pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs and pharmaceutically active metabolites.

In one preferred embodiment, for formula (I), each of R2and R3predstavljaetsja H.

In another embodiment of formula (I), Z represents a C.

In related embodiments, the implementation of formula (I)nis a 4, and each R1represents independently: H, halogen, hydroxyl, alkyl, alkoxy, thioalkyl, alkyl sulfoxide, alkyl sulfon, optionally substituted 3-8-membered aliphatic or aromatic or heterocyclic ring, amino, alkylamino, alkylsulfonyl, arylsulfonyl, nitro, cyano, substituted phenoxy, benzyloxy, substituted arylsulfonyl, substituted arylsulfonyl, substituted arylsulfonyl, substituted bansilalpet, substituted benzyloxy, substituted benzylmethyl or substituted phenylsulfanyl.

R1may also independently represent H, halogen, C1-4alkyl straight or branched chain, C1-4triptracker straight or branched chain, C1-4bergalli with straight or branched-chain, monocyclic or C3-8carbon ring, saturated or partially saturated.

In another preferred embodiment, two adjacent groups R1can be connected with the formation of optionally substituted 3-8-membered saturated or unsaturated carbocyclic or heterocyclic ring.

In another preferred embodiment, for formula (I) ka is every R 1independently selected from the group consisting of H, -Cl, -F, -Br, -I, -C1-4of alkyl, -CF3, -C3-8cycloalkyl, -SC1-4of alkyl, -S(O)C1-4of alkyl, -S(O)2C1-4of alkyl, -OCF3, -OC1-4of alkyl, -CN, -NO2, -NH2, -NH-C1-4alkyl-, pyrrolidin-, piperidine-, morpholine-, -CO2H, -NHS(O)2C1-4alkyl and-NH-C(O)C1-4alkyl-, phenyl-, benzyl-, phenoxy - and benzyloxy-.

In preferred embodiments, the implementation of formula (I) R1represents H, 5,6-dichloro, 5-trifluoromethyl, 5-chloro-6-fluoro, 5,6-dimethyl, 5-bromo, 5-methoxy, 4-chloro-6-trifluoromethyl, 5,6-dimethoxy, 4,5-dimethyl, 5-triptoreline, 5-bromo, 5,6-dichloro, 5-bromo, 5,6-dichloro, 5-chloro, 5-bromo-6,7-dimethyl, 4-chloro, 5-chloro-7-trifluoromethyl, 7-bromo-5-triptoreline, 6-chloro-5-trifluoromethyl, 4,5,6-trifter, 4-bromo-5,6-debtor, 6-chloro-4-methyl, 4,6-dichloro, 4-bromo-6-trifluoromethyl, 5,6-debtor, 4-bromo-6-chloro, 6-methanesulfonyl, 5-chloro-6-cyano, 6-chloro-5-nitro, 5-amino-6-chloro, 5-fluoro, 6-chloro-5-pyrrolidin-1-yl, 6-chloro-5-piperidine-1-yl, 6-chloro-5-morpholine-4-yl, 6-chloro-5-methoxy, 4-carboxy, 5-bromo-7-fluoro, 5-bromo-7-methyl, 6-methylsulfanyl-5-trifluoromethyl, 6-propylsulfonyl-5-trifluoromethyl, 6-isopropylphenyl-5-trifluoromethyl, 5-fluoro-6-methylsulfanyl, 5-chloro-6-methylsulfanyl, 5-chloro-6-ethylsulfanyl, 5-chloro-6-isopropylphenyl, 5-chloro-6-propylsulfonyl, 6-methylsulfanyl-5-triptoreline, 6-isopropylphenyl-5-triptoreline, 6-propels hanil-5-triptoreline, 5-chloro-6-econsulting, 5-chloro-6-econsultancy, 6-methanesulfonyl-5-trifluoromethyl, 5-fluoro-6-methanesulfonyl, 5-chloro-6-methanesulfonyl, 6-methanesulfonyl-5-triptoreline, 5-chloro-6-(propane-2-sulfonyl), 5-chloro-6-(propane-1-sulfonyl), 6-(propane-2-sulfonyl)-5-trifluoromethyl, 6-(propane-1-sulfonyl)-5-trifluoromethyl, 6-[(1-atility)sulfonyl]-5-(triptoreline, 6-(propane-2-sulfonyl)-5-triptoreline, 6-(methylsulfinyl)-5-(trifluoromethyl, 6-bromo-5-fluoro, 4-fluoro, 4,5-debtor, 4,6-debtor, 6-chloro-5-triptoreline, 5-fluoro-4-methyl, 5-piperidine-1-yl-6-(triptoreline, 5-fluoro-6-piperidine-1-yl, 6-ethoxy-5-fluoro, 4-bromo-6-fluoro, 5,6-bis-trifluoromethyl, 4,5,6-trichloro, 4-bromo-5,6-dichloro-6-fluoro-5-trifluoromethyl, 6-chloro-5-ethylamino, 6-chloro-5-Propylamine, 6-chloro-5-cyclopropanesulfonyl, 6-chloro-5-methanesulfonamide, 6-chloro-5-ethanolamin, 5-acetylamino-6-chloro, 6-chloro-5-propicillin, 5-ethylsulfanyl-6-trifluoromethyl, 5-ethylsulfanyl-6-triptoreline, 5-ethylsulfanyl-6-fluoro, 6-fluoro-5-propylsulfonyl, 6-fluoro-5-isopropylphenyl, 5-ethylsulfonyl-6-trifluoromethyl, 5-ethylsulfonyl-6-triptoreline, 5-ethylsulfonyl-6-fluoro, 6-fluoro-5-propylsulfonyl and 6-fluoro-5-isopropylphenyl.

In preferred embodiments, the implementation of formula (I), where each R1independently selected from the group consisting of H, 3-(3-chlorobenzoyloxy)-phenyl, 3-(2-chlorobenzoyloxy)-phenyl, 3-(4-chlorobenzoyloxy)-phenyl, 3-benzyloxyphenyl, 4-benzyloxy Anila, 3-triptoreline, 3,4-dichlorophenyl, 4-hydroxyphenyl, 3-hydroxyphenyl, 3,4-dichlorophenoxy)-6-trifloromethyl, 6-chloro-5-(4-chlorphenoxy), (4 chlorophenoxy)-6-triptoreline, 5-phenoxy-6-triptoreline, 4-pertenece)-6-trifloromethyl, (4 chlorophenoxy)-6-trifloromethyl, 5-phenoxy-6-trifloromethyl, 6-chloro-5-phenoxy, 5-benzyloxy-6-chlorine -, 6-chloro-5-m-tamilselvan, 6-chloro-5-(4-chlorophenylsulfonyl, 6-chloro-5-phenylsulfanyl, 6-chloro-5-(3,4-dichlorobenzenesulfonyl, 6-chloro-5-(3-methoxyphenylalanine, 6-chloro-5-(4-methoxyphenylalanine), 5-benzylmethyl-6-chloride, 4-tert-butylbenzenesulfonyl)-6-chlorine, 6-chloro-5-(4-farbenindustrie, 6-chloro-5-(2-chlorine-benzylmorphine, 6-chloro-5-penetralia, 6-chloro-5-(toluene-3-sulfonyl, 5-benzazolyl-6-chlorine, 6-chloro-5-(4-methoxybenzenesulfonyl, 6-chloro-5-(4-chlorobenzenesulfonyl, 6-chloro-5-(4-trifloromethyl, 6-chloro-5-(3,4-dichlorobenzenesulfonyl, 6-chloro-5-(3-methoxybenzenesulfonyl, 6-chloro-5-phenylmethanesulfonyl, 6-chloro-5-(2,4,6-trimethylphenylsulfonyl, 6-chloro-5-(4-methoxybenzenesulfonyl, chloro-5-(4-performanceline, 6-chloro-5-(2-chlorophenylsulfonyl, 6-chloro-5-(2-phenylethanolamine, 5-benzosulfimide-6-chlorine 5-phenylcarbamoyl, 5-benzylcarbamoyl, 5-(morpholine-4-yl-carbamoyl), 5-benzoyloxymethyl, 5-benzylamine, 6-chloro-5-phenylamine, 6-chloro-5-(2-morpholine-4-yl-ethylamine), 5-benzosulfimide-6-chlorine 5-benzoi the amino-6-chlorine, 6-chloro-5-(2-morpholine-4-yl-acetylamino), 6-chloro-5-(2-piperidine-1-yl-acetylamino), 6-chloro-5-[2-(4-methylpiperazin-1-yl, 6-chloro-5-(4-methoxyphenoxy), 6-chloro-5-(4-chloro-2-pertenece), 6-chloro-5-(4-triftormetilfosfinov), 6-chloro-5-(3-chloro-4-pertenece), 5-phenylsulfonyl-6-trifloromethyl, 5-(4-methoxybenzenesulfonyl)-6-trifloromethyl, 5-benzazolyl-6-trifloromethyl, 5-(4-methoxybenzenesulfonyl)-6-trifloromethyl, 6-chloro-5-(4-chloro-benzylmorphine, 6-chloro-5-(3-chlorobenzenesulfonyl), 6-chloro-5-cyclohexanesulfonyl, 6-chloro-5-(2-morpholine-4-yl-ethylsulfanyl), chloro-5-(3,4-dichlorobenzenesulfonyl, 6-chloro-5-(2,6-dichlorobenzenesulfonyl), 6-chloro-5-(4-methylbenzenesulfonyl), 6-chloro-5-(4-triftormetilfullerenov), 5-(2,4-bis-triftormetilfullerenov)-6-chloro, 6-chloro-5-(2'-cyanobiphenyl-4-yl-methylsulfanyl), 6-chloro-5-(4-chlorophenylsulfonyl), 6-chloro-5-(3-chlorophenylsulfonyl), chloro-5-cyclohexanesulfonyl, 6-chloro-5-(3,4-dichlorobenzenesulfonyl), 6-chloro-5-(2,6-dichlorobenzenesulfonyl), chloro-5-p-trimethylsulfonium, 6-chloro-5-(4-triftormetilfullerenov), 5-(2,4-bis-triftormetilfullerenov), chloro-5-(2'-cyanobiphenyl-4-yl-methanesulfonyl and 6-chloro-5-phenylsulfanyl.

Examples of compounds of the present invention are presented in the table below.

ExampleThe chemical is the resource name Enzyme pIC50Cell % stimulation of EPO
11-(1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,17,1
21-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,9151,91
31-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,6109,74
41-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,7132,79
51-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,12,1
61-(5-bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,4to 9.91
71-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid 6,416,8
81-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;6,820,97
91-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,44.26 deaths
101-(4,5-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid5,110,7
111-(5-triptoreline -1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,5123,68
121-{5-[3-(3-chlorobenzoyloxy)phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid7,58,76
131-{5-[3-(2-chlorobenzoyloxy)phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-7,618
carboxylic acid

1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid
141-{5-[3-(4-chlorobenzoyloxy)phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid7,420,15
151-[5-(3-benzyloxyphenyl) -1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,310,77
161-[5-(4-benzyloxyphenyl) -1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,76,97
171-[5-(3-triptoreline) -1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,15,8
181-[5-(3,4-dichlorophenyl) -1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,115,3
191-(5-bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid<4to 20.52
20<418,81
211-(5-bromo-1H-benzoimidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole-4-carboxylic acid4,27,24
221-(5,6-dichloro-1H-benzoimidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole-4-carboxylic acid<40,47
231-[5-(4-hydroxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,6of 6.49
241-[5-(3-hydroxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,5of 11.15
251-(5-chloro-1H-benzoimidazol-2-yl)-1H-6,371,87
pyrazole-4-carboxylic acid

26 1-(5-bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,411,9
271-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,119,12
281-(5-chloro-7-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,416,6
291-(7-bromo-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,857,55
301-(6-chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,14128,94
311-(4,5,6-Cryptor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid718,2
321-(4-bromo-5,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,7 33
331-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6the 13.4
341-(4,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,556,3
351-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,829,7
361-(5,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,679,4
371-(4-bromo-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,634,03
381-(6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,140,93

391-(6-chloro-5-cyano-1H -benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,429,93
401-(6-chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,5repossessed a 93.44
411-(5-amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,430
421-(5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,333,76
431-(6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,7177,5
441-(6-chloro-5-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,7138,8
451-(6-chloro-5-morpholine-4-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,630,85
461-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,576
472-(4-carboxybenzoyl-1-yl)-1H-benzoimidazol-5-carboxylic acid6,611
481-(5-bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,344
491-(5-bromo-7-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,124
501-[5-(3,4-dichlorophenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,417,98
511-[6-chloro-5-(4-chlorphenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-7,4150,4
carboxylic acid

521-[5-(4-chlorphenoxy)-6-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,421,55
531-(5-phenoxy-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,2137,71
541-[5-(4-pertenece)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,375,52
551-[5-(4-chlorphenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,544,23
561-(5-phenoxy-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,2142,55
571-(6-chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,955
58 1-(5-bromo-7-methyl-1H-imidazo[4,5-f]quinoline-2-yl)-1H-pyrazole-4-carboxylic acid7,250
591-(5-benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,455,9
601-(6-chloro-5-m-tamilselvan-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,942,30
611-[6-chloro-5-(4-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,07101,2
621-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,7545,84

631-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,1826,54
64 1-[6-chloro-5-(3-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,938,26
651-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,656,3
661-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,741,64
671-[5-(4-tert-butylbenzenesulfonyl)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,211,72
681-[6-chloro-5-(4-perpenicular)-1Hbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,858,37
691-[6-chloro-5-(2-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,885,3
701-(6-chloro-5-fanatics hanil-1 H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,774,24
711-(6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,1113,95
721-(6-propylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,1n/a

731-(6-isopropylphenyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,2n/a
741-(5-fluoro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,977,795
751-(5-chloro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7106,17
761-(5-chloro-6-utils hanil-1 H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,9211,75
771-(5-chloro-6-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,8152,89
781-(5-chloro-6-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7125,21
791-(6-methylsulfanyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,183,83
801-(6-isopropylphenyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7n/a
811-(6-propylsulfonyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7n/a
821-[6-chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H/i> -pyrazole-4-carboxylic acid7,4of 85.32
831-(5-benzazolyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acidEUR 7.57to 96.65

841-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,342,71
851-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,3to 51.64
861-[6-chloro-5-(4-trifloromethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,348,9
871-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acidof 6.6832,39
881-[6-chloro-5-(3-methoxybenzoic hanil)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,469,43
891-(6-chloro-5-phenylmethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,528,45
901-[6-chloro-5-(2,4,6-trimethylphenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,38,25
911-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,722,01
921-[6-chloro-5-(4-PerformanceCounter)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,561,2

931-[6-chloro-5-(2-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,578,5
94 1-[6-chloro-5-(2-phenylethanone)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,465,1
951-(5-chloro-6-econsulting-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,246,3
961-(5-chloro-6-econsultancy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,467
971-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,675,88
981-(5-fluoro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,341,37
991-(5-chloro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,434,85
1001-(6-methanesulfonyl-5-triptoreline-1H-benzoimidazol-2-yl)- H-pyrazole-4-carboxylic acid7,550,16
1011-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,362,2
1021-[5-chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,554,94
1031-[6-(propane-2-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,4n/a

1041-[6-(propane-1-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,5n/a
1051-[6-(propane-2-sulfonyl)-5-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,4n/a
1061-[6-(propane-1-sulfonyl)-5-is reformatory-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,5123,7
1071-(5-benzosulfimide-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,247,57
1081-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,320,41
1091-(6-bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,799
1101-(4-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,245,87
1111-(4,5-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,632,58
1121-(4,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,831,6
1131-(6-chloro-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,98109,33
1141-(1H-oil[2,3-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,3144,2
1151-(3H-oil[1,2-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,150
1161-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid5,818,3

1171-(5-piperidine-1-yl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,580
1181-(5-fluoro-6-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,8152
1191-(6-ethoxy-5-the top-1 H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,569
1201-(5-phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,9to 21.15
1211-(5-benzylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,118,5
1221-[5-(morpholine-4-ylcarbonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,6of 5.4
1231-(5-benzoyloxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,361,15
1241-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,32,4
1251-(8H-imidazo[4',5':3,4]benzo[2,1-d]triazole-7-yl)-1H-pyrazole-4-carboxylic acid6 46,75
1261-(5,6-bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,482,65
1271-(4,5,6-trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,970,6
1281-(4-bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,124,1

1291-(6-fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid770,8
1301-(6-chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,248
1311-(6-chloro-5-propylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,589
132 1-(5-benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,252,6
1331-(6-chloro-5-phenylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,977
1341-[6-chloro-5-(2-morpholine-4-yl-ethylamino-)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,356,5
1351-(6-chloro-5-cyclopropanemethylamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,817
1361-(6-chloro-5-methanesulfonamido-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,89
1371-(6-chloro-5-ethanolamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,611
1381-(5-benzosulfimide-6-chloro-1H-benzoimidazol--yl)-1 H-pyrazole-4-carboxylic acid6,819
1391-(5-acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,324

to 47.2
1401-(6-chloro-5-propionamido-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,410
1411-(5-benzoylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,633
1421-[6-chloro-5-(2-morpholine-4-yl-acetylamino-)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,417
1431-[6-chloro-5-(2-piperidine-1-yl-acetylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,220
1441-{6-chloro-5-[2-(4-methylpiperazin-1-yl)-acetylamino]-1H-benzoyl Gasol-2-yl}-1 H-pyrazole-4-carboxylic acid6,416
1451-[6-chloro-5-(4-methoxyphenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,113,92
1461-[6-chloro-5-(4-chloro-2-pertenece)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,249,85
1471-[6-chloro-5-(4-triftormetilfosfinov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,445,85
1481-[6-chloro-5-(3-chloro-2-pertenece)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,138,12
1491-(5-ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,357,8
1501-(5-ethylsulfanyl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,2

1511-(5-ethylsulfanyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,9106,61
1521-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,991,38
1531-(6-fluoro-5-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,9n/a
1541-(5-ethylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,653,82
1551-(5-ethylsulfonyl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,647,21
1561-(5-ethylsulfonyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,4 51,9
1571-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,4n/a
1581-(6-fluoro-5-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,3n/a
1591-(5-phenylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,4br11.01
1601-[5-(4-methoxybenzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,536,1
1611-(5-benzazolyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,698,15

1621-[5-(4-methoxybenzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid45,8
1631-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,536,98
1641-[6-chloro-5-(3-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,627,4
1651-(6-chloro-5-cyclohexanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid6,927,3
1661-[6-chloro-5-(2-morpholine-4-yl-ethylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid715,1
1671-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,425,8
1681-[6-chloro-5-(2,6-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,3 50,14
1691-[6-chloro-5-(4-methylbenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,7n/a
1701-[6-chloro-5-(4-triftormetilfullerenov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,7n/a

1711-[5-(2,4-bis-triftormetilfullerenov)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid6,7n/a
1721-[6-chloro-5-(2'-cyanobiphenyl-4-elmersolver)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,5n/a
1731-[6-chloro-5-(4-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,860,41
1741-[6-chloro-5-(3-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-ka is oil acid 7,6of 40.9
1751-(6-chloro-5-cyclohexanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,748,7
1761-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,644,23
1771-[6-chloro-5-(2,6-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,566,6
1781-(6-chloro-5-p-trimethylsulfonium-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,7n/a
1791-[6-chloro-5-(4-trifluoromethyl-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,7n/a

1801-[5-(2,4-bis-trifluoromethyl-phenylmethane hanil)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid 7,6n/a
1811-[6-chloro-5-(2'-cyano-biphenyl-4-elmersolver)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid7,7n/a
1821-(1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid5,5the 13.4
1831-(6,7-dichloro-1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid6,43,3
1841-(1H-imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid5,98,3
1851-(6-chloro-9H-purine-8-yl)-1H-pyrazole-4-carboxylic acid5,311,7
1861-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid7,439,1

The present invention also includes pharmaceutical is citiesi acceptable salts of compounds of formula (I), preferably from those described above, and of those of these compounds, examples of which are shown here, as well as methods of treatment using such salts.

The term "pharmaceutically acceptable salt" means a salt of the free acid or base compounds represented by formula (I), which is non-toxic, biologically tolerable, or otherwise biologically valid for the patient. See, basically, G.S. Paulekuhn, et al., "Trends in Active Pharmaceutical Ingredient Salt Selection based on Analysis of the Orange Book Database",J. Med. Chem., 2007, 50:6665-72, S.M. Berge, et al., "Pharmaceutical Salts",J Pharm Sci., 1977, 66:1-19, andHandbook of pharmaceutical salts, properties, selection and application,Stahl and Wermuth, Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceutically acceptable salts are those that have a pharmacological effect and are valid for contact with the tissues of patients without excessive irritating, toxic or allergic reactions. The compound of formula (I) may be sufficiently acidic group, a sufficiently basic group, or both types of functional groups and engage in corresponding reactions with a number of inorganic or organic bases and inorganic or organic acids with the formation of pharmaceutically acceptable salts. Examples of pharmaceutically acceptable salts include salts include sulfates, piros ifaty, bisulfate, sulfites, bisulfite, phosphates, monohydrogenphosphate, dihydrophosphate, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionate, decanoate, caprylate, acrylates, formats, isobutyrate, caproate, heptanoate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, Butin-1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalates, sulfonates, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, γ-hydroxybutyrate, glycolate, tartratami, methansulfonate, propanesulfonate, naphthalene-1-sulfonates, naphthalene-2-sulfonates and mandelate.

When the compound of formula (I) contains a nitrogenous base, the desired pharmaceutically acceptable salt may be prepared by any valid well-known methods, for example treatment of the free base of an inorganic acid, such as hydrochloric acid, Hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and the like, or organic acid, such as acetic acid, phenylacetic acid, propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleimide acid, setinova Ki the lot, succinic acid, valeric acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, oleic acid, palmitic acid, lauric acid, pyrenoidosa acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as mandelic acid, citric acid, or tartrate acid, an amino acid such as aspartic acid, glutaric acid or glutamic acid, aromatic acid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, a sulfonic acid, such as laurylsulphate acid, para-toluensulfonate acid, methanesulfonate acid, econsultancy acid, any compatible mixture of acids such as those given here as examples, and any other acid or a mixture thereof, which are considered equivalent or acceptable substitutes in the light of ordinary knowledge in this technology.

When the compound of formula I is an acid, such as carboxylic acid or sulfonic acid, the desired pharmaceutically acceptable salt may be prepared by any available method, for example, treatment of the free acid, inorganic or organic, founded the eat, such as an amine (primary, secondary, or tertiary), an alkali metal hydroxide, alkali earth metal hydroxide, any compatible mixture of bases, such as the one shown in the examples, and any other bases and mixtures thereof, which are considered equivalent or acceptable substitutes in the light of ordinary knowledge in this technology. Illustrative examples of acceptable salts include organic salts derived from amino acids such as N-methyl-D-glucamine, lysine, choline, glycine, and arginine, ammonium salts, carbonates, bicarbonates, primary, secondary and tertiary amines, and cyclic amines, such as tromethamine, benzylamine, pyrrolidine, piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

The invention also relates to pharmaceutically acceptable prodrugs of formula (I) and methods of treatment using such pharmaceutically acceptable prodrugs. The term "prodrug" means a precursor of a compound, which after the appointment, the patient gives compoundin vivothrough chemical or physiological process such as solvolysis or enzymatic cleavage, or under physiological conditions (e.g., a prodrug, converted to defined the physiological pH, transformed into a compound of formula (I)). "Pharmaceutically acceptable prodrug" means a prodrug, which is non-toxic, biologically tolerable, and otherwise biologically valid for the patient. Illustrative procedures for the selection and preparation of acceptable derivative prodrugs described, for example, in "Design of Prodrugs", ed. H. Bundgaard, Elsevier, 1985.

Examples of prodrugs include compounds having an amino acid residue, or a polypeptide chain of two or more (e.g. two, three or four) amino acid residues, covalently linked by amide or ether linkages with a free amino-, hydroxy-, or carboxypropyl the compounds of formula (I). Examples of amino acids include the twenty-existing in nature amino acids, which are usually denoted by three letters, as well as 4-hydroxyproline, hydroxylysine, demazin, isodesmosine, 3-methylhistidine, Norvaline, beta-alanine, gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithine and methanesulfonic.

Additional types of prodrugs can be obtained, for example, with the use of free carboxyl groups to the structures of formulas (I) to obtain the amide or alkylating derivatives. Examples of amides include derivatives of ammonia, primary C1-6alkylamines followed and secondary di(C1-6alkyl)amines. The secondary and the ins include 5 - or 6-membered components geteroseksualbnogo or heteroaryl ring. Examples of amides include derivatives of ammonia, primary C1-3alkylamines followed and di(C1-2alkyl)amines. Examples of the esters of the invention include C1-7alkyl, C5-7cycloalkyl, phenyl and phenyl(C1-6alkyl) esters. Preferred esters include methyl esters. Prodrugs can also be prepared by use of free hydroxyl groups to obtain derivatives with the use of groups, including hemisuccinate, phosphate esters, diethylaminoacetate and phosphorylethanolamine using procedures such as described in Fleisher et al.,Adv. Drug Delivery Rev.1996,19, 115-130. Urethane derivatives of hydroxy - and amino groups can also give prodrugs. Carbonate derivatives, sulphonate esters and sulfate esters of the hydroxy groups can also give prodrugs. To obtain prodrugs can be used hydroxy groups, such as (acyloxy)methyl and (acyloxy)ethyl esters, where the acyl group may be an alkyl ester, perhaps bearing as substituents one or more ether, amino or carboxyl functional groups, or where mentioned acyl group is an ester of the amino acids as described above. Prodrugs of this type can be prepared as described in Greenwald, et al.,J Med Chem.1996,39, 10, 1938-40. Free amino groups can also be used the Ana to obtain derivatives of amides, sulfonamides and phosphoramidon. All of these fragments of prodrugs may be the structure of the additional functional groups such as ether, amino and carboxyl groups.

The present invention also relates to pharmaceutically active metabolites of compounds of formula (I), which can also be used in the methods of the present invention. "Pharmaceutically active metabolite" means a pharmacologically active product of metabolism in the body of the compounds of formula (I) or its salt. Prodrugs and active metabolites of compounds can be determined using conventional methods known and available to the experts in this field. See, for example, Bertolini / Marian Fisher, et al.,J Med Chem. 1997,40, 2011-2016; Shan, et al.,J Pharm Sci. 1997,86 (7), 765-767; Bagshawe,Drug Dev Res. 1995,34, 220-230; Bodor,Adv Drug Res. 1984,13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press, 1985); and Larsen, Design and Application of Prodrugs, Drug Design and Development (Krogsgaard-Larsen, et al., eds., Harwood Academic Publishers, 1991).

The compounds of formula (I) and their pharmaceutically acceptable salts, pharmaceutically acceptable prodrugs, and pharmaceutically active metabolites of the present invention is suitable for use as modulators PHD in methods of the invention. The term "modulators" include both inhibitors and activators, where "inhibitors" refers to compounds that decrease, prevent, DEZ is kiviruut, desencibiliziruta or regulate the expression or activity of PHD in the fall, and "activators" - compounds that increase, activate, facilitate, sensibiliser or regulate the expression or activity of PHD on the increase.

The term "treat" or "treatment"as used herein, refers to the appointment of an active agent or compound of the present invention to a patient with the aim of therapeutic or prophylactic beneficial effects through the modulation of the activity of prolylhydroxylase. Treatment includes treatment of the flow, improvement, relief, slowing the progression of, reducing the sensitivity or prevention of a disease, disorder or condition, or one or more symptoms of such disease, disorder or condition caused by modulation of the activity of PHD. The term "patient" refers to a mammalian patient in need of such treatment, for example, to the person.

Accordingly, the invention relates to methods of using the compounds described herein for the treatment of those patients diagnosed with the disease, disorder or condition caused by prolylhydroxylase, such as anemia, cardiovascular disorders, metabolic disorders and wound healing. The symptoms of painful conditions should be included in the scope of the "m the medical conditions disorders or diseases.

The term "hypoxia" or "hypoxic disorder", as used herein, refers to a condition in which there is an insufficient level of oxygen in the blood or insufficient supply of tissues or organs with oxygen. The basis of hypoxic disorders can be a variety of mechanisms, including the lack of ability of blood to carry oxygen (i.e. anemia), inadequate blood flow to the tissue and / or organ, resulting from either heart failure or blockage of the blood vessels or arteries (i.e. ischemia), low barometric pressure (i.e. "mountain sickness" at high altitudes), or where the failed cells are unable to use oxygen properly (i.e. gistologicheskoe state). Accordingly, the person skilled in the art will understand that the present invention will be useful in the treatment of various hypoxic conditions, including anemia, heart failure, ischemic heart disease, thromboembolism, stroke, angina and the like.

In a preferred embodiment, molecules of the present invention is suitable for treatment or prevention of anemia, including the treatment of anemic conditions associated with such diseases as chronic kidney disease, politest the heat kidney disease, gipoplasticheskaya anemia, autoimmune anemia, anemia bone marrow transplantation, granulomatous allergic anghit, congenital gipoplasticheskaya anemia, Fanconi syndrome, the syndrome still's, graft versus host disease, transplantation of hematopoietic stem cells, hemolytic uremic syndrome, myelodysplastic syndrome, paroxysmal nocturnal hemoglobinuria, osteomielofibros, pancytopenia, true red cell aplasia, disease Seleina's disease, refractory anemia with excess of blasts, rheumatoid arthritis, syndrome Shwachman, sickle cell anemia, a large thalassemia minor thalassemia, thrombocytopenic greengourmet, anemic or nanimity patients undergoing surgical treatment, anemia associated with or which is the consequence of the injury, sideroblastic anemia, anemia, resulting from any treatment, including: inhibitors revertase for HIV treatment, corticosteroid hormones, cyclic chemotherapy cisplatin-containing or cisplatinbased drugs, Vinca alkaloids, inhibitors of mitosis, topoisomerase II inhibitors, anthracyclines, alkylating agents, in particular, anemia, resulting from inflammation, aging, and (or) chronic diseases. Inhibition of PHD may also be applicable to the treatment of symptoms of anemia, on the tea chronic fatigue, pallor and dizziness.

In another preferred embodiment, the molecules of the present invention is applicable for the treatment or prevention of diseases, metabolic disorders, including, without limitation, diabetes, and obesity. In another preferred embodiment, the molecules of the present invention is applicable for the treatment or prevention of vascular disorders. These disorders include but are not limited to, the following: diseases associated with hypoxia or healing wounds that require Pro-angiogenic mediators for the formation and development of blood vessels, development of blood vessels and arteriogenesis

In methods of treatment in accordance with this invention, an effective amount of the pharmaceutical agent in accordance with the invention is assigned to a patient with existing or diagnosed disease, disorder or condition. "Effective amount" means an amount or dose sufficient to achieve the overall desired therapeutic or prophylactic effect for a patient in need of such treatment at the specified disease, disorder or condition. The effective amount or dose of the compounds of the present invention can be evaluated by conventional means, such as modeling, studies with higher doses or Kleene is a mini-research as well as taking into account the usual factors such as the mode or method of administration or drug delivery, the pharmacokinetics of the compound, the severity and course of the disease, disorder or condition, previous or current treatment of the patient, health condition and response of the patient to the medicine, as well as the assessment of the attending physician. Example dose is in the range from about 0.001 to about 200 mg of the compound per 1 kg of body weight of the patient per day, preferably from about 0.05 to 100 mg/kg/day, or from about 1 to 35 mg/kg/day, in single or divided doses (for example, twice a day, three times a day, four times per day). For a person weighing 70 kg illustrative range of dosage is from about 0.05 to about 7 g/day, or from about 0.2 to about 2.5 g/day.

After improvement of the condition of the patient, relieve symptoms of diseases or disorders dosage can be adjusted for preventive or maintenance treatment. For example, the dosage, frequency of injection, or both can be reduced depending on the symptoms to a level that can support the desired therapeutic or prophylactic effect of the drug. Of course, if the symptoms are alleviated to an acceptable level, the treatment can be discontinued. However, if there is recurrence of symptoms the patient may require up to Sovremennoe periodic treatment.

In addition, the agents of the invention can be used in combination with additional active ingredients for the treatment of the aforementioned conditions. Additional compounds can be administered together, separately from the agent of the formula (I) or including such an agent as an additional active ingredient in the pharmaceutical composition in accordance with the invention. In the variant example of implementation of additional active ingredients are those known to be effective for treating conditions, disorders or diseases mediated by the enzyme PHD, or those that are active against other purposes associated with the particular condition, disorder or disease, such as alternative modulator PHD. The combination can serve to improve efficiency (for example, by including a combination of compounds that increase the effectiveness or efficiency of the connection in accordance with the invention), reducing one or more side effects or decrease the required dose of the compounds in accordance with the invention.

Compounds of the invention are applicable by themselves or in combination with one or more other active ingredients for the formulation of pharmaceutical compositions of the present invention. The pharmaceutical composition of the invention comprises: (a) an effective amount is and the compounds of formula (I) or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically active metabolite specified; and (b) pharmaceutically acceptable excipient.

The term "pharmaceutically acceptable excipient" means a non-toxic, biologically portable and on other parameters of biologically acceptable for administration to the patient a substance, such as an inert substance added to a pharmacological composition or otherwise used as a vehicle, carrier or diluent to facilitate the introduction of the agent and is compatible with the latter. Examples of fillers include calcium carbonate, calcium phosphate, various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and polyethylene glycols. Appropriate fillers may also include antioxidants. Such antioxidants can be used in the form of pharmaceutical compositions or environment for storage to increase the persistence of a pharmaceutical product.

Forms of delivery pharmaceutical compositions containing one or more dosage units of a compound of the invention may be prepared using appropriate pharmaceutical excipients and methods of making known now or in the future, or available to the person skilled in the art. In the methods of the invention compositions can be on the right by a local application, ocular, oral, parenteral, rectal, and by inhalation.

The drug may be in the form of tablets, capsules, sachets, pills, powders, granules, pastilles, powders for recovery, liquid preparations or suppositories. Preferably the composition is formulated for intravenous injection, topical application or oral administration. The preferred method of use of the invention is the topical application of inhibitors PHD, in particular, in those places where the fabric has become ischemic or was given in an ischemic state. This can be accomplished by a special catheter, a balloon for angioplasty or balloon located on the stent.

For oral administration the compounds of the invention can be presented in the form of tablets or capsules, or in the form of a solution, emulsion or suspension. For preparation of compositions for oral administration the compounds can be formulated to give a certain dose, for example from about 0.05 to about 100 mg/kg per day, or from about 0.05 to about 35 mg/kg per day, or from about 0.1 to about 10 mg/kg per day.

Tablets for oral administration can include connection in accordance with the invention, mixed with pharmaceutically acceptable excipients such as inert diluents, substances to improve raspadaemosti tablets, binding the matter of agents, lubricants, sweeteners, flavorings, colorants and preservatives. Appropriate inert fillers include carbonates of sodium and calcium, phosphates of sodium and calcium, lactose, starch, sugar, glucose, methylcellulose, magnesium stearate, mannitol, sorbitol and the like, Examples of liquid preparations for oral administration include ethanol, glycerol, water and the like, Starch, polyvinylpyrrolidone (PVP), sodium starch glycolate, microcrystalline cellulose, and alginic acid are acceptable substances to improve raspadaemosti tablets. Binding agents may include starch and gelatin. Lubricating agent, if present, may be magnesium stearate, stearic acid or talc. If necessary, the tablets can be coated with such a material as glycerylmonostearate or glycerylmonostearate to slow down the absorption in the gastrointestinal tract, or may have enterocoelous shell.

Capsules for oral administration may be solid and soft gelatin. For the preparation of hard gelatin capsules of the compounds of the invention can be mixed with solid, semi-solid or liquid diluent. Soft gelatin capsules can be prepared by mixing the compounds of the invention with water or oil, such as peanut oil or olive oil, liquid paraffin, what MESU mono - and diglycerides of fatty acids with short-chain, polyethylene glycol 400 or propylene glycol.

Liquid for oral administration can be in the form of suspensions, solutions, emulsions or syrups, or can be presented as a dry product for restore water or other acceptable media before use. The composition of such liquid compositions may include the following components: pharmaceutically acceptable excipients, such as suspendresume agents (e.g. sorbitol, methylcellulose, sodium alginate, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, gel-like aluminum stearate etc); non-aqueous media such as oils (e.g. almond oil or fractionated coconut oil), propylene glycol, ethyl alcohol or water; preservatives (e.g. methyl or propyl-p-hydroxybenzoate or sorbic acid); wetting agents such as lecithin; and, if necessary, flavors or dyes.

Active agents that are the subject of the present invention may also be administered to the patient neironalnam ways. For example, the compounds can be formulated for rectal application in the form of suppositories. For parenteral administration, including intravenous, intramuscular, intraperitoneal or subcutaneous, compounds of the invention can be presented in the form of sterile aqueous solutions or suspend the th, the buffer of appropriate pH and isotonicity or parenterally acceptable oil. Appropriate liquid carriers include ringer's solution and isotonic sodium chloride solution. These forms will be presented in the form of a standard dosage forms, such as ampoules or disposable devices for injection, in the form of multiple doses, such as flasks, of which can be selected adequate dose, or in solid form or in the form of primary concentrate, which can be used to prepare compositions suitable for administration. Illustrative dosage for infusion can vary from about 1 to 1000 μg/kg/min connection, mixed with a pharmaceutical carrier over time from several minutes to several days

For the local introduction of the compounds can be mixed with a pharmaceutical carrier in a concentration of from about 0.1% to about 10% of drugs in the media. In another way of introducing the compounds of the present invention can be used in the form of a patch for transdermal delivery.

Compounds of the invention may alternatively be administered in the methods of the present invention by inhalation through the nose or mouth, for example, in the form of a spray containing valid media.

Abbreviations and acronyms used in this document include the following:

The termThe acronym
DiisopropylethylamineDIEA
TetrahydrofuranTHF
DichloromethaneDCM
The sulfoxideDMSO
2-methoxyethoxymethylMEMCl or MEM-chloride
N,N-dimethylformamideDMF
EthanolEtOH
AcetonitrileACN
The ethyl acetateEtOAc
N-(3-dimethylaminopropyl)-N-ethylcarbodiimideEDCI
1,8-diazabicyclo[5.4.0]undec-7-ENDBU
DichloroethaneDCE
1,2,3,4,5-pentaphenyl-1'-(di-t-butylphosphino)ferroceneQ-Phos®
N-chlorosuccinimideNCS
N-bromosuccinimideNBS

Below are examples of compounds suitable for use in the methods of the present invention by reference to illustrative synthesis scheme for their preparation, and followed by specific examples. As will be clear to experts, to obtain various compounds raw materials can be selected accordingly so that the desired substituents kept in accordance with the scheme of the reaction in the presence or absence of protection, depending on the situation, and gave the desired product. Alternatively, it may be necessary or desirable to enter instead of the desired substituent corresponding group, which may be conducted through the reaction scheme and then replaced accordingly to the desired Deputy. Unless otherwise stated, the variables correspond to the definitions above in relation to formula (I). The reaction may be carried out in the interval between the melting temperature and the temperature phlegmy solvent and preferably between 0°C and the temperature phlegmy solvent. The reaction can also be carried out in a sealed pressure vessel above the temperature of phlegmy solvent.

In each of these diagrams the figures for each formula are provided for convenience only. Despite the fact that carried away the links, as a rule, belong to a specific schema, however, these links should not be construed as limiting, and each scheme, including all its elements, is widely applicable for different implementations of the present invention.

Scheme A

Referring to Scheme A, the protection of 2-chloro-1H-benzoimidazole (II) is achieved by using a reagent with an appropriate protecting group, such as 2-methoxyethoxymethyl (MEMCl) or 2-(trimethylsilyl)-ethoxymethylene (SEMCl) in the presence of a base, such as NaH or DIPEA in a solvent such as THF, gives the compounds of formula (III). Substitution of 2-chloromethylene using commercially available pyrazole-4-carboxylates of the formula (IV), where R2and R3are both H, CF3or CH3performed in a polar aprotic solvent such as DMF,N,N-dimethylacetamide (DMA), or THF, or a mixture thereof, in the presence of an appropriate base, such as Cs2CO3, K2CO3, Na2CO3, NaH or mixtures thereof, at elevated temperatures, typically in the range from 80°C to 120°C. Subsequent to unprotect a protected group with acid, such as HCl, in a suitable solvent, such as EtOH, to give the intermediate of formula (VIII). Saponification valid reason, such as wagnerstr NaOH, aqueous LiOH solution or an aqueous solution of KOH or a mixture in a solvent such as THF, gives the compounds of formula (I).

Scheme B

Arrowy ether and arrowy tiefer, intermediate compounds of formula (VIII), prepared according to Scheme B, where each R1can be H, -Cl, -F, -CF3or-OCF3provided that at least one R1represents-Cl or-F. commercially Available substituted galogenirovannami (VII) react with substituted phenols, thiophenolate and substituted phenyl-alkyl phenols in the presence of a base, such as K2CO3in a solvent such as DMF and the like, at temperatures from room temperature up to the temperature of phlegmy solvent, with the formation of intermediate compounds with nitro groups of the formula (VIII), where Rerepresents aryl, -C1-4alkylaryl or heteroaryl ring. Alkilany ether and touchily ether, intermediate compounds of formula (VIII), where Rerepresents a C1-6alkyl (straight or branched chain), prepared by the reaction of optionally substituted halogen-nitrophenylamino with alcohols and alkylsilane in the presence of a base such as sodium methoxide, tert-piperonyl sodium and the like, in a solvent such as MeOH, at a temperature from room temperature to temperature is URS phlegmy solvent. The reaction may also be carried out in a sealed tube at temperatures above the temperature of phlegmy solvent. Thioalkyl, intermediate compounds of formula (VIII), also synthesized by the reaction of optionally substituted halogennitroethylenes formula (VII) with thiomethoxam sodium, toetaksid sodium, diisopropoxide sodium and the like, in a solvent such as DMF, at temperatures from 80°C to 100°C.

Intermediate compounds with amino groups of the formula (X) prepared in accordance with Scheme B, where R1represents H, -Cl, -F, -CF3or-OCF3. Substituted halogen-nitro-phenylamine (IX) and cycloalkyl and heterocyclochain heated in a sealed tube at temperatures from 80°C to 100°C, which provides intermediate compounds with nitro groups of the formula (X).

Scheme C

2-nitrobenzylamine (XIV) prepared according to Scheme C. the Amines of General formula (XI), where one or more R1s represent H, -Cl,- CN, -F, and-CF3, react with acetic anhydride in a solvent such as toluene, in the presence of a base, such as DMAP, at temperatures from room temperature to the boiling point of the solvent, resulting in a gain acetylated intermediate compounds of formula (XII). Subsequent nitration is carried out on the reaction intermediate connection the settings of the formula (XII) with nitrous reagent, such as KNO3and acid, such as sulfuric acid, at a temperature of 0°C, resulting in a gain nitrated intermediate compounds of formula (XIII). Subsequent removal of the protection acetyl group using aqueous acid, such as hydrochloric acid, when heated, gives nitroaniline formula (XIV).

Scheme D

In accordance with Scheme D, 2-halogennitroalkane formula (XVI) is prepared by the reaction of nitroanilines formula (XV) with glorieuses or brainwashin reagent, such as NCS or NBS, at temperatures from 80°C to 120°C, in a solvent such as DMF. In addition, halogennitromethanes intermediate compounds of formula (XVII), where R1is an independently-F,- Br, impact solution of ammonia in MeOH (7M concentration) and heated in the usual manner or in a sealed tube to temperatures from 50°C to 70°C, resulting in a gain halogennitroalkane formula (XVIII).

Scheme E

2-chloro-1H-benzoimidazole, intermediate compounds of formula (XXV), prepared by three methods, as shown in Scheme E. Substituted nitroaniline (or available on the market nitrobenzylamine or known nitrobenzylamine or nitrobenzylamine prepared in accordance with schemes) restore obeys the local methods of recovery such as powder of zinc, in the presence of a saturated aqueous solution of NH4Cl in a solvent such as acetone and the like, at temperatures from 0°C to room temperature, resulting in a gain diamines, intermediate compounds of formula (XX). The reaction djaminovich intermediate compounds of formula (XX)are either commercially available or synthesized, with carbonyl diimidazol, in a solvent such as THF and the like, at temperatures from 0°C to room temperature, gives 1,3-dehydrobenzperidol-2-ones, the intermediate compounds of formula (XXI). Subsequent chlorination (XXI) according to well-known methods, for example, the use of pure phosphorus oxychloride (POCl3) when heated, gives 2-chloro-1H-benzoimidazole formula (XXII). Subsequent protection 1H-benzoimidazole (XXII) is achieved by using the appropriate reagent to block reactive groups, such as dimethylsulphamoyl, 2-methoxyethoxymethyl (MEMCl) or 2-(trimethylsilyl)-ethoxymethylene (SEMCl), in the presence of a valid reason in a solvent such as THF or DMF, which gives the compounds of formula (XXV).

In addition, benzoimidazole formula (XXIII) is prepared by ignoreaction method of synthesis of orthonitrophenol by the reaction of the reductive cyclization in the presence of an appropriate reducing agent, such as SnCl2.H2O diti is NAT sodium and the like, in the presence of aldehyde or equivalent aldehyde, such as triethylorthoformate and the like, or acid, such as acetic acid, formic acid and the like, by heating in the usual way, the heating in a sealed tube or heating by microwave radiation at temperatures from 80°C to 130°C. in Addition to the reaction dorectory reductive cyclization described above, 1H-benzoimidazole formula (XXIII) is also synthesized by the reaction of diamines of the formula (XX) in the presence of aldehyde or equivalent aldehyde, such as triethylorthoformate, and acid, such as HCl, at a temperature from 0°C to room temperature. Subsequent protection 1H-benzoimidazole (XXIII) is achieved by using a valid reagent to block reactive group, such as 2-methoxyethoxymethyl (MEMCl) or 2-(trimethylsilyl)-ethoxymethylene (SEMCl), in the presence of a base, such as NaH or DIPEA in a solvent such as THF, gives the compounds of formula (XXIV). The deprotonation protected 1H-benzoimidazole, intermediate compounds of formula (XXIV), using organolithium base, such as utility or diisopropylamide lithium, in a solvent such as THF, at temperatures from -80°C to -40°C and subsequent addition of N-chlorosuccinimide and the like, gives 2-chloro-1H-benzoimidazole, intermediate soy is inane formula (XXV).

Scheme F

With reference to Scheme F, the compounds of formula (III), where W represents-CO2C1-4alkyl, and R1represents H, -F, -Cl, -CF3or-OCF3, omelet using a valid excuse, such as aqueous NaOH solution, an aqueous LiOH solution or an aqueous solution of KOH or a mixture thereof, at temperatures from room temperature to the boiling point of the solvent, in a solvent such as THF, resulting in a gain of compounds of formula (XXVI). Subsequent amide bond formation by well-known methods gives benzoimidazole, intermediate compounds of formula (XXVII). Alternatively, benzoimidazole, intermediate compounds of formula (III), where W represents-CO2Me, restore, using an appropriate reducing agent, such as alumalite lithium, in a solvent such as THF, at a temperature of 0°C, to obtain the corresponding alcohols, intermediate compounds of formula (XXVIII). Alkylation of intermediate (XXVIII) using a base such as NaH, alkylating reagent, such as alkylhalogenide or aryl halides in a solvent such as DMF gives benzoimidazole, intermediate compounds of formula (XXIX).

Scheme G

Referring to Scheme G, benzoimidazole, Premiata the basic compounds of formula (XXX) in the reaction conditions, cross combination Suzuki, where W is a valid halogen or triflate, and each R1represents independently H, -Cl, -F, -CF3or-OCF3respond with arylboronic acids or esters, in the presence of metal catalysts in organic synthesis, such as PdCl2(dppf), and a valid reason, such as CsF, which gives burilnye intermediate compounds of formula (XXXI), where Y is a substituted or unsubstituted aryl or heteroaryl ring.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-S-C1-4alkyl or-S-Ar (where Ar represents a correspondingly substituted phenyl group), and each R1represents independently H, -F, -Cl, -CF3or-OCF3that is oxidized by known methods, for example, using an oxidant such as peroxomonosulfate potassium, 3-chloroperoxybenzoic acid and the like, resulting in a gain corresponding sulfonic and sulfoxide intermediate compounds of formula (XXXI), where Y represents-S(O)-C1-4alkyl, -S(O)2-C1-4alkyl, -S(O)-aryl or-S(O)2-aryl.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-NO2and each R1represents independently H, -Cl, -F, -CF3or-OCF3expose Rea is tion with a reducing agent according to well-known methods, that gives benzoimidazole, intermediate compounds of formula (XXXI), where Y represents --NH2and R1represents-Cl, -CF3or-OCF3.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-NH2and each R1represents independently H, -Cl, -F, -CF3or-OCF3in the conditions of reductive amination according to well-known methods, is subjected to reaction with alkyllithium and replaced by arelargely that gives alkyl - and benzylamine derivatives, intermediate compounds of formula (XXXI), where Y is-NH-C1-4alkyl or-NH-CH2-aryl.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-NH2and each R1represents independently H, -Cl, -F, -CF3or-OCF3, is subjected to reaction with alkyl-, aryl - and cycloalkylcarbonyl, acyl - and arylhalides, 2-bromoacetamide, etc. that gives the corresponding substituted sulfonamidnuyu and amide intermediate compound.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-NH2and each R1represents independently H, -Cl, -F, -CF3or-OCF3, is subjected to reaction under conditions of amination with kilbrandon, IU aliceson a catalyst for organic synthesis, such as Pd(dba)2, ligand, such as Q-Phos, a valid reason, such astert-piperonyl sodium in a solvent such as toluene, at temperatures from room temperature to the boiling temperature of the solvent that provides intermediate compounds of formula (XXXI), where Y represents-NHAr.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-NC(O)CH2Br and each R1represents independently H, -Cl, -F, -CF3or-OCF3, is subjected to reaction with heterocyclisation, such as morpholine,N-methylpiperazine, piperidine and the like, in a solvent such as dichloromethane, at temperatures from 0°C to room temperature, which gives the substituted acetyl-amino benzimidazole intermediate connection.

Referring to Scheme G, benzoimidazole, intermediate compounds of formula (XXX), where W represents-S-tBu and each R1represents independently H, -F, -Cl, -CF3or-OCF3handle 2-nitrobenzenesulfonamide in the presence of a base, such as K2CO3that gives disulfide intermediate connection. Subsequent recovery of disulfide using a reducing agent such as NaBH4in aqueous EtOH, at a temperature of 0°C gives thiol intermediate connection (in certain conditions thiol prom which mediate the connection can timeresults with the formation of disulfide as a by-product of the reaction). Alkylation of the thiol with the use of benzyl - and were synthesized in the presence of a base, such as K2CO3gives trialkylamine benzoimidazole, intermediate compounds of formula (XXXI), where Y represents-S-C1-4alkyl or-S-C1-4alkyl-aryl. In addition, a disulfide, a by-product of the reaction described above, is subjected to reaction with NCS and water solution of HCl in a solvent such as acetonitrile, at a temperature of 0°C, which gives chlorosulfonyl intermediate compounds (A. Nishiguchi, K. Maeda, S. Miki.Synthesis, 2006, 24, 4131-4134), subsequent reaction with an appropriate amine in a solvent such as pyridine, gives arylsulfonyl, intermediate compounds of formula (XXXI), where Y represents-SO2-NH-aryl.

Removing protection from a blocked reactive groups of the intermediate compound (XXXI) with an acid, such as HCl, in an appropriate solvent, such as EtOH, and subsequent saponification of carboxypropyl on the pyrazole ringwith valid reason, such as aqueous NaOH solution, an aqueous LiOH solution or an aqueous solution of KOH or a mixture thereof in a solvent such as THF, at temperatures from room temperature up to the temperature of phlegmy solvent gives compounds of formula (I).

In addition, the conversion of intermediates of formula (XXXI) in the compounds of formula (I) is the one-stage with acetic acid and aqueous hydrochloric acid at temperatures from 80°C to 100°C.

Scheme H

Benzoimidazole formula (VI) can also be prepared according to Scheme H. Bromoaniline General formula (XXXII) process benzoylisothiocyanate in a solvent such as toluene, in the presence of a base, such as DMAP at room temperature, which gives the corresponding derived thiourea of the formula (XXXIII). Benzoyloxy group is removed using a base such as sodium methoxide, in a solvent such as MeOH at a temperature of 0°C, which gives the derivative of thiourea of the formula (XXXIV). The reaction of thioureas of the formula (XXXIV) with digitalization of lead (II) in the presence of a base such as potassium hydroxide, in a solvent such as water, at temperatures from 80°C to 100°C, gives cyanamide intermediate compounds of formula (XXXV). Subsequent reaction cyanamide intermediate compounds with ethyl ether 1H-pyrazole-4-carboxylic acid, in the presence of an anhydrous acid, such as HCl, in a solvent such as dioxane, at elevated temperatures from 80°C to 100°C, gives handinavi intermediate compounds of formula (XXXVI). Further processing guaninovykh intermediates reagent reaction combinations, such as CuI and a base, such as Cs2CO3in a solvent such as DMF, at temperatures from 60°C to 100°C, gives benzoimidazole, the intermediate joint is of the formula (VI).

Scheme I

Benzoimidazole, intermediate compounds of formula (XXXIX), synthesized in accordance with Scheme I. commercially Available ethyl ester 1H-pyrazole-4-carboxylic acid (IV)is treated with cyanamide in a solvent such as dioxane, in the presence of acid, such as a solution of 4M HCl in dioxane, at temperatures from 80°C to 100°C, which gives the ethyl ester of carbamimidoyl-pyrazole-4-carboxylic acid of the formula (XXXVII). Subsequent reaction of the ethyl esters of carbamimidoyl-pyrazole-4-carboxylic acid (XXXVII) with commercially available 2,3-dihalogen-aromatic intermediate compounds of formula (XXXVIII), where Z represents one or two N (for example, 2,3-dichloro-cinoxacin), and a base, such as Cs2CO3(optionally, you can apply a catalyst such as CuI and the like)in a solvent such as DMF, DMA and the like, at temperatures from room temperature to the boiling point of the solvent, gives benzoimidazole, intermediate compounds of formula (XXXIX).

The compounds of formula (I) can be converted into the corresponding salts using methods known to experts in this field. For example, acids of the formula (I) can be processed K2CO3in the water in a solvent such as EtOH, at a temperature from room temperature to the temperature of phlegmy solvent that gives relevant the existing form of salt.

Compounds prepared according to the schemes described above can be obtained as single enantiomers, diastereomers or regioisomers by enantio, GeoStereo or regiospecific synthesis or by separation. Compounds prepared in accordance with the scheme described above, the alternative can be obtained as a racemic (1:1) or nerezisca (not 1:1) mixture or as a mixture of diastereoisomers or of regioisomers. In that case, if you get the racemic and nerezisca mixture of enantiomers, individual enantiomers can be separated by conventional separation methods known to experts in this field, such as chiral chromatography, recrystallization, education diastereomeric salt, turning in diastereomeric adducts, biotransformation or enzymatic transformation. In that case, if you get regioisomeric or diastereomeric mixture, the individual isomers can be prepared by conventional methods such as chromatography or crystallization.

If the requirement to source materials included certain stereospecific chemical structure of amino acids, these materials were purchased in the form of preferred stereospecific enantiomers, retained their specificity in the fusion reaction.

In the trail of the common examples is illustrated in more detail the present invention and the preferred options for its implementation.

Compounds prepared according to the schemes described above can be obtained as single enantiomers, diastereomers or regioisomers by enantio, GeoStereo or regiospecific synthesis or by separation. Compounds prepared in accordance with the scheme described above, the alternative can be obtained as a racemic (1:1) or nerezisca (not 1:1) mixture or as a mixture of diastereoisomers or of regioisomers. In that case, if you get the racemic and nerezisca mixture of enantiomers, individual enantiomers can be separated by conventional separation methods known to experts in this field, such as chiral chromatography, recrystallization, education diastereomeric salt, turning in diastereomeric adducts, biotransformation or enzymatic transformation. In that case, if you get regioisomeric or diastereomeric mixture, the individual isomers can be prepared by conventional methods such as chromatography or crystallization.

If the requirement to source materials included certain stereospecific chemical structure of amino acids, these materials were purchased in the form of preferred stereospecific enantiomers, retained their specificity in the fusion reaction.

In the trail of the common examples is illustrated in more detail the present invention and the preferred options for its implementation.

Examples

The chemistry.

Unless otherwise stated, to obtain described in the examples below, compounds and related analytical data, we used the following experimental and analytical procedures.

Unless otherwise specified, the reaction mixture was stirred on a magnetic stirrer at room temperature (RT). If the solutions were "drained", usually used for this purpose drying agent such as Na2SO4or MgSO4. If mixtures, solutions and extracts were concentrated, then they are usually concentrated on a rotary evaporator under reduced pressure.

Thin-layer chromatography (TLC) was performed on plates coated with silicagel coated Merck silica gel 60 F254a 2.5×7.5 cm 250 μm or 5.0×10.0 cm 250 μm. Preparative thin-layer chromatography was performed on plates coated with silicagel coating EM Science silica gel 60 F25420×20 cm, 0.5 mm with concentrating zone 20×4 see

Column flash chromatography normal phase (KFH) was performed on silikagelevye columns (SiO2), eluruumid 2 M solution of NH3in MeOH/DCM, unless otherwise noted. Obratsova HPLC was performed on the instrument Hewlett Packard 1100 HPLC with column Phenomenex Luna C18 (5 μm, a 4.6×150 mm). Detection conducted at λ=230, 254 and 280 nm. Used the gradient was from 10 to 99% acetonitrile/water (0.05% of triperoxonane acid) in order for a 5.0 min at speed flow 1 ml/min Alternatively, HPLC was performed on a Dionex instrument APS2000 LC/MS with column Phenomenex Gemini C18 (5 μm, 30×100 mm)used the gradient ranged from 5 to 100% acetonitrile/water (20 mm NH4OH) in the course of 16.3 min at a velocity of the flow 30 ml/min

Unless otherwise stated, the mass spectra (MS) were obtained using the instrument Agilent 1100 series MSD equipped with multimode ESI/APCI source positive and negative ionization.

NMR spectra (NMR) were obtained on a spectrometer Bruker model DRX. Below is the format1H NMR: chemical shift in ppm in the weak field from the signal used as a standard tetramethylsilane (observed multipletness, constant spin-spin interactionJin Hz, integral). Chemical names were generated using the software ChemDraw version 6.0.2 (CambridgeSoft, Cambridge, MA) or ACD/Name version 9 (Advanced Chemistry Development, Toronto, Ontario, Canada).

Example 1: 1-(1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: preparation of 2-chloro-1-(2-trimethylsilylethynyl)-1H-benzoimidazole. In accordance with Scheme A, a mixture of NaH (60% dispersion in oil, 0.40 g, 9.8 mmol) and THF (10 ml) was cooled to 0°C, then for 10 min was added in parts solid 2-chlorobenzimidazole (1.0 g, 6.5 mmol). The resulting mixture was stirred at 0°C for 1 h, PEFC is what was added 2-(trimethylsilyl)-ethoxymethylene (1.5 ml, 8.5 mmol). The reaction mixture is allowed to heat up to a temperature of 23°C and was stirred for 16 hours the Mixture was carefully poured onto ice (200 g)and then extracted with Et2O (3×100 ml). The combined organic extracts were dried, filtered, and concentrated. The residue was purified (KFH) (from 1:99 to 15:85 EtOAc/hexane) to obtain the desired compound, which was described previously (WO 2005/012296, Janssen Pharmaceutica N.V., Example 7).

Stage B: 1-[1-(2-trimethylsilylethynyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester. A mixture of 2-chloro-1-(2-trimethylsilylethynyl)-1H-benzoimidazole (0.34 g, 1.2 mmol), atypical-4-carboxylate (0.24 g, 1.7 mmol), cesium carbonate (0,78 g, 2.4 mmol) and anhydrous DMF (2.5 ml) was stirred at 100°C for 5 h the Mixture was given the opportunity to cool to 23°C and spread her EtOAc, then was filtered through a pad of silica gel. The resulting solution was concentrated. The residue was purified (KFH) (from 5:95 to 40:60 EtOAc/hexane) to obtain the desired compound (0.36 g, 77%).1H NMR (500 MHz, CDCl3): 8,88 (s, 1H), 8,18 (s, 1H), to 7.77-of 7.69 (m, 1H), 7,60 is 7.50 (m, 1H), 7,40-7,30 (m, 2H), 6,03 (s, 2H), 4,34 (K,J=the 7.1 Hz, 2H), 3,57-to 3.50 (m, 2H), 1,37 (t,J=the 7.1 Hz, 3H), 0,87-0,80 (m, 2H), -0,11 (s, 9H).

Stage C: ethyl ether 1-(1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid hydrochloride. HCl and dioxane (4M, 2 ml, 8 mmol) was added to a mixture of ethyl ester of 1-[1-(2-trimethylsilyloxy is methyl)-1H-benzoimidazol-2-yl]-1H-pyrrole-3-carboxylic acid (0,30 g, 0.78 mmol) and EtOH (4 ml). The reaction mixture was heated at a temperature of phlegmy for 30 min, then was cooled to 23°C. was Added Et2O (20 ml) and the mixture was cooled to 0°C for a period of 10 minutes the precipitate was collected by filtration and well washed Et2O obtaining the desired compound (0.18 g, 91%). Mass spectroscopy (ESI/CI): calc. mass for C13H12N4O2, 256,3; received m/z: 257,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,96 (s, 1H), 8.33 (s, 1H), 7,56 (s, 2H), 7,28-7,21 (m, 2H), 4,30 (K,J=the 7.1 Hz, 2H), 1,32 (t,J=the 7.1 Hz, 3H)

Stage D: 1-(1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The LiOH solution and H2O (1,0 M, 1.0 ml, 1.0 mmol) was added to a mixture of the hydrochloride of the ethyl ester 1-(1H-benzoimidazol-2-yl)-1H-pyrrole-3-carboxylic acid (0,040 g, 0.16 mmol) and THF (2.0 ml) and the reaction mixture was stirred at 23°C for 16 h THF was removedunder vacuum,, then added an aqueous solution of HCl (1,0 M, 2 ml, 2 mmol) at 0°C. the precipitate was collected and washed with water to obtain the desired compound (0,033 g, 90%). Mass spectroscopy (ESI/CI): calc. mass for C11H8N4O2, to 228.2; received m/z: 229,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,32 (s, 1H), 13,00-12,86 (ush. s, 1H), 8,90 (l,J=0.6 Hz, 1H), 8,28 (l,J=0.6 Hz, 1H), to 7.64 (d,J=4.6 Hz, 1H), 7,49 (l,J=and 5.5 Hz, 1H), 7,28-7,20 (m, 2H).

Example 2: 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The way A:

The desired compound was obtained in the same way as described in EXAMPLE 1 except for the use of 2,5,6-trichloro-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H6Cl2N4O2, 297,1; received m/z: 296,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 14,18-to 12.52 (ush s, 2H), 8,89 (l,J=0.5 Hz, 1H), 8,31 (l,J=0.5 Hz, 1H), 7,80 (s, 2H).

The way B:

Stage A: 5,6-dichloro-1,3-dehydrobenzperidol-2-it: To a solution of 4,5-dichlorobenzene-1,2-diamine (25 g, 0.14 mol) in anhydrous DMF (200 ml), was added CDI (23 g, 0.14 mol) as a solid. The reaction mixture was stirred at room temperature for 1 h, then added water (500 ml). Precipitated solid precipitate was collected by filtration, washed with water and thoroughly dried to obtain the desired substance (26,0 g, 90%). The crude product was used in the following reaction without further purification.

Stage B: 2,5,6-trichloro-1H-benzoimidazol: carefully dried 5,6-dichloro-1,3-dehydrobenzperidol-2-he (28.4 g, 0.14 mol) suspended in POCl3(75 ml). The reaction solution was heated at a temperature of phlegmy for 3 h and then cooled to room temperature. The solution slowly with constant stirring, poured into a mixture of crushed ice and water (1.5 l). The solution was neutralized with NaOH to pH=7.0. Precipitated solid is Sadok was collected by filtration, washed with water and dried to obtain the desired substance (27.9 g, 90%). The crude product was used in the following reaction without further purification.

Stage C: 1-(5,6-dichloro-1-dimethylsulphamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester. 2,5,6-trichloro-1H-benzoimidazol 2 (27,6 g, 0.125 mol) was dissolved in anhydrous DMF (200 ml), then added K2CO3(20.7 g, 0.15 mol) and dimethylsulphamoyl chloride (17.9 g, 0.125 mol). The reaction mixture was stirred at room temperature for 16 hours Analysis by HPLC showed the formation in the reaction of dimethylamine 2,5,6-trichloropyridinol-1-sulfonic acid. In the same vessel, without allocation of dimethylamide 2,5,6-trichloropyridinol-1-sulfonic acid, was added ethyl ester 1H-pyrazole-4-carboxylic acid (17.5 g, 0.125 mol) and K2CO3(20.7 g, 0.15 mol). The reaction mixture was stirred at 70°C for 4 h, after which, until the reaction mixture was still hot, added water (500 ml). The reaction solution was cooled to room temperature. Precipitated precipitated solid substance was separated by filtration, washed with water and dried. The crude product was used in the following reaction without further purification.

Stage D: 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The crude ethyl ester of 1-(5,6-dichloro-1-dimethylsulfone the Il-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid was dissolved in THF (125 ml) then added a solution of LiOH·H2O (21 g, 0.5 mol) in water (250 ml). The reaction mixture was stirred at a temperature of phlegmy for 2 h and cooled to room temperature. Added concentrated HCl, bringing the pH to 2.0. Precipitated precipitated solid substance was separated by filtration, washed with water and dried. Solid rastolkli in hot EtOAc (1 l). After cooling to room temperature and filtering, there was obtained a pure compound as a yellowish brown solid (18.5 g, 50%). Mass spectroscopy [M+H]+the resulting value 297,0.1H NMR (500 MHz, DMSO-d6): 13,71 (s, 1H), 12,99 (s, 1H), of 8.90 (s, 1H), 8,32 (s, 1H), 7,94 (s, 1H), to 7.67 (s, 1H). Potassium salt of 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid was obtained by suspension of the free acid (55 g, 1.7 mol) in EtOH (1.5 l) at a temperature of phlegmy with the subsequent addition of a solution of K2CO3(12,79 g, 0.85 mol) in 20 ml of water dropwise over 5 minutes To ensure proper mixing was used by intensive mechanical mixing. The suspension was stirred for 8 hours at a temperature of phlegmy, then for 5 h, cooled to room temperature. The precipitated solids were collected by filtration and washed with water (100 ml), and then EtOH. Potassium salt was obtained in the form of a white solid (38 g, 65%). The mother liquor was concentrated and opican the th above process was repeated again to obtain the second part of the potassium salt (13 g, 22%). Mass spectroscopy [M+H]+=297,0.1H NMR (500 MHz, DMSO-d6): 8,65 (s, 1H); of 7.96 (s, 1H); EUR 7.57 (s, 2H).

Example 3: 1-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 2-chloro-5-trifluoromethyl-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H7F3N4O2, 296,2; received m/z: 295,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 14,44-12,32 (ush s, 2H), to 8.94 (d,J=0.5 Hz, 1H), 8,33 (l,J=0.5 Hz, 1H), of 7.96-7,83 (ush. s, 1H), 7,75 (ush. d, 1H), 7,58 (DD,J=8,49, 1,41 Hz, 1H).

Example 4: 1-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 2-chloro-6-fluoro-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H6ClFN4O2, 280,7; received m/z: 279,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 14,21-12,25 (ush. s, 2H), 8,88 (l,J=0.6 Hz, 1H), 8.30 to (q,J=0.6 Hz, 1H), 7,81-to 7.67 (ush. s, 1H), 7,65-7,52 (ush. s, 1H).

Example 5: 1-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained analogously to the WMD, as described in EXAMPLE 1, except using 2-chloro-5,6-dimethyl-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H12N4O2, 256,3; received m/z: 257,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,16-12,81 (m, 2H), cent to 8.85 (d,J=0.6 Hz, 1H), 8,25 (l,J=0.6 Hz, 1H), 7,43-7,21 (ush. s, 2H), 2,31 (s, 6H).

Example 6: 1-(5-bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 5-bromo-2-chloro-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H7BrN4O2, 306,0; received m/z: 307,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,82 (l,J=0.5 Hz, 1H), they were 8.22 (s, 1H), to 7.67 (d,J=1.2 Hz, 1H), 7,45 (l,J=8.5 Hz, 1H), 7,32 (DD,J=to 8.5, 1.9 Hz, 1H).

Example 7: 1-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 2-chloro-5-methoxy-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H10N4O3, 258,2; received m/z: 259,1 [M+H]+.1H NMR (500 MHz, DMSO-d6, tautomeric mixture): 13,16 (s, 1H), 12,91 (who, 1H), 8,84 (s, 1H), compared to 8.26 (s, 1H), 6,83-rate of 7.54 (m, 3H), of 3.80 (s, 3H).

Example 8: 1-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except for using 2,4-dichloro-6-trifluoromethyl-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6ClF3N4O2, 330,7; received m/z: 329,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 13,90-14,50 (ush. s, 1H), was 12.75-13,45 (ush. s, 1H), of 8.95 (s, 1H), at 8.36 (s, 1H), 7,72 (s, 1H), of 7.70 (s, 1H).

Example 9: 1-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 2-chloro-5,6-dimethoxy-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H12N4O4, 288,3; received m/z: 289,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,81 (s, 1H), of 8.25 (s, 1H), to 7.09 (s, 2H), 3,80 (s, 6H).

Example 10: 1-(4,5-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 2-chloro-4,5-dimethyl-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage Amass spectrometry (ESI/CI): calc. mass for C13H12N4O2, 256,3; received m/z: 257,2 [M+H]+.1H NMR (500 MHz, DMSO-d6, tautomeric mixture): 12,60-13,30 (ush. m, 2H), 8,83-of 8.90 (m, 1H), 8,23-8,29 (m, 1H), 7,0-7,35 (m, 2H), 2,47 (s, 3H), of 2.33 (s, 3H).

Example 11: 1-(5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 2-chloro-5-triptoreline-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H7F3N4O3312,0; received m/z: 313,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,91 (s, 1H); 8,31 (s, 1H); 7,83-7,41 (m, 2H); 7,30-7,21 (m, 2H).

Example 12: 1-{5-[3-(3-chlorobenzoyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-{5-[3-(3-chlorobenzoyloxy)-phenyl]-1-(2-trimethylsilylethynyl)-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid and ethyl ester of 1-{6-[3-(3-chlorobenzoyloxy)-phenyl]-1-(2-trimethylsilylethynyl)-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid. In accordance with Scheme B, [1,1'-bis(diphenylphosphino)ferrocene]dehority palladium (0.12 g, 0.16 mmol) was added to a mixture of cesium fluoride (0.33 g, 2.2 mmol), 3-(3'-chlorobenzoyloxy)phenylboronic acid (0.3 g, 1.3 mmol), ethyl ester 1-[5-bromo-1-(2-trimethylsilylethynyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid and ethyl ester 1-[6-bromo-1-(2-trimethylsilylethynyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate reaction product from Example 6). Mass spectroscopy (ESI/CI): calc. mass for C19H25BrN4O3Si, 464,1; received m/z: 465,1), (0.5 g, 1.1 mmol) and DME (5 ml) in a sealed tube. The reaction mixture was stirred at 80°C. After 3 h the mixture was cooled to room temperature, then was diluted with EtOAc (50 ml) and filtered. The filtrate was concentrated. The residue was purified (farm) (15:85 EtOAc/hexane) to obtain the desired compounds in the form of a regioisomeric mixture of 0.47 g, 72%). Mass spectroscopy (ESI/CI): calc. mass for C32H35ClN4O4Si, 602,2; received m/z: 603,2 [M+H]+.

Stage B: 1-{5-[3-(3-chlorobenzoyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 1, Stage C-D. Mass spectroscopy (ESI/CI): calc. mass for C24H17ClN4O3444,1; received m/z: 445,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,93 (l,J=0.5 Hz, 1H), 8,32 (s, 1H), 7,84-7,79 (m, 1H), 7.68 per-7,63 (m, 1H), 7,60-of 7.55 (m, 2H), 7,52-7,37 (m, 4H), of 7.36-7,27 (m, 2H), 7,03 (DD,J=of 7.8, 2.1 Hz, 1H), 5,26 (s, 2H).

Example 13: 1-{5-[3-(2-chlorobenzoyloxy)-phenyl]-1H-benzo idazole-2-yl}-1 H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 3-(2'-chlorobenzoyloxy)phenylboronic acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C24H17ClN4O3, 444,1; received m/z: 445,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,91 (s, 1H), 8.30 to (s, 1H), 7,80 (s, 1H), 7,72-of 7.60 (m, 2H), to 7.59-of 7.48 (m, 2H), of 7.48 and 7.36 (m, 3H), of 7.36-7,25 (m, 2H), 7,02 (DD,J=for 8.1, 1.9 Hz, 1H), 5,27 (s, 2H).

Example 14: 1-{5-[3-(4-chlorobenzoyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 3-(4'-chlorobenzoyloxy)phenylboronic acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C24H17ClN4O3, 444,1; received m/z: 445,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,91 (s, 1H), 8.30 to (s, 1H), 7,98 is 7.50 (m, 5H), 7,50-7,44 (m, 2H), 7,43-7,35 (m, 1H), 7,35-7,22 (m, 2H), 7,00 (s, 1H), 5,22 (s, 2H).

Example 15: 1-[5-(3-benzyloxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using the Finance 3-(benzyloxy)phenylboronic acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid in Stage A. Mass spectroscopy (ESI/CI): calc. mass for C24H18N4O3, 410,1; received m/z:411,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,99 (s, 1H), scored 8.38 (s, 1H), 8,02-7,28 (m, 11H), to 7.09 (DD,J=for 8.1, 1.9 Hz, 1H), 5,31 (s, 2H).

Example 16: 1-[5-(4-benzyloxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 4-(benzyloxy)phenylboronic acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C24H18N4O3, 410,1; received m/z: 411,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 9,00 (s, 1H), 8,39 (s, 1H), 7,81-7,39 (m, 10H), 7,20 (m,J=8,8 Hz, 2H), 5,26 (s, 2H).

Example 17: 1-[5-(3-triptoreline)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 3-triftormetilfullerenov acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H11F3N4O2, 372,1; received m/z: 373,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,91 (s, 1H); 8,31 (s, 1H); 8,11-7,79 (m, 3H); 7,78-7,52 (m, 4H).

Example 18: 1-[5-(3,4-dichlorophenyl)-1H-benzoimidazol--Il]-1 H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 3,4-dichlorophenylamino acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H10Cl2N4O2372,0; received m/z: 373,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 9,01 (s, 1H), to 8.41 (s, 1H), of 8.06 (s, 1H), 7,95 (s, 1H), 7,81 (l,J=1.2 Hz, 2H), 7,74 (l,J=and 8.4 Hz, 1H), 7,69 (DD,J=an 8.5 and 1.7 Hz, 1H).

Example 19: 1-(5-bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 5-bromo-2-chloro-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage and ethyl ester of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid instead of atypical-4-carboxylate in Stage B. Mass spectrometry (ESI/CI): calc. mass for C12H6BrF3N4O2, 374,0; received m/z: 375,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,69 (ush. s, 1H), which is 9.09 (s, 1H), 7,79 (ush. s, 1H), 7,55 (ush. s, 1H), 7,43 (DD,J=to 8.4, 1.6 Hz, 1H).

Example 20: 1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as the description is but in EXAMPLE 1, except 2,5,6-trichloro-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage and ethyl ester of 3-trifluoromethyl-1H-pyrazole-4-carboxylic acid instead of atypical-4-carboxylate in Stage B. Mass spectrometry (ESI/CI): calc. mass for C12H5Cl2F3N4O2, 365,1; received m/z: 363,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,25-14,30 (ush s, 2H), 9,10 (s, 1H), 7,87 (ush s, 2H).

Example 21: 1-(5-bromo-1H-benzoimidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 5-bromo-2-chloro-1H-benzimidazole instead of 2-chlorobenzimidazole on A Stage and 3,5-dimethyl-1H-4-triazol-4-carboxylate instead of atypical-4-carboxylate Century at the Stage Mass spectroscopy (ESI/CI): calc. mass for C13H11BrN4O2, 334,0; received m/z: 335,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,21 (ush s, 1H), 12,77 (ush s, 1H), 7,73 (ush s, 1H), 7,51 (ush s, 1H), was 7.36 (DD,J=to 8.4, 1.6 Hz, 1H), 2,98 (s, 3H), of 2.46 (s, 3H).

Example 22: 1-(5,6-dichloro-1H-benzoimidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1 except for the use of 2,5,6-trichloro-1H-benzimidazole instead of 2-chlorobenzimidazole on A Stage and 3,5-dimethyl-1 -4-triazol-4-carboxylate instead of atypical-4-carboxylate in Stage B, and purification by the method of preparative HPLC. Mass spectroscopy (ESI/CI): calc. mass for C13H11Cl2N4O2, 325,2; received m/z: 327,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 7,79 (s, 2H); 2,98 (s, 3H); to 2.46 (s, 3H).

Example 23: 1-[5-(4-hydroxy-phenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 4-hydroxyphenylarsonic acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H12N4O3, 320,3; received m/z: 321,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): to 12.52-13,80 (ush s, 1H), 9,25 of 10.05 (ush s, 1H), 8,84 (s, 1H), of 8.25 (s, 1H), 7,43-7,80 (m, 5H), 6,86 (l,J=8,6, 2H).

Example 24: 1-[5-(3-hydroxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 12, except for using 3-hydroxyphenylpropionic acid instead of 3-(3'-chlorobenzoyloxy)phenylboronic acid at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H12N4O3, 320,3; received m/z: 321,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,50-13.56MHz (ush m, 2H), 9,54 (ush s, 1), 8,91 (s, 1H), 8.30 to (s, 1H), 7,45-7,88 (ush m, 3H), 7,26 (t,J=7.8 Hz, 1H),? 7.04 baby mortality-7,14 (m, 2H), 6.75 in (DD,J=8,0, 1.7 Hz, 1H).

Example 25: 1-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except for using 2,5-dichloro-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H7ClN4O2, 262,0; received m/z: 263,0 [M+H]+.1H NMR (400 MHz, CD3OD, tautomeric broadening): 8,89 (s, 1H), 8,17 (s, 1H), to 7.67-7,44 (m, 2H), 7,26 (DD,J=to 8.6, 1.9 Hz, 1H).

Example 26: 1-(5-bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 1, except using 5-bromo-2-chloro-6,7-dimethyl-1H-benzimidazole instead of 2-chlorobenzimidazole on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H7ClN4O2, 334,0; received m/z: 335,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,51-12,68 (m, 2H), 8,88 (s, 1H), 8,29 (s, 1H), 7,80-7,40 (m, 1H), has 2.56 (s, 3H), 2.40 a (s, 3H).

Example 27: 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 3-chlorobenzene-1,2-diamine. To a solution containing 3-chloro-2-nitrophenylamino (1.73 g, 10.0 mmol), NH4l (2,68 g, 50.0 mmol), acetone (40 ml) and water (10 ml)in parts, was added powdered zinc (three equal portions over 5 min) (3,26 g, 50.0 mmol) at 0°C. the Mixture was stirred for 2 h, then was heated to 23°C. the Mixture was filtered through Celite®after which the solvents were concentrated under reduced pressure. The mixture was re-dissolved in EtOAc/DCM, the second time was filtered through Celite®and removed the solvent by evaporation. The crude mixture was dissolved in EtOAc (100 ml), washed brine (40 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-50% EtOAc/hexane) to obtain the desired compound (1,00 g, 70%). Mass spectroscopy (ESI/CI): calc. mass for C6H7ClN2, 142,0; received m/z: 143,1 [M+H]+.1H NMR (500 MHz, CDCl3): 6,86-of 6.78 (m, 1H), 6,65 return of 6.58 (m, 2H), 3,74 (ush s, 2H), 3.46 in (ush s, 2H).

Stage B: 4-chloro-1,3-dehydrobenzperidol-2-it. To a solution of 3-chlorobenzene-1,2-diamine (0,820 g of 5.75 mmol) and THF (25 ml) was added carbonyldiimidazole (1.12 g, of 6.90 mmol) at 0°C. the Mixture was stirred for 16 h and was heated to 23°C. To the reaction mixture was added aqueous 1M HCl solution (25 ml) at 0°C, then water (100 ml) and the mixture was stirred for 1 h the precipitated solid was filtered and dried under a deep vacuum for 18 h to obtain the desired compound, which was used in subsequent studies additional purification (0.800 to g, 83%). Mass spectroscopy (ESI/CI): calc. mass for C7H5ClN2O, 168,0; received m/z: 169,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 11,13 (s, 1H), 10,88 (s, 1H), 7,00-6,86 (m, 3H).

Stage C: 2,4-dichloro-1H-benzoimidazol. The phosphorus oxychloride (10 ml) was added to the compound 4-chloro-1,3-dehydrobenzperidol-2-he (0,750 g of 4.45 mmol) and the mixture was heated at 80°C for 48 hours the Mixture was cooled to 23°C and removed POCl3under reduced pressure. The residue was cooled to 0°C and carefully added a cold saturated aqueous solution of NaHCO3(20 ml). After stirring at 23°C for 15 min, the mixture was subjected to ultrasonic treatment and the formed precipitate was filtered to obtain the desired compound (0,760 g, 92%)which was used in the next stage without additional purification. Mass spectroscopy (ESI/CI): calc. mass for C7H5Cl2N2, of 186.0; received m/z: 187,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,68 (s, 1H), 7,51-7,42 (m, 1H), 7,32-7,25 (m, 1H), 7,22 (m, 1H).

Stage D: 2,4-dichloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol. To a mixture of 2,4-dichloro-1H-benzoimidazole (0,550 g, to 2.94 mmol) and THF (15 ml) was added DIPEA (1,54 ml, 8,82 mmol)and then 1-chloromethoxy-2-methoxyethane (0,550 g, to 4.41 mmol) at 23°C. After stirring for 18 h was added EtOAc (100 ml). The organic layer was washed aqueous saturated solution of NaHCO3(30 ml) and brine (30 ml). The organic layer is combined, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-50% EtOAc/hexane) and got the desired compound in the form of a mixture of regioisomers (0,660 g, 82%). Mass spectroscopy (ESI/CI): calc. mass for C11H12Cl2N2O2, 274,0; received m/z: 275,1 [M+H]+.1H NMR (500 MHz, CDCl3): 7.61 (DD,J=to 8.0, 1.0 Hz, 1H), 7,41 (DD,J=for 8.1, 0.9 Hz, 1H), 7,33 (DD,J=to 7.9, 1.0 Hz, 1H), 7,31-7,20 (m, 3H), 5,98 (s, 2H), to 5.66 (s, 2H), 3,76 at 3.69 (m, 2H), 3,67-of 3.60 (m, 2H), 3,55-of 3.46 (m, 4H), 3,37 (s, 3H), on 3.36 (s, 3H).

Stage E: ethyl ester 1-[4-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of 2,4-dichloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazole (0,660 g is 2.40 mmol) and DMF (10 ml) was added Cs2CO3(1.88 g, USD 5.76 mmol) and ethyl ester 1H-pyrazole-4-carboxylic acid (0.400 g, is 2.88 mmol). The resulting mixture was heated at 80°C for 2 hours the Mixture was cooled to 23°C, poured into brine (40 ml) and was extracted with EtOAc (3×40 ml). The combined organic layers were washed brine (40 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-50% EtOAc/hexane) and got the desired compound in the form of a mixture of regioisomers (0,880 g, 97%). Mass spectroscopy (ESI/CI): calc. mass for C17H19ClN4O4, 378,1; received m/z: 379,1 [M+H]+.1H NMR (500 MHz, CDCl3): 8,97 (s, 1H), 8,80 (1H), by 8.22 (s, 1H), to 8.20 (s, 1H), 7,65 (s, 1H), 7,53 (s, 1H), 7,40-of 7.23 (m, 4H), 6,38 (s, 2H), 6,16 (s, 2H), to 4.41-or 4.31 (m, 4H), 3,68-3,59 (m, 2H), 3,57-to 3.49 (m, 2H), 3,48-to 3.41 (m, 2H), 3,41-to 3.35 (m, 2H), and 3.31 (s, 3H)at 3.25 (s, 3H), 1,38 (TD,J=7,1, 1.2 Hz, 6H).

Stage F: ethyl ester of 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester 1-[4-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,370 g, 0,980 mmol) and EtOH (2.5 ml) was added 4M solution of HCl in dioxane (2.5 ml, 10 mmol). The mixture was stirred for 18 h at 23°C. the Obtained white precipitate was filtered and washed with EtOH getting the required connection (is 0.260 g, 93%). Mass spectroscopy (ESI/CI): calc. mass for C13H11ClN4O2, 290,1; received m/z: 291,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,83 (s, 1H), 8,98 (s, 1H), 8,45-8,29 (m, 1H), 7,46 (s, 1H), 7,38-7,16 (m, 2H), 4,59-4,01 (m, 2H), 1.60-to a 1.01 (m, 3H).

Stage G: obtain 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (0,180 g, 0,550 mmol), THF (3 ml) and water (1 ml) was added LiOH·H2O (95,0 mg of 2.20 mmol). The mixture was stirred for 18 h at 23°C. the Solvent is evaporated, was added water (3 ml) and the mixture was acidified with aq. 1M HCl. The obtained white precipitate was filtered and dried to obtain the desired compound (0,130 g, 90%). Mass spectroscopy (ESI/CI): calc. mass for C11/sub> H7ClN4O2, 262,0; received m/z: 263,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,64 (s, 1H), 12,97 (s, 1H), of 8.90 (s, 1H), 8.30 to (s, 1H), of 7.48 (d,J=7,4 Hz, 1H), 7,32 (DD,J=to 7.8, 1.0 Hz, 1H), 7,25 (t,J=7.9 Hz, 1H).

Example 28: 1-(5-chloro-7-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 4-chloro-2-nitro-6-triptoreline instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6ClF3N4O2, 330,0; received m/z: 331,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 14,08 (s, 1H), 12,97 (s, 1H), 8,87 (s, 1H), 8.34 per (s, 1H), 7,80 (s, 1H), of 7.64-7,58 (m, 1H).

Example 29: 1-(7-bromo-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except for using 2-bromo-6-nitro-4-triphtalocyaninine instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6BrF3N4O3, 390,0; received m/z: 391,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,98 (s, 1H), 12,94 (s, 1H), of 8.90 (s, 1H), 8,32 (l,J=0,4 Hz, 1H), EUR 7.57-7,52 (m, 1H), of 7.48 (s, 1H).

Example 30: 1-(6-chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 4-chloro-2-nitro-5-triptoreline instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6ClF3N4O2, 330,0; received m/z: 331,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,93 (s, 1H), 8.34 per (s, 1H), to 7.99 (s, 1H), a 7.85 (s, 1H).

Example 31: 1-(4,5,6-Cryptor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 2,3,4-Cryptor-6-nitrophenylamino instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H5F3N4O2, 282,0; received m/z: 283,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,95 (s, 1H), 12,96 (s, 1H), of 8.92 (s, 1H), 8,31 (s, 1H), 7,42 (s, 1H).

Example 32: 1-(4-bromo-5,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, Stage B-G, except using 3-bromo-4,5-differenza-1,2-diamine instead of 3-chlorobenzene-1,2-diamine in Stage B. Mass spectrometry (ESI/CI): calc. mass for C11H5BrF2N4O2, 342,0; received m/z: 343,0 [M+H]+ 1H NMR (400 MHz, DMSO-d6): 13,93 (s, 1H), 12,93 (s, 1H), 8,88 (s, 1H), 8.30 to (s, 1H), 7,55 (s, 1H).

Example 33: 1-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 4-chloro-2-methyl-6-nitrophenylamino instead of 3-chloro-2-nitro-phenylamine in Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H9ClN4O2, 276,0; received m/z: 277,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,77-13,17 (m, 1H), 8,87 (s, 1H), 8,29 (s, 1H), 7,39 (s, 1H), 7,11 (DD,J=to 1.9, 0.8 Hz, 1H), 2,53 (s, 3H).

Example 34: 1-(4,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 2,4-dichloro-6-nitrophenylamino instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H6Cl2N4O2, 296,0; received m/z: 297,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,76-13,08 (m, 1H), 8,89 (s, 1H), 8,29 (s, 1H), 7,49 (s, 1H), 7,40 (l,J=1.7 Hz, 1H).

Example 35: 1-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except ISOE is isawanya 2-bromo-6-nitro-4-triptoreline instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6BrF3N4O2, 375,0; received m/z: 376,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 14,21 (s, 1H), 13,02 (s, 1H), to 8.94 (s, 1H), at 8.36 (s, 1H), 7,81 (s, 1H), 7,78 (s, 1H).

Example 36: 1-(5,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, Stages D-G, except for using 2-chloro-5,6-debtor-1H-benzoimidazole (J. Med. Chem.1997,40(5), 811-818) instead of 2,4-dichloro-1H-benzoimidazole on Stage D. Mass spectroscopy (CI): calc. mass for C11H6F2N4O2, 264,1; received m/z: 263,0 [M-H]-.1H NMR (500 MHz, DMSO-d6): 12,50-14,10 (ush m, 2H), 8,86 (s, 1H), 8,28 (s, 1H), 7,55-7,66 (ush s, 2H).

Example 37: 1-(4-bromo-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except for using 2-bromo-4-chloro-6-nitrophenylamino instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H6BrClN4O2, 339,9; received m/z: 340,9 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,72 (s, 1H), 8,00 (s, 1H), was 7.36 (d,J=1.8 Hz, 1H), 7,11 (l,J=1.7 Hz, 1H).

Example 38: 1-(6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-irsal-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 4-methanesulfonyl-2-nitrophenylamino instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H10N4O4S, 306,0; received m/z: to 307.1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,94 (ush s, 1H), 13,02 (ush s, 1H), 8,96 (l,J=0,4 Hz, 1H), 8,35 (s, 1H), 8,29-of 7.60 (m, 3H), 3,24 (s, 3H).

Example 39: 1-(6-chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A:N-(4-chloro-3-cyanophenyl)-ndimethylacetamide. Mixed acetic anhydride (2,79 ml, 29.5 mmol), 5-amino-2-chlorobenzonitrile (3.00 g, of 19.7 mmol),N,N-dimethylaminopyridine (0,241 g, 1.97 mmol) and toluene (50 ml) and was heated at a temperature of phlegmy for 1.5 hours, the Reaction mixture was cooled and added water and EtOAc (150 ml). Remaining in the mixture, the solid was collected and set aside. The aqueous layer was extracted once more with EtOAc and the combined layers were washed with saline. Then saved the residue was dissolved in EtOAc, which was washed with salt solution. All organic layers were combined, dried, filtered and concentrated. The precipitate was washed with DCM/hexane and got the desired compound (3,52 g, yield 92%). For this connection has not been obtained by mass Spectro is etnicheskie data. 1H NMR (400 MHz, CDCl3): a 7.92 (d,J=1.0 Hz, 1H), EUR 7.57 (DD,J=2,1, 1.2 Hz, 2H), 2,17 (s, 3H).

Stage B:N-(4-chloro-5-cyano-2-nitrophenyl)-ndimethylacetamide.N-(4-chloro-3-cyanophenyl)-ndimethylacetamide (3.00 g, to 15.4 mmol) was dissolved in concentrated sulfuric acid (15 ml) and cooled to 0°C. With stirring dropwise added a solution of potassium nitrate (3.12 g, 30,8 mmol) in concentrated sulfuric acid (15 ml). The reaction mixture was stirred at 0°C for 3.5 h, and then slowly poured into a mixture of ice and water. The precipitate was collected, dissolved in EtOAc, dried, filtered, and concentrated. The residue was purified (KFH) (10-80% EtOAc/hexane) and obtained the desired compound (1.06 g, yield 29%). For this connection has not been obtained mass spectrometric data.1H NMR (400 MHz, CDCl3): or 10.60 (s, 1H), 9,18 (s, 1H), 8,58 (s, 1H), a 2.36 (s, 3H).

Stage C: 4-amino-2-chloro-5-nitrobenzonitrile.N-(4-chloro-5-cyano-2-nitrophenyl)-ndimethylacetamide (1.06 g, 4,415 mmol) was added 2M HCl (45 ml) and was heated at a temperature of phlegmy for 2 h, after which stood at 60°C for 16 hours, the Reaction mixture was cooled and brought to pH to 9 with saturated aqueous sodium bicarbonate solution. The mixture was subjected to extraction with EtOAc (3×50 ml), washed brine (1×15 ml), dried, filtered and concentrated, obtaining the desired compound (0,868 g, 99%). For this connection has not been obtained massspectrometric data. 1H NMR (400 MHz, CDCl3): 8,49 (s, 1H), 7.23 percent (ush s, 2H), 7,02 (s, 1H), 2.40 a (s, 3H).

Stage D: 1-(6-chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, except using 4-amino-2-chloro-5-nitrobenzonitrile instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6ClN5O2, 287,0; received m/z: 288,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,51 (ush s, 1H), 8,93 (l,J=0.5 Hz, 1H), 8,33 (l,J=0,4 Hz, 1H), 8,19 (s, 1H), to 7.84 (s, 1H).

Example 40: 1-(6-chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 5-chloro-6-nitro-1,3-dehydrobenzperidol-2-it. To a solution containing 4-chloro-5-nitrobenzene-1,2-diamine (a 8.34 g, 44.4 mmol) and THF (625 ml), was added the carbonyl diimidazole (8.65 g, 53.3 per mmol) at 0°C. the Reaction mixture allowed to warm to 23°C and stirred at this temperature for 20 hours the Reaction mixture was concentrated to a volume of 300 ml and added to 500 ml of aqueous 1M HCl solution, and then water (total volume 2 l). The resulting suspension was cooled to 0°C for 2 h, the precipitate was collected and dried on the filter. Next, the precipitate was washed with cold EtOAc (20 ml) and washed EtOAc (2×5 ml) to give the desired compound (7,26 g, yield 76%). Mass spectroscopy (ESI/CI): calc. mass for C7H4ClN 3O3, 213,0; received m/z: 214,0 [M+H]+.

Stage B: 2,6-dichloro-5-nitro-1H-benzoimidazol. To the compound 5-chloro-6-nitro-1,3-dehydrobenzperidol-2-he (5,63 g, 26,35 mmol) was added phosphorus oxychloride (35 ml) and heated the reaction mixture at 85°C for 36 h, the Reaction mixture was concentrated and the residue was washed with cold saturated aqueous sodium bicarbonate (to pH 8, 0.8 l). The precipitate was collected and dried to obtain the desired compound (5,43 g, yield 89%). Mass spectroscopy (ESI/CI): calc. mass for C7H3Cl2N3O2, 231,0; received m/z: 232,0 [M+H]+.

Stage C: 2,6-dichloro-1-(2-methoxyethoxymethyl)-5-nitro-1H-benzoimidazol. To a mixed solution containing 2,6-dichloro-5-nitro-1H-benzoimidazol (5,43 g and 23.4 mmol), diisopropylethylamine (12,2 ml of 70.2 mmol) and THF (120 ml), by parts added 1 chloromethoxy-2-methoxyethane (3,30 ml, 28.1 mmol). The reaction mixture was stirred for 2.5 h and concentrated. To the precipitate was added water (50 ml) and was extracted with the mixture with EtOAc (3×125 ml). The combined organic layers were washed brine (100 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (20-55% EtOAc/hexane) to obtain the desired compound (6,23 g, yield 83%) as a mixture of regioisomers 1:1. Mass spectroscopy (ESI/CI): calc. mass for C11H11Cl2N 3O4, 319,0; received m/z: 320,0 [M+H]+.1H NMR (400 MHz, CDCl3): 8,24 (s, 1H), 8,16 (s, 1H), 7,83 (s, 1H), 7,69 (s, 1H), 5,71 (s, 2H), of 5.68 (s, 2H), 3.72 points-to 3.64 (m, 4H), 3,57-to 3.50 (m, 4H), to 3.35 (s, 3H), at 3.35 (s, 3H).

Stage D: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-nitro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester of 2,6-dichloro-1-(2-methoxyethoxymethyl)-5-nitro-1H-benzoimidazol (x 6.15 g, 19.2 mmol), 1H-pyrazole-4-carboxylic acid (2,96 g, 21.1 mmol) and DMF (40 ml) was added cesium carbonate (12.5 g, 38.4 mmol) in a pressurized vessel, designed to work under pressure. The vessel was purged with nitrogen, sealed and heated at 60°C for 2 h, the Reaction mixture was poured into a mixture of brine and water 1:1 (80 ml) and was extracted with EtOAc (3×125 ml). The combined organic layers were washed brine (3×125 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (5-45% EtOAc/hexane) to obtain the desired compound (8,09 g, 98%) as a mixture of regioisomers. Mass spectroscopy (ESI/CI): calc. mass for C17H18ClN5O6, 423,1; received m/z: 424,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,93 (l,J=0.6 Hz, 1H), 8,28 (s, 1H), they were 8.22 (d,J=0.6 Hz, 1H), 7,83 (s, 1H), of 6.26 (s, 2H), 4,37 (kV,J=7,1 Hz, 2H), of 3.73-to 3.67 (m, 2H), 3,49-3,44 (m, 2H), 3,29 (s, 3H), 1.39 in (t,J=7,1 Hz, 3H).

Stage E: 1-(6-chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-PI is an azole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C11H6ClN5O4, 307,0; received m/z: 308,0 [M+H]+.1H NMR (600 MHz, DMSO-d6, tautomeric broadening): 14,14 (ush s, 1H), 13,03 (ush s, 1H), to 8.94 (s, 1H), 8,57-7,52 (m, 3H).

Example 41: 1-(5-amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

STAGE A. Ethyl ester 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution containing ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-nitro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product D reactions from Example 40) (7,88 g of 18.6 mmol), ammonium chloride (14.9 g, 0,279 mol), acetone (75 ml) and water (15 ml), at 0°C in parts) was added zinc powder (12.2 g, 0,186 mol). The reaction mixture was removed from ice bath and after 15 min, filtered through Celite®/hard-shelled earth and washed with EtOAc. The filtrate was concentrated and the remaining substance was separated between EtOAc (300 ml) and saturated aqueous sodium bicarbonate (55 ml). The aqueous layer was further extracted with EtOAc (2×125 ml). The combined organic layers were washed brine (2×40 ml), dried, filtered and concentrated under reduced pressure. The sediment on iStyle (KFH) (5-65% EtOAc/hexane) to obtain the desired compound (6,29 g, yield 86%) as a mixture of regioisomers 1:1. Mass spectroscopy (ESI/CI): calc. mass for C17H20ClN5O4, 393,1; received m/z: 394,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,83 (l,J=0.6 Hz, 1H), 8,78 (l,J=0.6 Hz, 1H), 8,16 (DD,J=1,9, 0.6 Hz, 2H), 7,63 (s, 1H), 7,54 (s, 1H), to 7.09 (s, 1H), of 6.96 (s, 1H), 6,03 (s, 2H), 6,00 (s, 2H), 4,35 (kV,J=7,1 Hz, 4H), 4,18 (s, 2H), 4,07 (s, 2H), 3,66-of 3.60 (m, 4H), 3,49-of 3.42 (m, 4H), of 3.32 (s, 3H), and 3.31 (s, 3H), of 1.37 (t,J=7,1 Hz, 6H).

Stage B: 1-(5-amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C11H8ClN5O2, 277,0; received m/z: 278,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,90 (ush s, 1H), 8,81 (s, 1H), of 8.25 (s, 1H), 7,47 (s, 1H), 6,98 (s, 1H).

Example 42: 1-(5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 27, Stage B-G, except for using 4-torbenson-1,2-diamine instead of 3-chlorobenzene-1,2-diamine in Stage B. Mass spectrometry (ESI/CI): calc. mass for C11H7FN4O2, 246,1; received m/z: 247,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,47 (s, 1H), 12,94 (s, 1H), 8,88 (s, 1H), 8,29 (s, 1H), 7,54 (ush s, 1H), 7,39 (ush s, 1H), 7,13-7,07 (m, 1H).

Example 43: 1-(6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazol-2-yl)-1H-irsal-4-carboxylic acid.

Stage A: 4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine. Pyrrolidine (6 ml) was added 4,5-dichloro-2-nitrophenylamino (2.58 g, 12.5 mmol) in a sealed tube and heated the mixture at 100°C for 6 hours the Mixture was cooled to 23°C, poured into water (100 ml) and was extracted with EtOAc (3×100 ml). The combined organic layers were washed brine (50 ml), dried, filtered and concentrated under reduced pressure to obtain the desired compound (3.00 g, 99%). Mass spectroscopy (ESI/CI): calc. mass for C10H12ClN3O2, 241,1; received m/z: 242,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,08 (s, 1H), the 6.06 (s, 2H), of 5.82 (s, 1H), to 3.58 (DDD,J=6,6, 4,2, 2.7 Hz, 4H), 2,02-1,90 (m, 4H).

Stage B: 6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazol. Formic acid (2.9 ml) was added to a mixture of 4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine (0,240 g, 1.00 mmol) and SnCl2·H2O (0,680 g, 3.00 mmol), after which the mixture was heated at 130°C in a microwave reactor for 5 minutes In one Cup held six reactions. The combined crude mixture was filtered and washed EtOAc (100 ml). The organic layer was treated with water (25 ml) and neutralized aqueous 6M NaOH solution. The aqueous layer was extracted with EtOAc (3×30 ml). The combined organic layers were washed brine (50 ml), dried, filtered and concentrated under decreased the pressure. The precipitate was washed with EtOAc, collected solid material, having the desired compound (1.08 g, 70%) as a salt of formic acid. Mass spectroscopy (ESI/CI): calc. mass for C11H12ClN3, to 221.1; received m/z: 222,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,84-12,16 (ush s, 1H), 8,13 (s, 1H), 8,11 (s, 1H), to 7.59 (s, 1H), 7,20 (s, 1H), 3,20 (t,J=6.3 Hz, 4H), 2.06 to of 1.66 (m, 4H).

Stage C: 5-chloro-1-(2-methoxyethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazol. To a mixture of 6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazole (0,443 g, 2.00 mmol) and THF (5 ml) was added NaH (96.0 mg, 60% dispersion in mineral oil, is 2.40 mmol) at 0°C. After stirring the reaction mixture for 30 min at 0°C was added to the mixture 1 chloromethoxy-2-methoxyethane (0,299 g is 2.40 mmol) and the mixture was stirred for 18 hours, the Reaction mixture was extinguished with water and the aqueous layer was extracted with EtOAc (3×50 ml). The combined organic layers were washed brine (2×20 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-10% MeOH/DCM) and got the desired compound in the form of a mixture of regioisomers (0,240 g, 39%) with a purity of 90%. Mass spectroscopy (ESI/CI): calc. mass for C15H20ClN3O2, 309,1; received m/z: 310,1 [M+H]+.

Stage D: 2,5-dichloro-1-(2-methoxyethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazol. A solution of 5-chloro-1-(2-methoxyethoxymethyl)-6-pyrrolidin-1-yl-1H-benzoimidazole (,221 g, 0,714 mmol) and THF (2.5 ml) was cooled to -78°C in a bath of acetone and dry ice. Dropwise added diisopropylamide lithium (2,0M solution in a mixture of THF/heptane/ethylbenzene, of 0.90 ml, 1.8 mmol) and stirred the reaction mixture at -78°C for 30 minutes At -78°C was addedN-chlorosuccinimide (267 mg, 2.00 mmol), the reaction mixture is heated to 23°C and was stirred for 2 hours was Added a saturated aqueous solution of NH4Cl (20 ml) and the crude product is extracted into EtOAc (3×50 ml). The combined organic layers were washed brine (50 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-100% EtOAc/hexane) and obtained the desired compound (0,240 g, 71%) in the form of a mixture of regioisomers with a purity of 70%. Mass spectroscopy (ESI/CI): calc. mass for C15H19Cl2N3O2, 343,1; received m/z: 344,1 [M+H]+.

Stage E: 1-(6-chloro-5-pyrrolidin-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stages E-g Mass spectroscopy (ESI/CI): calc. mass for C15H14ClN5O2, 331,1; received m/z: 332,1 [M+H]+.1H NMR (DMSO-d6): 13,35 (s, 1H), 12,88 (s, 1H), cent to 8.85 (s, 1H), 8,28 (l,J=0.6 Hz, 1H), 7,71 (s, 0,6H), 7,50 (s, 0,4H), 7,44 (s, 0,4H), 7,20 (s, 0,6H), 3,83-and 3.72 (m, 4H), 3,03-2,89 (m, 4H).

Example 44: 1-(6-chloro-5-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-CT is about acid.

Stage A: 4-chloro-2-nitro-5-piperidine-1-yl-phenylamine: the desired compound was obtained in the same way as described in Example 43, except using piperidine instead of pyrrolidine on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H14ClN3O2, 255,1; received m/z: 256,1 [M+H]+.

Stage B: 1-(6-chloro-5-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid: the Desired compound was obtained in the same way as described in EXAMPLE 27. Mass spectroscopy (ESI/CI): calc. mass for C16H16ClN5O2, 345,1; received m/z: 346,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,86 (s, 1H), 8,29 (s, 1H), 7,63 (s, 1H), 7,35 (s, 1H), 2,99 (s, 4H), 1,72 (s, 4H), and 1.56 (s, 2H).

Example 45: 1-(6-chloro-5-morpholine-4-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 4-chloro-5-morpholine-4-yl-2-nitrophenylamino: the desired compound was obtained in the same way as described in Example 43, except for the use of the research instead of pyrrolidine on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C10H12ClN3O3, 257,1; received m/z: 258,1 [M+H]+.

Stage B: 1-(6-chloro-5-morpholine-4-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27. Mass spectros the opium (ESI/CI): calc. mass for C15H14ClN5O3, 347,1; received m/z: 348,1 [M+H]+.1H NMR (DMSO-d6): 13,17 (s, 1H), 12,86 (s, 1H), 8,83 (l,J=0,4 Hz, 1H), compared to 8.26 (s, 1H), 7.62mm (s, 0,7H), 7,43 (s, 0,3H), 7,31 (s, 0,3H), was 7.08 (s, 0,7H), 3,23 (s, 5H), 1,90 (s, 4H).

Example 46: 1-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 4-chloro-5-methoxy-2-nitrophenylamino. To a mixture of 4,5-dichloro-2-nitrophenylamino (1.29 g, 6,23 mmol) and anhydrous MeOH (2 ml) was added 25% by weight solution of sodium methoxide in MeOH (10 ml) and the mixture was stirred for 6 h at 100°C in a sealed tube. The mixture was cooled to 23°C, poured into water (50 ml) and was extracted with EtOAc (3×50 ml). The combined organic layers were washed brine (25 ml), dried, filtered and concentrated under reduced pressure to obtain the desired compound (0,700 g, 56%). The crude material in the following reaction was used without further purification.

Stage B: 5-chloro-6-methoxy-1H-benzoimidazol. The desired compound was obtained in the same way as described in Example 45, step B, except using 4-chloro-5-methoxy-2-nitrophenylamino instead of 4-chloro-2-nitro-5-pyrrolidin-1-yl-phenylamine. Mass spectroscopy (ESI/CI): calc. mass for C8H7ClN2O, 182,1; received m/z: 183,1 [M+H]+.

Stage C: 5-chloro-6-methoxy-1-(2-methoxyethoxymethyl)-1HBen is imidazol. To a mixture of 5-chloro-6-methoxy-1H-benzoimidazole (0,320 g of 1.75 mmol) and THF (10 ml) was added DIPEA (0,850 ml, 4.9 mmol)and then 1-chloromethoxy-2-methoxyethane (0,310 g, 2.45 mmol) at 23°C. After stirring for 18 h was added EtOAc (50 ml). The organic layer is washed with saline (20 ml), dried, filtered, and concentrated under reduced pressure, obtaining the crude material (0.31 g), which was used in the next reaction without purification.

Stage D: 1-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in Example 43, Stage D-E. Mass spectrometry (ESI/CI): calc. mass for C12H9ClN4O3, 292,0; received m/z: 293,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): cent to 8.85 (d,J=0.6 Hz, 1H), 8,29 (l,J=0.6 Hz, 1H), 7,63 (s, 1H), 7.23 percent (s, 1H), 3,90 (s, 3H). You should pay attention to the fact that the Stages D-E refer to another example

Example 47: 2-(4-carboxy-pyrazole-1-yl)-1H-benzoimidazol-5-carboxylic acid.

Stage A: methyl ester of 2-(4-ethoxycarbonylmethyl-1-yl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stage B-E, except using methyl ester of 3,4-diamino-benzoic acid instead of 3-chloro-benzene-1,2-diamine in Stage B, d is I get a mixture of regioisomers. Mass spectroscopy (ESI/CI): calc. mass for C19H22N4O6, 402,2; received m/z: 403,2 [M+H]+.1H NMR (600 MHz, DMSO-d6): of 9.02 (s, 1H), 9,01 (s, 1H), 8,40 (s, 2H), 8,39 (s, 1H), 8,29 (s, 1H), 8,03 (DD,J=8,6, and 1.4 Hz, 1H), 7,98 (DD,J=an 8.5 and 1.4 Hz, 1H), to $ 7.91 (d,J=8.6 Hz, 1H), 7,83 (l,J=8,5 Hz, 1H), between 6.08 (s, 2H), 6,01 (s, 2H), or 4.31 (kV,J=7,1 Hz, 4H), 3,91 (s, 3H), 3,90 (s, 3H), 3,55-to 3.52 (m, 4H), 3.33 and-3,30 (m, 4H), 3,11 (s, 3H), 3,11 (s, 3H), 1,32 (t,J=7,1 Hz, 6H).

Stage B: 2-(4-carboxybenzoyl-1-yl)-1H-benzoimidazol-5-carboxylic acid. To a stirred solution of methyl ester of 2-(4-ethoxycarbonylmethyl-1-yl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid (0,150 g, 0,373 mmol) and acetic acid (4.5 ml) dobavili aqueous solution of hydrochloric acid (6M, and 4.5 ml). The reaction mixture was heated at 100°C for 18 h, then was cooled to 23°C. the precipitate was collected, having the desired compound (0.30 mg, 30%yield). Mass spectroscopy (ESI/CI): calc. mass for C12H8N4O4, 272,1; received m/z: 273,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): to 8.94 (s, 1H), 8,32 (s, 1H), 8,14 (s, 1H), 7,87 (DD,J=to 8.4, 1.5 Hz, 1H), 7,63 (l,J=8,4 Hz, 1H).

Example 48: 1-(5-bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 5-bromo-3-torbenson-1,2-diamine. To a solution containing 5-bromo-3-fluoro-2-nitrophenylamino (2 g, 8.5 mmol), NH4Cl (for 6.81 g, uniforms, 127.6 mmol), is ceton (100 ml) and water (20 ml), was in pieces added powdered zinc (three equal portions over 5 min) (a 8.34 g, uniforms, 127.6 mmol) at 0°C. the Mixture was stirred for 2 h, then was heated to 23°C. the Mixture was filtered through Celite®after which the solvents were concentrated under reduced pressure. The mixture was re-dissolved in EtOAc/DCM, the second time was filtered through Celite®and removed the solvent by evaporation. The crude mixture was dissolved in EtOAc (200 ml), washed brine (40 ml), dried, filtered and concentrated under reduced pressure. The obtained residue was used in next reaction without further purification.

Stage B: 1-(5-bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 47, except using 5-bromo-3-torbenson-1,2-diamine instead of 3-chlorobenzene-1,2-diamine in Stage A. Mass spectroscopy (ESI/CI): calc. mass for C11H6BrFN4O2, 324,0; received m/z: 325,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,88 (s, 1H), 8.30 to (s, 1H), 7,45 (DD,J=9,5, 2.3 Hz, 1H), 7,34 (l,J=7,6 Hz, 1H).

Example 49: 1-(5-bromo-7-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 47, except using 5-bromo-methylbenzol-1,2-diamine instead of 3-chlorobenzene-1,2-diamine in Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H9BrN4O2, 320,0; received m/z: 321,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,88 (s, 1H), 8,29 (s, 1H), 7,53 (s, 1H), 7.23 percent (s, 1H), 2,53 (s, 3H).

Example 50: 1-[5-(3,4-dichlorophenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: 5-(3,4-dichlorophenoxy)-2-nitro-4-triptorelin. To a mixture of 5-chloro-2-nitro-4-triptoreline (1,00 g of 4.16 mmol) and DMA (21 ml) was added K2CO3(1,15 g, 8,32 mmol) and 3,4-dichlorophenol (1,36 g, 8,32 mmol). The mixture was heated at 85°C for 18 hours the Mixture was cooled to 23°C and poured into ice-cold water. The precipitate was collected, dissolved in EtOAc (150 ml) and was washed brine (2×30 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure, obtaining the desired compound (1.51 g, 99%).1H NMR (500 MHz, CDCl3): charged 8.52 (s, 1H), 7,53 (l,J=8,7 Hz, 1H), 7,26 (l,J=3.2 Hz, 1H), 7,00 (DD,J=to 8.7, 2.7 Hz, 1H), 6,37 (s, 2H), the 6.06 (s, 1H).

Stage B: 1-[5-(3,4-dichlorophenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27. Mass spectroscopy (ESI/CI): calc. mass for C18H9Cl2F3N4O3, 456,0; received m/z: 457,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): to 13.29 (s, 2H), 8,90 (l,J=0,4 Hz, 1H), 8,32 (s, H), of 7.96 (s, 1H), 7,63 (l,J=a 8.9 Hz, 1H), 7,38 (s, 1H), 7,33 (l,J=2,8 Hz, 1H), 7,01 (DD,J=8,9, 2,9 Hz, 1H).

Example 51: 1-[6-chloro-5-(4-chlorphenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for using 4-chlorophenol instead of 3,4-dichlorophenol and use of 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H10Cl2N4O3, 388,0; received m/z: 389,0 [M+H]+.1H NMR (DMSO-d6): 13,25 (ush s, 2H), 8,88 (s, 1H), 8,29 (s, 1H), 7,78 (s, 1H), 7,50-7,22 (m, 3H),? 7.04 baby mortality-to 6.80 (m, 2H).

Example 52: 1-[5-(4-chlorphenoxy)-6-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for using 4-chlorophenol instead of 3,4-dichloro-phenol and 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H10ClF3N4O4, 438,0; received m/z: 439,0 [M+H]+.1H NMR (DMSO-d6): 8,82 (s, 1H), they were 8.22 (s, 1H), to 7.67 (s, 1H), 7,41 (l,J=9,0 Hz, 2H), 7,33 (s, 1H), 6,99 (l,J=9,0 Hz, 2H).

Example 53: 1-(5-phenoxy-6-triptoreline-1H-benzo idazole-2-yl)-1 H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for the use of phenol instead of 3,4-dichloro-phenol and 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H11F3N4O4, 404,1; received m/z: 405,1 [M+H]+.1H NMR (DMSO-d6): 13,30 (s, 1H), 8,88 (s, 1H), 8.30 to (s, 1H), 7,72 (s, 1H), of 7.48-7,34 (m, 2H), 7,27 (s, 1H), 7,14 (t,J=7,4 Hz, 1H), 7,00 (l,J=7.9 Hz, 2H).

Example 54: 1-[5-(4-pertenece)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for using 4-terfenol instead of 3,4-dichlorophenol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H10F4N4O3, 406,1; received m/z: 407,1 [M+H]+.1H NMR (DMSO-d6): 13,30 (s, 2H), 8,87 (s, 1H), 8,29 (s, 1H), to 7.93 (s, 1H), 7,31-to 7.18 (m, 2H), 7,10 (DDD,J=6,7, to 5.4, 3.1 Hz, 3H).

Example 55: 1-[5-(4-chlorphenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for using 4-chlorophenol instead of 34-dichlorphenol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H10ClF3N4O3, 422,0; received m/z: 423,0 [M+H]+.1H NMR (DMSO-d6): 8,81 (s, 1H), 8,18 (s, 1H), 7,87 (s, 1H), 7,50-to 7.32 (m, 2H), 7,18 (s, 1H), 7,07-6,91 (m, 2H).

Example 56: 1-(5-phenoxy-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for the use of phenol instead of 3,4-dichlorophenol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H11F3N4O3, 388,1; received m/z: 389,1 [M+H]+.1H NMR (DMSO-d6): 13,32 (s, 2H), 8,87 (s, 1H), 8,28 (s, 1H), to 7.93 (s, 1H), 7,41 (t,J=7.9 Hz, 2H), 7,16 (DD,J=16,1, to 8.7 Hz, 2H),? 7.04 baby mortality (l,J=8.0 Hz, 2H).

Example 57: 1-(6-chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 5-chloro-2-nitro-4-phenoxyphenyl. To a solution of phenol (0,500 g, 5,31 mmol) in anhydrous DMF (20 ml) was added solid tert-piperonyl sodium (0,510 g, 5,31 mmol). The mixture was heated at 100°C for 60 min, then was added 4,5-dichloro-2-nitrophenylamino (1,00 g of 4.83 mmol) and heated the reaction mixture at 100°C for 19 h Then the reaction mixture allowed to cool to room temperature. The reaction mixture is poured into water and was extracted with EtOAc. The combined organic layers industrial and a solution of 1M Na 2CO3, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (hexane:EtOAc, 5% to 30% for 20 min) and got the desired compound in the form of solid orange (0,821 g, 64%).1H NMR (400 MHz, CDCl3): of 8.27 (s, 1H), 7,50-7,34 (m, 2H), 7,27 (l,J=a 8.9 Hz, 2H), 7,10 (DD,J=to 8.6, 1.1 Hz, 2H), 6,02 (s, 3H).

Stage B: 6-chloro-5-phenoxy-1H-benzoimidazol. To a solution of 5-chloro-2-nitro-4-phenoxyphenyl (0.810 g, a 3.06 mmol) in DMF (12 ml) was added triethylorthoformate (12 ml), and then dithionite sodium (2.66 g, and 15.3 mmol) and glacial acetic acid (1.5 ml). The reaction mixture was heated in a sealed tube at 100°C for 14 hours Added an additional portion of dithionite sodium (0.5 g) and acetic acid (1 ml), after which the mixture continued to heat at 120°C for another 3 hours the Reaction vessel was cooled on ice, the mixture is carefully poured in Polynesians solution of sodium bicarbonate (300 ml) and was extracted with EtOAc. The combined organic layers were washed with 5% solution of NaHCO3, saline solution, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (hexane:EtOAc from 0% to 5% for 20 min) and got the desired compound in the form of an amorphous solid yellow (0,57 g, 76%), a mixture of tautomers. Mass spectroscopy (ESI/CI): calc. mass for C13H9ClN2 O, 244; m/z: 245 [M+H]+.1H NMR (500 MHz, CDCl3): of 9.55 (s, 1H), of 8.06 (s, 1H), 8.0 to about 7.2 (m, 2H), 7,32 (t,J=7.9 Hz, 2H), 7,09 (t,J=7,3 Hz, 1H), of 6.96 (d,J=8,3 Hz, 2H).

Stage C: 6-chloro-1-(2-methoxyethoxymethyl)-5-phenoxy-1H-benzoimidazol. To a solution of 6-chloro-5-phenoxy-1H-benzoimidazole (0.565 g, 2,31 mmol) and diisopropylethylamine (0,890 ml, 5.08 mmol) in anhydrous DMF (10 ml) was added MEM chloride (0,29 ml, 2.54 mmol) at 0°C. After standing for 3 days at room temperature the reaction mixture was infused in a saturated solution of NH4Cl (100 ml) and extracted with EtOAc. The combined organic layers were washed with 0.5 M citric acid, 5% NaHCO3and brine, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (DCM:MeOH from 0% to 5% within 10 min) and got the desired compound as a red oil, which is a mixture of regioisomers in a ratio of 1:1 (0,563 g, 73%). This material was directly used in the next stage.

Stage D: 2,6-dichloro-1-(2-methoxyethoxymethyl)-5-phenoxy-1H-benzoimidazol. To a solution of Diisopropylamine (260 l of 1.85 mmol) in anhydrous THF (2 ml), cooled in a bath to -78°C, was added a solution ofn-utility in hexano (1,16 ml of 1.6 M). After 45 min the contents of the flask through a syringe was injected into cooled to -78°C a solution of 6-chloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzo is midazole (0,560 g, by 1.68 mmol) in anhydrous THF (2 ml). After 60 min, the dark solution was added via syringe a solution ofNchlorosuccinimide (0,247 g of 1.85 mmol) in THF (3 ml), resulting in the color changed to light brown. The reaction mixture is allowed to warm to room temperature, then added it to the saturated aq. a solution of NH4Cl and extracted with EtOAc. The combined organic layers were washed with 0.5 M citric acid solution, 5% aq. a solution of NaHCO3, saline solution, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) and got the desired compound in the form of a mixture of regioisomers (0,251 g, 41%; orange oil). Mass spectroscopy (ESI/CI): calc. mass for C17H16Cl2N2O3, 366; m/z: 367 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7,80 (s, 1H), 7.62mm (s, 1H), 7,37 (s, 1H), was 7.36-7,29 (m, 4H), 7,18 (s, 1H), 7,14? 7.04 baby mortality (m, 2H), 6,98-of 6.90 (m, 4H), 5,63 (s, 2H), 5,54 (s, 2H), 3.72 points-3,63 (m, 2H), 3,63 is 3.57 (m, 2H), 3,57-to 3.50 (m, 2H), 3,49-of 3.42 (m, 2H), 3,38 (s, 3H), of 3.28 (s, 3H).

Stage E: ethyl ester of 1-(6-chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a stirred solution of 2,6-dichloro-1-(2-methoxy-ethoxymethyl)-5-phenoxy-1H-benzoimidazole (0,251 g, 0,684 mmol) and aripirazole-4-carboxylate (0,115 g, 0,820 mmol) in anhydrous DMF (4 ml) was added anhydrous cesium carbonate (0,535 g of 1.64 mmol). The mixed suspension was heated in a bath at a temperature of 80°C in germ the automated test tube for 2 hours After cooling to room temperature the reaction mixture was poured into ice water (100 ml)was acidified using 1N HCl (3 ml) and was extracted in dichloromethane. The combined organic layers were washed with water, brine, dried, filtered, and concentrated under reduced pressure, obtaining the desired product in the form of a crude orange pasty substances (0,361 g). Mass spectroscopy (ESI/CI): calc. mass for C23H23ClN4O5, 470; the resulting m/z: 471 [M+H]+.

Stage F: 1-(6-chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. Ethyl ester of 1-(6-chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (0,361 g) was dissolved in glacial acetic acid (9 ml) and 6N HCl (9 ml) and heated in a sealed tube at 100°C for 6 hours After cooling, ice was added water (5 ml), collected solid is filtered, washed with water and dried under vacuum (60°C, 1.3 kPa (10 mm RT. Art.)). The obtained yellowish-brown powder was recrystallized from a mixture of MeOH:water (10 ml, 10:1), collected by filtration and dried under reduced pressure to obtain the desired compound as a yellowish brown solid (115 mg, 90%). Melting point = 134-138°C (Dec.). Mass spectroscopy (ESI/CI): calc. mass for C17H11ClN4O3, 354; the resulting m/z: 355 [M+H]+, 396 [MH+MeCN]+.1 H NMR (mixture of tautomers) (500 MHz, DMSO-d6): 13,60 (s, 0,5H), 13,50 (s, 0,5H), 12,93 (s, 1H), 8,89 (s, 1H), 8.30 to (s, 1H), of 7.90 (s, 0,5H), the 7.65 (s, 0,5H), 7,42 (m, 2,5H), to 7.15 (m, 1,5H), 7,02 to 6.75 (m, 2H).

Example 58: 1-(5-bromo-7-methyl-1H-imidazo[4,5-f]quinoline-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in Example 57, Stage B-F, except for using 8-bromo-2-methyl-6-nitroquinoline-5-ylamine instead of 5-chloro-2-nitro-4-phenoxybenzamine on Stage B. Mass spectrometry (ESI/CI): calc. mass for C15H10BrN5O2, 371,0; received m/z: 372,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): to 8.94 (s, 1H), 8,83 (l,J=8,3 Hz, 1H), with 8.33 (s, 1H), 8,28 (s, 1H), 7.62mm (l,J=8,4 Hz, 1H), 2,74 (s, 3H).

Example 59: 1-(5-benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: obtain 5-benzyloxy-4-chloro-2-nitrophenylamino. Benzyl alcohol (12.5 ml, 0,121 mol)of 4,5-dichloro-2-nitrophenylamino (5,00 g, and 24.2 mmol), cesium carbonate (15.7 g, to 48.3 mmol) and DMA (110 ml) were mixed in a pressurized vessel, designed to work under pressure. The vessel was purged with nitrogen, sealed and heated at 80°C for 17 hours Reactional mixture was poured into brine (400 ml) and cooled to 0°C. the precipitate was collected and dissolved in EtOAc (400 ml). The organic layer was washed with water (50 ml) and brine (50 ml). the content of inorganic fillers layers were combined dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (1-50% EtOAc/hexane, download without water) and obtained the desired compound (2,47 g, yield 37%). Mass spectroscopy (ESI/CI): calc. mass for C13H11ClN2O3, 278,1; received m/z: 279,2 [M+H]+.1H NMR (400 MHz, CDCl3): to 8.20 (s, 1H), 7,50-7,30 (m, 5H), 6,23 (s, 1H), to 6.19 (ush s, 2H), 5,16 (s, 2H).

Stage B: 1-(5-benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27. Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O3, 368,1; received m/z: 369,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,45-13,28 (m, 1H), 12,93 (ush s, 1H), 8,84 (s, 1H), of 8.27 (s, 1H), 7,81-7,13 (m, 7H), a 5.25 (s, 2H).

Example 60: 1-(6-chloro-5-m-tamilselvan-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 4-chloro-2-nitro-5-m-tolilsulfonil. A mixture containing 3-methylbenzoyl (2.30 ml, and 19.3 mmol), 4,5-dichloro-2-nitroaniline (2.00 g, to 9.66 mmol), potassium carbonate (2.67 g, and 19.3 mmol) and DMF (48 ml)was heated at 90°C for 16 hours, the Reaction mixture was cooled to 23°C. was Added EtOAc and the organic layer washed aqueous saturated solution of NaHCO3(2×80 ml) and brine (1×80 ml). The aqueous layers were extracted with EtOA (3×80 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-100% EtOAc/hexane) and obtained the desired compound (2.30 g, 81%).1H NMR (400 MHz, CDCl3): to 8.12 (s, 1H), 7,41 and 7.36 (m, 3H), 7,34-7,30 (m, 1H), 5,95 (s, 1H), 5,88 (ush s, 2H), 2,41 (s, 3H).

Stage B: obtain 4-chloro-5-m-tolilsulfonil-1,2-diamine.

It chilled in an ice bath (0°C) solution containing 4-chloro-2-nitro-5-m-tolilsulfonil (2.30 g, 7,80 mmol), ammonium chloride (6,26 g, 117 mmol), acetone (32,5 ml) and water (6.5 ml), was in parts added powdered zinc (5.10 g, 78,0 mmol). The reaction mixture was removed from ice bath and after 30 min, filtered through Celite®and washed with EtOAc. The filtrate was placed in a separating funnel and the collected organic layer. The organic layers were dried, filtered and concentrated under reduced pressure. The crude material in the following reaction was used without further purification.

Stage C: obtain 6-chloro-5-m-tamilselvan-1H-benzoimidazole. To a cooled (0°C) solution containing 4-chloro-5-m-tolilsulfonil-1,2-diamine (2,07 g, 7,80 mmol) and trimethyl orthoformate (5,81 ml, to 53.0 mmol)was added concentrated HCl (0,722 ml, 11.5 mmol). The reaction mixture was heated at 23°C for 16 h, then concentrated under reduced pressure. To the crude product was added to the EtOAc (100 ml) and the organic layer was washed saturated aqueous NaHCO 3(2×75 ml). The aqueous layer was extracted with EtOAc (2×50 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure. The crude material was used in the next stage without additional purification. Mass spectroscopy (ESI/CI): calc. mass for C14H11ClN2S, 274,0; received m/z: 275,1 [M+H]+.

Stage D: 6-chloro-1-(2-methoxyethoxymethyl)-5-m-tamilselvan-1H-benzoimidazol. To a cooled solution (0°C)containing 6-chloro-5-m-tamilselvan-1H-benzoimidazol (2.14 g, 7,78 mmol) and THF (39 ml)was added DIPEA (2,71 ml, 15.6 mmol). Further dropwise added 1 chloromethoxy-2-methoxyethane (0,977 ml, 8,56 mmol) and gave the reaction mixture to warm to 23°C for 16 hours, the Reaction mixture was concentrated. The residue was purified (KFH) (0-100% EtOAc/hexane) and obtained the desired compound (1.89 g, 67%) as a mixture of regioisomers in a ratio of 1:1. Mass spectroscopy (ESI/CI): calc. mass for C18H19ClN2O2S, 362,1; received m/z: 363,1 [M+H]+.1H NMR (500 MHz, CDCl3): of 7.95 (s, 1H), 7,92 (s, 1H), 7,88 (s, 1H), to 7.64 (s, 1H), to 7.59 (s, 1H), 7,41 (s, 1H), 7,22-to 7.18 (m, 3H), 7,16-7,13 (m, 2H), 7,11-7,05 (m, 3H), to 5.56 (s, 2H), vs. 5.47 (s, 2H), 3,57-of 3.54 (m, 2H), 3,52-to 3.49 (m, 2H), 3,48 is-3.45 (m, 2H), 3,44-of 3.42 (m, 2H), 3,35 (s, 3H), 3,30 (s, 3H), of 2.30 (s, 6H).

Stage E: 2,6-dichloro-1-(2-methoxyethoxymethyl)-5-m-tamilselvan-1H-benzoimidazol. A solution containing 6-chloro-1-(2-methoxyethoxymethyl)-5-m-Alisultanov-1 H-benzoimidazol (1.89 g, to 5.21 mmol) and THF (13 ml)was cooled to -78°C in a bath of acetone and dry ice. Dropwise added utility (2,2M solution in hexano, 2,60 ml, 5,73 mmol) and stirred the reaction mixture at -78°C for 1 h (as the base can also be used diisopropylamide lithium in the form of 2,0M solution in a mixture of THF/heptane/ethylbenzene). Added a solution ofNchlorosuccinimide (765 mg, 5,73 mmol) in THF (11.5 ml). The reaction mixture is allowed to warm to 23°C and was stirred for 2 hours was Added a saturated aqueous solution of NH4Cl (20 ml) and was extracted crude product in CH2Cl2(3×75 ml). The organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-100% EtOAc/hexane) and obtained the desired compound (1,46 g, 71%) as a mixture of regioisomers 1:1. Mass spectroscopy (ESI/CI): calc. mass for C18H18Cl2N2O2S, 396,0; received m/z: 397,0 [M+H]+.1H NMR (500 MHz, CDCl3): 7,74 (s, 1H), EUR 7.57 (s, 1H), 7,40 (s, 1H), 7,29 (s, 1H), 7.23 percent-to 7.18 (m, 3H), 7.18 in-7,14 (m, 2H), 7,12-7,07 (m, 3H), to 5.58 (s, 2H), 5,48 (s, 2H), 3,64-of 3.60 (m, 2H), 3,54-of 3.48 (m, 4H), 3.43 points is 3.40 (m, 2H), 3,34 (s, 3H), 3,29 (s, 3H), of 2.30 (s, 6H).

Stage F: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-m-tamilselvan-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of 2,6-dichloro-1-(2-methoxyethoxymethyl)-5-m-tamilselvan-1H-benzoimidazole (0,500 g of 1.26 mmol who) and DMF (2,52 ml) was added cesium carbonate (0,820 g, 2,52 mmol) and ethyl ester 1H-pyrazole-4-carboxylic acid (0,194 g, 1.38 mmol). The mixture was heated at 80°C for 2 h in a sealed tube. The mixture was cooled to 23°C, poured into brine (40 ml) and was extracted with EtOAc (3×50 ml). The organic layers were washed brine (40 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-50% EtOAc/hexane) to obtain the desired compound (0,387 g, 61%) as a mixture of regioisomers 1:1.1H NMR (500 MHz, CDCl3): 8,84 (s, 1H), 8,79 (s, 1H), 8,14 (s, 2H), to 7.77 (s, 1H), 7,68 (s, 1H), 7,44 (s, 1H), 7,41 (s, 1H), 7.23 percent-to 7.18 (m, 4H), 7.18 in-7,16 (m, 1H), 7,12 (l,J=7,6 Hz, 2H), 7,09 (l,J=7.5 Hz, 1H), 6,09 (s, 2H), 5,98 (s, 2H), 4,36-4,27 (m, 4H), 3,66-of 3.60 (m, 2H), 3,55-to 3.50 (m, 2H), 3,48-of 3.42 (m, 2H), 3,38-to 3.34 (m, 2H), or 3.28 (s, 3H), 3,24 (s, 3H), 2,32 (s, 3H), 2,31 (s, 3H), 1,38-of 1.30 (m, 6H).

Stage G: ethyl ester of 1-(6-chloro-5-m-tamilselvan-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester 1-[6-chloro-1-(2-methoxy-ethoxymethyl)-5-m-tamilselvan-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,190 g, 0,379 mmol) and EtOH (1 ml) was added 4M solution of HCl in dioxane (1 ml). The mixture was stirred for 3 h at 23°C. the Reaction mixture was concentrated and added Et2O (10 ml). The solids were filtered and washed Et2O, having the desired compound (0,143 g, 91%). Mass spectroscopy (ESI/CI): calc. mass for C20H17ClN4O2+.1H NMR (400 MHz, DMSO-d6): of 8.95 (s, 1H), 8,35 (s, 1H), to 7.77 (s, 1H), 7,41 (s, 1H), 7,29 (t,J=7.7 Hz, 1H), 7,19-7,14 (m, 2H), 7,12-7,06 (m, 1H), 4,30 (kV,J=7,1 Hz, 2H), to 2.29 (s, 3H), 1,31 (t,J=7,0 Hz, 3H).

Stage H: 1-(6-chloro-5-m-tamilselvan-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(6-chloro-5-m-tamilselvan-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (0,100 g, 0,242 mmol), THF (1 ml) and water (0.3 ml) was added LiOH·H2O (40,7 mg, 0,969 mmol). The mixture was stirred for 18 h at 23°C. the Solvent is evaporated, was added water (3 ml) and the mixture was acidified with 1M HCl. The obtained white precipitate was filtered and dried to obtain the desired compound (85,0 mg, 89%). Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O2S, 384,0; received m/z: 385,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,82 (s, 1H), they were 8.22 (s, 1H), 7,73 (s, 1H), 7,43 (s, 1H), 7,27 (t,J=7.9 Hz, 1H), 7,15-7,10 (m, 2H),? 7.04 baby mortality (l,J=7.9 Hz, 1H), and 2.27 (s, 3H).

Example 61: 1-[6-chloro-5-(4-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using 4-chlorbenzoyl instead of 3-methylbenzoyl on A Stage and use diisopropylamide lithium instead of utility on Stage E. Mass SPECT is oscope (ESI/CI): calc. mass for C17H10Cl2N4O2S, 404,0; received m/z: 405,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,84 (s, 1H), 8,23 (s, 1H), 7,76 (s, 1H), EUR 7.57 (s, 1H), 7,44-7,40 (m, 2H), 7.23 percent-to 7.18 (m, 2H).

Example 62: 1-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using bentolila instead of 3-methylbenzoyl on A Stage and use diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C17H11ClN4O2S, 370,0; received m/z: 371,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,93 (s, 1H), 8,87 (s, 1H), 8,29 (s, 1H), 7,78 (ush s, 1H), 7,49-7,37 (m, 3H), 7,37-7,27 (m, 3H).

Example 63: 1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using 3,4-dichlorobenzoyl instead of 3-methylbenzoyl on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H9Cl3N4O2S, 437,9; received m/z: 438,9 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,82 (s, 1H), 8,17 (s, 1H), 7,78 (s, 1H), of 7.75 (s, 1H), 7,56 (l,J=8,5 Hz, 1H), 7,33 (l,J=1.8 Hz, 1H), 7,06 (DD,J=an 8.5 and 2.2 Hz, 1H).

Example 64: 1-[6-chloro-5-(3-m is toxigenicity)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using 3-methoxybenzoyl instead of 3-methylbenzoyl on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O3S, 400,0; received m/z: 401,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,87 (l,J=0.5 Hz, 1H), 8,28 (l,J=0.5 Hz, 1H), 7,78 (ush s, 1H), 7,50 (ush s, 1H), 7,32-7,29 (m, 1H), 6.89 in (DDD,J=8,3, the 2.4, 0.9 Hz, 1H), 6,82-6,79 (m, 2H), and 3.72 (s, 3H).

Example 65: 1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using 4-methoxybenzoyl instead of 3-methylbenzoyl on A Stage and use diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C18H13ClN4O3S, 400,0; received m/z: 401,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,72 (s, 1H), 8,14 (s, 1H), to 7.64 (s, 1H), 7,39 (l,J=8.6 Hz, 2H), was 7.08 (s, 1H),? 7.04 baby mortality (l,J=8,8 Hz, 2H), 3,80 (s, 3H).

Example 66: 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The way A:

Stage A: 5-benzylmethyl-4-chloro-2-nitrophenyl is in. To a mixture of 4,5-dichloro-2-nitrophenylamino (3.00 g, 14.5 mmol) and DMF (72 ml) was added K2CO3(5.31g, 29,0 mmol) and phenylmethanol (3.94 g, and 31.7 mmol). The mixture was heated at 70°C for 18 h, then was cooled to 23°C. the Reaction mixture was dissolved in EtOAc (200 ml), washed with saturated sodium bicarbonate solution (100 ml), washed with brine (3×100 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (5-45% EtOAc/hexane) to obtain the desired compound (2,39 g, 56%). Mass spectroscopy (ESI/CI): calc. mass for C13H11ClN2O2S, 294,0; received m/z: 295,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): of 7.96 (s, 1H), 7,56 (s, 2H), 7,50 (d,J=7.2 Hz, 2H), 7,37 (t,J=7.5 Hz, 2H), 7,31 (t,J=7,4 Hz, 1H), 7,05 (s, 1H), 4,27 (s, 2H).

Stage B: ethyl ester of 1-[5-benzylmethyl-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stages a-E, except using 5-benzylmethyl-4-chloro-2-nitrophenylamino instead of 3-chloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C24H25ClN4O4S, 500,1; received m/z: 501,1 [M+H]+.

Stage C: ethyl ester of 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. the mixture ethyl ester 1-[5-benzylmethyl-6-chloro-1-(2-methoxyethoxymethyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (96.0 mg, 0,192 mmol) and EtOH (5 ml) was added 4M solution of HCl in dioxane (5 ml, 20 mmol). The mixture was stirred for 18 h at 23°C. the Reaction mixture was concentrated under reduced pressure and the obtained residue was rubbed in Et2O. the resulting suspension was filtered and washed Et2O, having the desired compound (69,0 mg, 87%). Mass spectroscopy (ESI/CI): calc. mass for C20H17ClN4O2S, 412,1; received m/z: 413,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,53 (l,J=12.3 Hz, 1H), of 8.95 (s, 1H), 8,35 (s, 1H), 7,78 (s, 0,5H), the 7.65 (s, 0,5H), 7,55 (s, 0,5H), 7,44 (s, 0,5H), 7,38 (d,J=7.2 Hz, 2H), 7,31 (t,J=7,4 Hz, 2H), 7,25 (s, 1H), 4,32-4.26 deaths (m, 4H), 1,32 (t,J=7,1 Hz, 3H).

Stage D: 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (57,0 mg, to 0.127 mmol), THF (2 ml) and water (of 0.67 ml) was added LiOH·H2O (27.0 mg, 0,654 mmol). The mixture was stirred for 18 h at 23°C. the Reaction mixture was concentrated under reduced pressure, added water (3 ml) and the mixture was acidified to pH=3 using 1M HCl. The obtained white precipitate was filtered and dried to obtain the desired compound (39,0 mg, 80%). Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O2S, 384,0; received m/z: 385,0 [M+H]+ 1H NMR (600 MHz, DMSO-d6): 8,86 (s, 1H), 8,29 (s, 1H), to 7.67 (s, 1H), 7,53 (s, 1H), 7,39 (l,J=7,4 Hz, 2H), 7,31 (t,J=7,4 Hz, 2H), 7,25 (t,J=7,1 Hz, 1H), 4,29 (s, 2H).

The way B:

Stage A: ethyl ester of 1-[5-tert-butylsulfonyl-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 66, Method A, Phase A-B, except using 2-methyl-propane-2-thiol instead of phenyl-methanethiol on A Stage, to obtain a mixture of regioisomers with 1:1 ratio Mass spectrometry (ESI/CI): calc. mass for C21H27ClN4O4S, 466,1; received m/z: 467,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,89-8,88 (m, 2H), 8,19 (s, 2H), 8,03 (s, 1H), to 7.93 (s, 1H), a 7.85 (s, 1H), 7,78 (s, 1H), 6,17 (s, 2H), 6,13 (s, 2H), 4,39-to 4.33 (m, 4H), 3,71-to 3.64 (m, 4H), 3,50-of 3.42 (m, 4H), and 3.31 (s,J=5,1 Hz, 3H), 3,30 (s, 3H), 1,43-of 1.29 (m, 24H).

Stage B: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(2-nitrophenylacetonitrile)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixed solution containing ethyl ester 1-[5-tert-butylsulfonyl-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (3.00 g, 6.42 per mmol) and DCM (32 ml), added potassium carbonate (1.78 g, 12.9 mmol). The reaction mixture was treated with 2-nitrobenzenesulfonamide (3,05 g, 16,1 mmol) and stirred at 23°C for 16 hours Received ocado is concentrated and purified by the method of KFH (5-30% EtOAc/hexane) to obtain the desired compound (2,99 g, crude yield 82%) as a mixture of regioisomers with a 2:1 ratio. This compound was used in subsequent reactions without further purification. Mass spectroscopy (ESI/CI): calc. mass for C23H22ClN5O6S2, 563,1; received m/z: 564,1 [M+H]+.1H NMR (600 MHz, CDCl3): cent to 8.85-8,82 (m, 2H), 8,17 (s, 2H), of 7.75 (s, 0,66H), 7,72 (s, 1,34H), 7,68 (s, 1,34H), to 7.64 (s, 0,66H), 7,45-7,42 (m, 4H), 7,31-7,26 (m, 4H), 6,09 (l,J=2.1 Hz, 4H), 4,36 (K,J=7,1 Hz, 4H), 3,67-3,62 (m, 4H), 3,49-of 3.42 (m, 4H), and 3.31 (d,J=1,9, 6H), to 1.38 (t,J=7,1 Hz, 6H).

Stage C: ethyl ester of 1-[6-chloro-5-mercapto-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a stirred cooled (0°C) solution containing ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(2-nitrophenylacetonitrile)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (2,99 g of 5.29 mmol) and EtOH (24 ml)was added dropwise a solution of NaBH4(advanced 0.729 g, and 19.3 mmol), EtOH (24 ml) and water (10 ml) for 10 min. the Reaction mixture was stirred 15 min, then added a new portion NaBH4(0,486 g, 12.8 mmol) in EtOH (16 ml) and water (6,7 ml). The reaction mixture was stirred for another 30 min, after which he divided between DCM (200 ml) and water (200 ml). The aqueous layer was acidified to pH 5 with 1M HCl and the product was extracted into DCM (3×300 ml). The organic layers were combined, dried, filtered and concentrated under reduced giving the situation. The residue was purified (KFH) (5-80% EtOAc/hexane) to obtain the desired compound (1.27 g, 48%) as a mixture of regioisomers 2:1. Mass spectroscopy (ESI/CI): calc. mass for C17H19ClN4O4S, 410,1; received m/z: 411,1 [M+H]+.1H NMR (600 MHz, CDCl3): cent to 8.85-8,84 (m, 2H), 8,17 (s, 2H), of 7.75 (s, 0,67H), 7,72 (s, 1,33 H), 7,68 (s, 1,33H), to 7.64 (s, 0,67H), 6,10-6,09 (m, 4H), 4,36 (K,J=7,1 Hz, 4H), was 4.02 (s, 0,67H), 3,93 (s, 1,33H), 3,66-3,62 (m, 4H), 3,47-3,44 (m, 4H), 3,31-3,30 (m, 6H), to 1.38 (t,J=7,1 Hz, 6H). For large-scale synthesis of the desired compounds are also obtained dimeric by-product dimer bond which is a sulfide bond with the formation of disulfide intermediate compound ethyl ester 1-[6-chloro-5-mercapto-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid, a byproduct of which was allocated, but not yet tested: mass spectroscopy (ESI/CI): calc. mass for C34H36Cl2N8O8S2, 818,1; received m/z: 819,1 [M+H]+.

Stage D: ethyl ester of 1-[5-benzylmethyl-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution containing ethyl ester 1-[6-chloro-5-mercapto-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,300 g, at 0.730 mmol), benzyl bromide (0,130 ml, 1.10 mmol) and DMF (20 ml), added potassium carbonate (0,151 g, 1.10 mmol). Reactio the ing the mixture was stirred for 15 min at 23°C and poured into water (40 ml). The product was extracted with EtOAc (3×50 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (2-50% EtOAc/hexane) to obtain the desired compound (0,330 g, 90%). Mass spectroscopy (ESI/CI): calc. mass for C24H25ClN4O4S, 500,1; received m/z: 501,1 [M+H]+.

Stage E: ethyl ester of 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester 1-[5-benzylmethyl-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (160 mg, 0,319 mmol) and EtOH (3.2 ml) was added 4M solution of HCl in dioxane (3,21 ml, 12.8 mmol). The mixture was stirred for 18 h at 23°C. the Reaction mixture was concentrated and the obtained residue was rubbed in Et2O. the Suspension was filtered and washed Et2O obtaining the desired compound (0.125 g, 95%). Mass spectroscopy (ESI/CI): calc. mass for C20H17ClN4O2S, 412,1; received m/z: 413,1 [M+H]+.1H NMR (600 MHz, DMSO-d6); 13,53 (l,J=12.3 Hz, 1H), of 8.95 (s, 1H), 8,35 (s, 1H), 7,78 (s, 0,5H), the 7.65 (s, 0,5H), 7,55 (s, 0,5H), 7,44 (s, 0,5H), 7,38 (d,J=7.2 Hz, 2H), 7,31 (t,J=7,4 Hz, 2H), 7,25 (s, 1H), 4,32-4.26 deaths (m, 4H), 1,32 (t,J=7,1 Hz, 3H).

Stage F: 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1 H-pyrazole-4-carboxylic acid (0,115 g, 0,256 mmol), THF (4.8 ml) and water (1.2 ml) was added LiOH·H2O (0,107 g, 2.56 mmol). The mixture was stirred for 18 h at 23°C. the Solvent is evaporated, was added water (3 ml) and the mixture was acidified to pH 3 with 1M HCl. The obtained white precipitate was filtered and dried to obtain the desired compound (97,0 mg, 99%). Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O2S, 384,0; received m/z: 385,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,86 (s, 1H), 8,29 (s, 1H), to 7.67 (s, 1H), 7,53 (s, 1H), 7,39 (l,J=7,4 Hz, 2H), 7,31 (t,J=7,4 Hz, 2H), 7,25 (t,J=7,1 Hz, 1H), 4,29 (s, 2H).

Example 67: 1-[5-(4-tert-butylbenzenesulfonyl)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method A, except for using (4-tert-butylphenyl)-methanethiol instead phenylmethanol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C22H21ClN4O2S, 440,1; received m/z: 441,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,80 (s, 1H), 8,21 (s, 1H), to 7.64 (s, 1H), to 7.59 (s, 1H), 7,34-of 7.23 (m, 4H), is 4.21 (s, 2H), 1.26 in (s, 9H).

Example 68: 1-[6-chloro-5-(4-perpenicular)-1Hbenzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as the description is but in EXAMPLE 66, Method A, except for using (4-forfinal)-methanethiol instead phenylmethanol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H12ClFN4O2S, 402,0; received m/z: 403,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): cent to 8.85 (s, 1H), 8,28 (s, 1H), to 7.67 (s, 1H), 7,60-7,46 (m, 1H), 7,39 (DD,J=to 8.7, 5.5 Hz, 2H), 7,19-7,06 (m, 2H), 4,27 (s, 2H).

Example 69: 1-[6-chloro-5-(2-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method A, except using (2-chlorophenyl)-methanethiol instead phenylmethanol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H12Cl2N4O2S, 418,0; received m/z: 419,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,84 (s, 1H), compared to 8.26 (s, 1H), 7,68 (s, 1H), 7,52 (s, 1H), 7,46 (DD,J=to 7.9, 1.2 Hz, 1H), 7,34 (DD,J=to 7.5 and 1.7 Hz, 1H), 7,29 (TD,J=to 7.6, 1.8 Hz, 1H), 7,24 (TD,J=to 7.4, 1.3 Hz, 1H), or 4.31 (s, 2H).

Example 70: 1-(6-chloro-5-penicillanic-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method A, except using 2-phenylethanol instead phenylmethanol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C19H15ClN4O2S, 398,1; received m/z: 39,0 [M+H] +.1H NMR (600 MHz, DMSO-d6): 13,26 (s, 1H), 8,86 (s, 1H), 8,28 (s, 1H), 7,69 (s, 1H), 7,60 (s, 1H), 7,34-7,29 (m, 4H), 7.24 to 7,21 (m, 1H), 3,30-of 3.25 (m, 2H), 2.95 and-2,90 (m, 2H).

Example 71: 1-(6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 5-methylsulfanyl-2-nitro-4-triptorelin. To a solution of 5-chloro-2-nitro-4-triptoreline (2,02 g of 8.40 mmol) in DMF (40 ml) was added thiamethoxam sodium (0,618 g, 8,82 mmol). The mixture was heated at 90°C for 50 min, then poured into brine. Added water, bringing the total volume to 300 ml and gathered orange precipitate, having the desired compound (2,02 g, 95%).1H NMR (400 MHz, CDCl3): 8,42 (s, 1H), 6,51 (s, 1H), 6,39 (ush s, 2H), 2,53 (s, 3H).

Stage B: ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stages a-E, except using 5-methylsulfanyl-2-nitro-4-triptoreline instead of 3-chloro-2-nitrophenylamino on Stage A. the Final product was obtained as a mixture of regioisomers 1:1. Mass spectroscopy (ESI/CI): calc. mass for C19H21F3N4O4S, 458,1; received m/z: 459,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,91 (s, 1H), 8,88 (s, 1H), 8,21-8,19 (m, 2H), 8,03 (s, 1H), of 7.96 (s, 1H), 7,76 (s, 1H), 7,65 (s, 1H), 6.22 per 6,9 (m, 4H), 4,37 (kV,J=7,1 Hz, 4H), 3,70-3,63 (m, 4H), 3,49 is-3.45 (m, 4H), 3,32-3,30 (m, 6H), 2,61-to 2.57 (m, 6H), 1.39 in (t,J=7,1 Hz, 6H).

Stage C: 1-(6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a stirred solution of ethyl ester 1-[1-(2-methoxyethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,200 g, 0,436 mmol) and acetic acid (1.3 ml) was added aqueous 6M hydrochloric acid (1.3 ml). The reaction mixture was heated at 100°C for 18 h, then was cooled to 23°C. the Precipitate was collected, having the desired compound in the form of HCl salt (amount of 0.118 g, 71%yield). Mass spectroscopy (ESI/CI): calc. mass for C13H9F3N4O2S, 342,0; received m/z: 343,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 8.92 (d,J=0.6 Hz, 1H), 8,33 (l,J=0,4 Hz, 1H), of 7.90 (s, 1H), 7,68 (s, 1H), 2,59 (s, 3H).

Example 72: 1-(6-propylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 2-nitro-5-propylsulfonyl-4-triptorelin. To a mixture of 5-chloro-2-nitro-4-triptoreline (1.50 g, 6.26 mmol), potassium carbonate (1,72 g, 12.5 mmol) and DMF (31 ml) was added 1-propanethiol (0,620 ml, 6,86 mmol). The reaction mixture was heated at 90°C for 16 h, then allowed to cool to 23°C and poured into a mixture of ice and brine (300 ml). Received the yellow precipitate was collected, having obtained the desired compound (1.67 mg, 95%). Mass spectroscopy (ESI/CI): calc. mass for C10H11F3N2O2S, 280,1; received m/z: 281,0 [M+H]+.1H NMR (400 MHz, CDCl3): to 8.41 (s, 1H), return of 6.58 (s, 1H), 6,36 (ush s, 2H), 2,97 (t,J=7,3 Hz, 2H), 1,87-1,72 (m, 2H), 1,10 (t,J=7,4 Hz, 3H).

Stage B: 1-(6-propylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 71, Stage B-C. the Residue was purified by the method of back-phase HPLC to obtain the desired compound. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O2S, 370,1; received m/z: 371,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,77 (s, 1H), 13,02 (s, 1H), 8,92 (l,J=0.6 Hz, 1H), 8.34 per (e,J=0.6 Hz, 1H), 8.17-a rate of 7.54 (m, 2H), to 3.02 (t,J=7,1 Hz, 2H), 1,68-of 1.52 (m, 2H), and 0.98 (t,J=7,3 Hz, 3H).

Example 73: 1-(6-isopropylphenyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 72, except using 2-propandiol instead of 1-propanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O2S, 370,1; received m/z: 371,1 [M+H]+.1H NMR (400 MHz, CD3OD, tautomeric broadening): to 8.94 (s, 1H), 8,21 (s, 1H), 8,03 for 7.78 (m, 2H), 3,533,38 (m, 1H), 1,29 (l,J=6,7 Hz, 6H).

Example 74: 1-(5-fluoro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 71, except 4,5-debtor-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H9FN4O2S, 292,0; received m/z: 293,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,87 (s, 1H), 8,29 (s, 1H), of 7.48 (d,J=6,7 Hz, 1H), 7,43 (l,J=10.1 Hz, 1H), 2,52 (s, 3H).

Example 75: 1-(5-chloro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 71, except for the use of 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H9ClN4O2S, 308,0; received m/z: 309,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,87 (l,J=0.6 Hz, 1H), 8.30 to (q,J=0.5 Hz, 1H), to 7.67 (s, 1H), 7,43 (s, 1H), 2,54 (s, 3H).

Example 76: 1-(5-chloro-6-ethylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 71, except for the use of the 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline and use titoxd sodium instead of timelocked sodium in Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H11ClN4O2S, 322,0; received m/z: 323,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): cent to 8.85 (s, 1H), of 8.27 (s, 1H), 7,65 (s, 1H), 7,53 (s, 1H), 2,99 (K,J=7,3 Hz, 2H), 1,25 (t,J=7,3 Hz, 3H).

Example 77: 1-(5-chloro-6-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 71, except for the use of 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline and use diisopropoxide sodium instead of timelocked sodium on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H13ClN4O2S, 336,0; received m/z: 337,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,89 (s, 1H), 8.30 to (s, 1H), of 7.70 (s, 1H), 7,68 (s, 1H), 3,56-of 3.48 (m, 1H), 1.27mm (l,J=6,6 Hz, 6H).

Example 78: 1-(5-chloro-6-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 71, except for the use of 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on A Stage; and emitting the final connection at the Stage B without cleaning method of back-phase HPLC. Mass spectroscopy (ESI/CI): calc. mass for C14H13ClN4O2S, 36,0; the obtained m/z: 337,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,88 (s, 1H), 8.30 to (s, 1H), 7,68 (s, 1H), 7,55 (s, 1H), 2,98 (t,J=7.2 Hz, 2H), 1,64 (h,J=7,3 Hz, 2H), 1,02 (t,J=7,3 Hz, 3H).

Example 79: 1-(6-methylsulfanyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 71, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H9F3N4O3S, 358,0; received m/z: 359,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,00 (ush s, 1H), 8,88 (s, 1H), 8,32 (s, 1H), 7,81 for 7.12 (m, 2H), 2,54 (s, 3H).

Example 80: 1-(6-isopropylphenyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 72, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline and use 2-propandiol instead of 1-propanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O3S, 386,1; received m/z: 387,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,65 (s, 1H), 13,00 (s, 1H) 8,89 (l, J=0.5 Hz, 1H), 8,32 (l,J=0.5 Hz, 1H), 7,65 (ush s, 2H), 3,57-3,44 (ush m, 1H), 1,24 (l,J=6,6 Hz, 6H).

Example 81: 1-(6-propylsulfonyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 72, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O3S, 386,1; received m/z: 387,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,80-was 12.75 (m, 2H), 8,88 (l,J=0.6 Hz, 1H), 8,32 (l,J=0.6 Hz, 1H), EUR 7.57 (s, 2H), 2,98 (t,J=7.2 Hz, 2H), 1,68-of 1.53 (m, 2H), 0,99 (t,J=7,3 Hz, 3H).

Example 82: 1-[6-chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-m-tamilselvan-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of EXAMPLE 60, the product of Stage (F) (0,160 g, 0,319 mmol) and MeOH (1.6 ml) was added a solution of reagent Oxone®(0,412 g, 0,671 mmol) in water (1.7 ml) at 23°C. the Reaction mixture was stirred PR is 23°C for 16 hours Added dichloromethane (30 ml)and then sodium thiosulfate solution (0,106 g, 0,670 mmol) in saturated at 80% aqueous solution of NaHCO3(30 ml). The mixture was thoroughly stirred until both layers were not transparent. The organic layer was collected and the aqueous layer was extracted with the help of CH2Cl2(2×50 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-100% EtOAc/hexane), having the desired compound (0,105 mg, 62%) as a mixture of regioisomers. Mass spectroscopy (ESI/CI): calc. mass for C24H25ClN4O6S, 532,1; received m/z: 533,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,90 (l,J=0.6 Hz, 1,5H), 8,89 (l,J=0.6 Hz, 0,5H), 8,73 (ush, 1,5H), 8,69 (ush, 0,5H), 8,19 (l,J=0.6 Hz, 0,5H), 8,18 (l,Jor =0.6, 1,5H), 7,79 to 7.75 (m, 2H), 7,75-7,72 (m, 2H), 7,71 (s, 0,5H), to 7.67 (s, 1,5H), 7,39 was 7.36 (m, 4H), 6,27 (s, 1H), 6,14 (s, 3H), 4,40-4,32 (m, 4H), 3,71-to 3.67 (m, 1H), 3,66-3,61 (m, 3H), 3,49 is-3.45 (m, 1H), 3,44-3,39 (m, 3H), of 3.28 (s, 1,5H), 3,24 (C, 4,5H), 2,38 (ush s, 6H), to 1.38 and 1.33 (m, 6H).

Stage B: 1-[6-chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 60, Stage G-H. Mass spectrometry (ESI/CI): calc. mass for C18H13ClN4O4S, 416,0; received m/z: 417,1 [M+H]+.1H NMR (400 MHz, DMSO-d6):8,93 (l,J=0.5 Hz, 1H), 8,44 (s, 1H), 8,33 (l,J=0,4 Hz, 1H), 7,75-of 7.69 (m, 3H), 7,53-of 7.48 (m, 2H), is 2.37 (s, 3H).

<> Example 83: 1-(5-benzazolyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 82, ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-phenylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product from Example 62). Mass spectroscopy (ESI/CI): calc. mass for C17H11ClN4O4S, 402,0; received m/z: 403,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): to 8.94 (s, 1H), of 8.47 (s, 1H), 8,35 (s, 1H), 7.95 is-7,89 (m, 2H), 7,76 (ush s, 1H), 7,74-to 7.67 (m, 1H), 7,65-7,58 (m, 2H).

Example 84: 1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 82, ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product from Example 65). Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O5S, 432,0; received m/z: 433,0 [M+H]+.1H NMR (600 MHz, DMSO-d6):14,09 (ush s, 1H), 13,04 (ush s, 1H), to 8.94 (s, 1H), 8,42 (s, 1H), 8,35 (s, 1H), 7,89-to 7.84 (m, 2H), 7,75 (ush s, 1H), 7,14-7,10 (m, 2H), of 3.84 (s, 3H).

Example 85: 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-Kurbanova the acid.

Stage A: ethyl ester of 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-chloro-5-(4-chlorophenylsulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product from Example 61) (2,69 g, 5,16 mmol) and dichloromethane (26 ml) addedmCPBA (2,43 g to 10.8 mmol) at 23°C. the Reaction mixture was stirred for 16 h at 23°C. was Added dichloromethane (30 ml)and then sodium thiosulfate solution (1,71 g to 10.8 mmol) in saturated at 80% aqueous solution of NaHCO3(30 ml). The mixture was thoroughly stirred until both layers were not transparent. The organic layer was collected and the aqueous layer was extracted with the help of CH2Cl2(2×80 ml). The organic layers were combined, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-100% EtOAc/hexane), having the desired compound (2.55 g, 89%) as a mixture of regioisomers. Mass spectroscopy (ESI/CI): calc. mass for C23H22Cl2N4O6S, 552,1; received m/z: 553,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,91-8,89 (m, 2H), 8,73 (s, 1,4H), 8,68 (s, 0,6H), to 8.20 (d,J=0.6 Hz, 0,6H), 8,18 (l,J=0.6 Hz, 1,4H), to $ 7.91-7,87 (m, 4H), 7,72 (s, 0,6H), 7,68 (s, 1,4H), of 7.48-the 7.43 (m, 4H), 6,27 (C, 1,2 H)x 6.15 (s, 2,8H), 4,39-4,32 (m, 4H), 3,71-3,66 (m, 1,2H), 3,67-3,62 (m, 2,8H), 3,48 is-3.45 (m, 1,2H), 3,44 is 3.40 (m, 2,8H), 3,2 (s, 1,8H), 3,24 (C, 4,2H), 1,40 is 1.34 (m, 6H).

Stage B: ethyl ester of 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (2.55 g, 4.61 mmol) and EtOH (11.5 ml) was added 4M solution of HCl in dioxane (11.5 ml). The mixture was stirred for 3 h at 23°C. the Reaction mixture was concentrated and added Et2O. the Solids were filtered and washed Et2O, having the desired compound (1.92 g, 89%). Mass spectroscopy (ESI/CI): calc. mass for C19H14Cl2N4O4S, 464,0; received m/z: 465,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): of 9.02 (s, 1H), 8,45 (s, 1H), 8,40 (s, 1H), 7.95 is-a 7.92 (m, 2H), 7,76 (ush s, 1H), 7,70-to 7.67 (m, 2H), 4,30 (K,J=7,1 Hz, 2H), 1,32 (t,J=7,1 Hz, 3H).

Stage C: 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (1.92 g, 4,13 mmol), THF (16 ml) and water (5 ml) was added LiOH·H2O (0,693 g, 16.5 mmol). The mixture was stirred for 18 h at 23°C. the Solvent is evaporated, was added water (10 ml) and the mixture was acidified with 1M HCl. The precipitate was filtered and dried to obtain the desired compound (1.73 g, 94%). Mass Spectro is a copy (ESI/CI): calc. mass for C17H10Cl2N4O4S, km 436.0; received m/z: 437,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,89 (s, 1H), 8,40 (s, 1H), of 8.25 (s, 1H), 7,93-of 7.90 (m, 2H), 7,69-7,66 (m, 3H).

Example 86: 1-[6-chloro-5-(4-trifloromethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(4-cryptomaterial)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in Example 60, Stage A-F, except for using 4-triptoreline-bentolila instead of 3-methyl-bentolila at the Stage of A.

Stage B: 1-[6-chloro-5-(4-trifloromethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in Example 85. Mass spectroscopy (ESI/CI): calc. mass for C18H10ClF3N4O5S, of 486.0; received m/z: 487,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,77 (s, 1H), 8,29 (s, 1H), 8,02 (s, 1H), 8,01-of 7.97 (m, 2H), 7,56 (l,J=8,1 Hz, 2H), 7,45 (s, 1H).

Example 87: 1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(3,4-dichlorphenamide who yl)-1-(2-methoxyethoxymethyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 63). Mass spectroscopy (CI): calc. mass for C17H9Cl3N4O4S, 469,9; received m/z: 468,9 [M-H]-.1H NMR (600 MHz, DMSO-d6): of 8.95 (s, 1H), 8,48 (ush s, 1H), 8.34 per (s, 1H), 8,16 (l,J=1,6 Hz, 1H), 7,92-7,88 (m, 2H), 7,78 (ush s, 1H).

Example 88: 1-[6-chloro-5-(3-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(3-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 64). Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O5S, 432,0; received m/z: 433,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 14,15 (s, 1H), 13,04 (s, 1H), 8,95 (l,J=0.5 Hz, 1H), 8,45 (s, 1H), at 8.36 (s, 1H), to 7.77 (ush s, 1H), 7,53 (t,J=8.0 Hz, 1H), of 7.48-the 7.43 (m, 1H), 7,41-7,38 (m, 1H), 7,27 (DDD,J=8,3, and 2.6, 1.0 Hz, 1H), 3,81 (s, 3H).

Example 89: 1-(6-chloro-5-phenylmethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[5-benzylmethyl-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-karbonovoi acid (intermediate product of Example 66). Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O4S, 416,0; received m/z: 417,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 8.92 (s, 1H), with 8.33 (s, 1H), 7,98-of 7.82 (m, 2H), 7,33-to 7.15 (m, 5H), a 4.86 (s, 2H).

Example 90: 1-[6-chloro-5-(2,4,6-trimethylphenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(2,4,6-trimethylbenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 66, Method A, Phase A-B, except using (2,4,6-trimetilfenil)-methanethiol instead of phenyl-methanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C27H31ClN4O4S, 542,2; received m/z: 543,2 [M+H]+.

Stage B: 1-[6-chloro-5-(2,4,6-trimethylphenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in Example 85. Mass spectroscopy (ESI/CI): calc. mass for C21H19ClN4O4S, 458,1; received m/z: 459,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): of 8.95 (s, 1H), 8,35 (s, 1H), 8,13 (s, 1H), 7,94 (s, 1H), 6.90 to (s, 2H), around 4.85 (s, 2H), 2,32 (s, 6H), of 2.23 (s, 3H).

Example 91: 1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 66, Method A, Phase A-B, except for using (4-methoxyphenyl)-methanethiol instead phenylmethanol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C25H27ClN4O5S, 530,1; received m/z: 531,1 [M+H]+.

Stage B: 1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in Example 85. Mass spectroscopy (ESI/CI): calc. mass for C19H15ClN4O5S, 446,1; received m/z: 447,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): of 8.92 (s, 1H), 8.34 per (s, 1H), 8,03 (s, 0,6H), 7,92 (s, 0,4H), 7,83 (s, 0,6H), 7,74 (s, 0,4H), 7,11 (l,J=8,7 Hz, 2H), PC 6.82 (d,J=8,4 Hz, 2H), 4,79 (s, 2H), 3,68 (s, 3H).

Example 92: 1-[6-chloro-5-(4-PerformanceCounter)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(4-perpenicular)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 68). Mass spectroscopy (ESI/CI): calc. mass for C1 H12ClFN4O4S, 434,0; received m/z: 435,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): of 8.92 (s, 1H), 8,32 (s, 1H), 7.95 is-7,83 (m, 2H), 7,26-7,21 (m, 2H), 7,11 (t,J=8,8 Hz, 2H), to 4.87 (s, 2H).

Example 93: 1-[6-chloro-5-(2-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(2-chlorobenzenesulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 69). Mass spectroscopy (ESI/CI): calc. mass for C18H12Cl2N4O4S, 450,0; received m/z: 451,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 14,05 (s, 1H), 13,02 (s, 1H), to 8.94 (s, 1H), 8.34 per (s, 1H), 8,04-7,83 (m, 2H), 7,43 (DD,J=7,2 Hz and 2.1 Hz, 1H), 7,40 (DD,J=7,7 Hz / 1.5, 1H), 7,34 (pd,J=7,3 Hz, 1.8 Hz, 2H), 5,02 (s, 2H).

Example 94: 1-[6-chloro-5-(2-phenylethanone)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-penicillanic-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 70). Mass spectroscopy (ESI/CI): calc. mass for C19H15ClN4O4S, 430,1; received m/z: 431,0 [M+H] +.1H NMR (600 MHz, DMSO-d6): of 8.95 (s, 1H), 8,35 (s, 1H), 8,16 (s, 1H), to 7.84 (s, 1H), 7,22-7,16 (m, 4H), 7,15-7,11 (m, 1H), 3,88-3,82 (m, 2H), 2,96-2,87 (m, 2H).

Example 95: 1-(5-chloro-6-econsulting-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 71, Stage A-B, except for the use of 4,5-dichloro-2-nitro-phenylamine instead of 5-chloro-2-nitro-4-triptoreline and use titoxd sodium instead of timelocked sodium on Stage A. was Observed mixture of regioisomers in a ratio of 1:1.1H NMR (600 MHz, CDCl3): 8,86 (l,J=0.6 Hz, 1H), cent to 8.85 (d,J=0.6 Hz, 1H), 8,18 (s, 2H), of 7.75 (s, 1H), 7,68 (s, 1H), to 7.67 (s, 1H), 7,56 (s, 1H), 6,14 (s, 2H), 6,10 (s, 2H), 4,36 (kV,J=7,1 Hz, 4H), 3,68-3,63 (m, 4H), 3,48-3,44 (m, 4H), and 3.31 (s, 3H), and 3.31 (s, 3H), 3,02 (p,J=7,3 Hz, 4H), 1.41 to about 1.36 (m, 12H).

Stage B: ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,501 g to 1.14 mmol) and MeOH (5.7 ml) was added a solution of reagent Oxone®/ potassium peroxymonosulfate (1.47 g, is 2.40 mmol) in the ode (5.7 ml). The mixture was stirred for 44 h at 23°C. was Added EtOAc (50 ml) and water (30 ml) and the biphasic mixture stirred it up. The layers were separated and the aqueous layer was subjected to extraction with EtOAc (50 ml). The combined organic layers are washed with saline, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-80% EtOAc/hexane), having the desired compound (0,232 g, yield 45%, mixture of regioisomers 2:1) and ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,260 g, yield 48%, mixture of regioisomers 5:2). Mass spectroscopy (ESI/CI): calc. mass for C13H23ClN4O5S, 454,1; received m/z: 455,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,90 (l,J=0.6 Hz, 1H), 8,20 (l,J=0.6 Hz, 1H), 8,13 (s, 1H), 7,74 (s, 1H), 6,25-6,16 (m, 2H), 4,37 (kV,J=7,1 Hz, 2H), 3,68-3,62 (m, 2H), 3.46 in-to 3.41 (m, 2H), 3.27 to (s, 3H), 3,26-3,13 (m, 1H), 2,94-and 2.83 (m, 1H), 1.39 in (t,J=7,1 Hz, 3H), 1.27mm (t,J=7,4 Hz, 3H).

Stage C: ethyl ester of 1-(5-chloro-6-econsulting-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,191 g, 0,420 mmol) in ethanol (2 ml) was added 4M solution of HCl in dioxane (2 ml). The reaction mixture was stirred at 23°C for 2 hours the precipitate was collected and washed etilovym ether, having obtained the desired compound (0,103 g, yield 67%). Mass spectroscopy (ESI/CI): calc. mass for C15H15ClN4O3S, 366,1; received m/z: 367,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 9,02 (l,J=0.6 Hz, 1H), 8,40 (l,J=0.6 Hz, 1H), 7,87 (s, 1H), 7,80 (s, 1H), 4,30 (kV,J=7,1 Hz, 2H), 3,17 (DQC,J=14,6, 7,3 Hz, 1H), 2,84 (DQC,J=14,6, 7,4 Hz, 1H), 1,32 (t,J=7,1 Hz, 3H), of 1.08 (t,J=7,3 Hz, 3H).

Stage D: 1-(5-chloro-6-econsulting-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution containing ethyl ester 1-(5-chloro-6-econsulting-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (100 mg, 0,273 mmol), THF (1.0 ml) and water (0.33 ml)was added lithium hydroxide (31,3 mg, 0,818 mmol). The mixture was subjected to a short ultrasonic treatment and was stirred at 23°C for 56 h, the Solvent is boiled away, added water and the resulting solution was acidified to pH 1 with 1M aqueous HCl. Collected sediment and got the desired compound (79,1 mg, yield 85%). Mass spectroscopy (ESI/CI): calc. mass for C13H11ClN4O3S, 338,0; received m/z: 339,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,88 (ush s, 1H), 13,01 (ush s, 1H), to 8.94 (s, 1H), 8,40 (s, 1H), 8,03-of 7.55 (m, 2H), 3,23-3,11 (m, 1H), 2,89-2,78 (m, 1H), 1,08 (t,J=7,4 Hz, 3H).

Example 96: 1-(5-chloro-6-econsultancy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stud is I A: ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (EXAMPLE 95, the product of Stage A) (0,501 g to 1.14 mmol) and methanol (5.7 ml) was added a solution of reagent Oxone®/potassium peroxymonosulfate (1.47 g, is 2.40 mmol) in water (5.7 ml). The mixture was stirred for 44 h at 23°C. was Added EtOAc (50 ml) and water (30 ml) and the biphasic mixture stirred it up. The layers were separated and the aqueous layer was subjected to extraction with EtOAc (50 ml). The combined organic layers are washed with saline, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-80% EtOAc/hexane), having the desired connection is 0.260 g, yield 48%, mixture of regioisomers 5:2) and ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,232 g, yield 45%, mixture of regioisomers 2:1). Mass spectroscopy (ESI/CI): calc. mass for C13H23ClN4O6S, 470,1; received m/z: 471,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,91 (l,J=0.6 Hz, 1H), 8,53 (s, 1H), 8,20 (l,J=0.6 Hz, 1H), 7,82 (s, 1H), 6,21 (s, 2H), 4,37 (kV,J=7,1 Hz, 2H), 3.72 points-to 3.67 (m, 2H), 3,53-of 3.42 (m, 4H), 3,29 (s, 3H), 1.39 in (t,J=7,1 Hz, 3H), of 1.30 (t,J=7,4 Hz, 3H).

Stage B: 1-(5-chloro-6-econsultancy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carbon is the second acid. The desired compound was obtained in the same way as described in EXAMPLE 95, Stage C-D, ethyl ester 1-[1-(2-methoxyethoxymethyl)-6-ethylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. Mass spectroscopy (ESI/CI): calc. mass for C13H11ClN4O4S, 354,0; received m/z: 355,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,02 (ush s, 1H), 8,95 (l,J=0.6 Hz, 1H), at 8.36 (d,J=0.5 Hz, 1H), 8,18 (s, 1H), of 7.90 (ush s, 1H), 3,53 (K,J=7,4 Hz, 2H), 1.14 in (t,J=7,4 Hz, 3H).

Example 97: 1-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 95, except using 5-chloro-2-nitro-4-triptoreline instead of 4,5-dichloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H9F3N4O4S, 374,0; received m/z: 375,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,41 (ush s, 1H), 13,08 (ush s, 1H), 8,99 (s, 1H), 8,60-a 7.85 (m, 3H), of 3.33 (s, 3H).

Example 98: 1-(5-fluoro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in Example 95, except 4,5-debtor-2-nitrophenylamino instead of the 5-chloro-2-nitro-4-triptorelin on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H9FN4O4S, 324,0; received m/z: 325,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,03 (ush s, 1H), 13,04 (ush s, 1H), 8,95 (l,J=0,4 Hz, 1H), at 8.36 (s, 1H), 8,15-7,41 (m, 2H), 3,35 (s, 3H).

Example 99: 1-(5-chloro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in Example 95, except for the use of 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H9ClN4O4S, 340,0; received m/z: 341,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,10 (ush s, 1H), of 13.05 (ush s, 1H), 8,96 (s, 1H), of 8.37 (s, 1H), 8,32-7,63 (m, 2H), 3,40 (s, 3H).

Example 100: 1-(6-methanesulfonyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in Example 95, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H9F3N4O5S, 390,0; received m/z: 391,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,19 (ush s, 1H),13,07 (ush with, 1H), of 8.95 (s, 1H), scored 8.38 (s, 1H), 8,11 (ush s, 1H), 7,81 (ush s, 1H), 3.33 and (s, 3H).

Example 101: 1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: 4-chloro-5-isopropylphenyl-2-nitrophenylamino. To a solution of 4,5-dichloro-2-nitrophenylamino (3 g, 14.5 mmol) and DMF (73 ml) was added diisopropoxide sodium (4,95 g of 45.6 mmol). The solution was heated at 100°C for 4 days, cooled and poured into brine (300 ml). The aqueous layer was further extracted with EtOAc (3×200 ml)and the combined organic layers were washed with water (3×200 ml) and brine (1×200 ml), dried, filtered and concentrated under reduced pressure. The crude product was used in the next stage of the reaction without additional purification. Mass spectroscopy (ESI/CI): calc. mass for C9H11ClN2O2S, 246,0; received m/z: 247,0 [M+H]+.

Stage B: ethyl ester of 1-[5-chloro-1-(2-methoxyethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stages a-E, except using 4-chloro-5-isopropylphenyl-2-nitrophenylamino instead of 3-chloro-2-nitrophenylamino at the Stage A. have Received a mixture of regioisomers in a ratio of 1:1. Mass spectroscopy (ESI/CI): calc. mass for C20H25ClN4O4S, 452,1; is luceno m/z: 453,1 [M+H] +.1H NMR (600 MHz, CDCl3): 8,87-8,86 (m, 2H), 8,18 (l,J=0,4 Hz, 2H), 7,81 (s, 1H), to 7.77 (s, 1H), 7,72 (s, 1H), of 7.70 (s, 1H), 6,14 (s, 2H), 6,11 (s, 2H), 4,36 (K,J=7,1 Hz, 4H), 3,69-3,62 (m, 4H), 3,55-of 3.43 (m, 6H), and 3.31 (s, 3H), 3,30 (s, 3H), 1,38 (t,J=7,1 Hz, 6H), of 1.35 (DD,J=6,7, 2.0 Hz, 12H).

Stage C: ethyl ester of 1-[5-chloro-1-(2-methoxyethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[5-chloro-1-(2-methoxyethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,249 g, 0,550 mmol) and dichloromethane (2.8 ml) addedm-CPBA (0,259 g, 1.15 mmol, 77% by weight). The reaction mixture was stirred for 2.5 days at 23°C. was Added ethyl acetate (20 ml) and a solution of sodium thiosulfate (of 0.182 g, 1.15 mmol) in saturated at 80% aqueous solution of sodium carbonate (10 ml), after which the layers were intensively stirred for 10 min until the mixture became transparent. The layers were separated and the aqueous phase was extracted with EtOAc (2×30 ml). The combined organic layers are washed with saline (10 ml), dried and concentrated under reduced pressure. The residue was purified (KFH) (10-60% EtOAc/hexane) to obtain the desired compound (0,254 g, yield 95%) as a mixture of regioisomers 10:9. Mass spectroscopy (ESI/CI): calc. mass for C20H25ClN4O6S, Ozenmunaygas given KZT 484.1 ecological; the resulting m/z: 485,1 [M+H]+.1H NMR (600 MHz, CDCl3): 8,91 (l,J=0.5 Hz, 1H),8,51 (s, 1H), 8,20 (l,J=0.5 Hz, 1H), 7,81 (s, 1H), 6,21 (s, 2H), 4,37 (kV,J=7,1 Hz, 2H), 3,90-a 3.83 (m, 1H), 3.72 points-3,68 (m, 2H), 3,49 is-3.45 (m, 2H), 3,29 (s, 3H), 1.39 in (t,J=7,1 Hz, 3H), of 1.35 (d,J=6,8 Hz, 6H).

Stage D: ethyl ester of 1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[5-chloro-1-(2-methoxyethoxymethyl)-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,243 g, 0,501 mmol) in ethanol (1.8 ml) was added 4M solution of HCl in dioxane (1.8 ml). The reaction mixture was stirred at 23°C for 1.5 hours Added diethyl ether and collected sludge having the desired compound (0,183 g, yield 92%). Mass spectroscopy (ESI/CI): calc. mass for C16H17ClN4O4S, 369,1; received m/z: 397,1 [M+H]+.1H NMR (400 MHz, DMSO): 9,03 (l,J=0.6 Hz, 1H), 8,42 (l,J=0.6 Hz, 1H), 8,16 (s, 1H), of 7.90 (s, 1H), or 4.31 (kV,J=7,1 Hz, 2H), 3,89 is 3.76 (m, 1H), 1,33 (t,J=7,1 Hz, 3H), 1,21 (l,J=6,8 Hz, 6H).

Stage E: 1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution containing ethyl ester 1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,179 mg, 0,451 mmol), THF (1.7 ml) and water (0,55 ml), was added LiOH·H2O (56,8 mg, 1.35 mmol). The mixture was subjected to a short ultrasonic treatment and was stirred at 23°C for 56 h, the Solvent is boiled away, added water and the resulting Rast is the PR was acidified to pH 1 with 1M aqueous HCl. Collected sludge having the desired compound (0,146 g, yield 86%). Mass spectroscopy (ESI/CI): calc. mass for C14H13ClN4O4S, 368,0; received m/z: 369,0 [M+H]+.1H NMR (600 MHz, DMSO-d6, tautomeric broadening): 14,07 (s, 1H), 13,03 (s, 1H), 8,95 (l,J=0,4 Hz, 1H), at 8.36 (s, 1H), 8,16 (s, 1H), 8,09-to 7.64 (m, 1H), 3,88 is 3.76 (m, 1H), 1,22 (l,J=7.9 Hz, 6H).

Example 102: 1-[5-chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: 4-chloro-2-nitro-5-propylsulfonyl. To a mixture of 4,5-dichloro-2-nitrophenylamino (3.50 g, 16.9% mmol), potassium carbonate (4,67 g, 33.8 mmol) and DMF (85 ml) was added 1-propanethiol (2.30 ml, and 25.4 mmol). The reaction mixture is passed at a temperature of 90°C for 1.5 h and gave it to cool to a temperature of 23°C. the mixture is Then added to a mixture of saline ice (600 ml) and collected sludge having the desired compound (4.09 g, 98%).1H NMR (600 MHz, CDCl3): 8,11 (s, 1H); 6,46 (s, 1H); 6,10 (ush s, 2H); 2.91 in (t,J=7,3 Hz, 2H); 1.85 to to 1.76 (m, 2H); 1.12 in (t,J=7,4 Hz, 3H).

Stage B: 1-[5-chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 101, Stage B-E. Mass spectrometry (ESI/CI): calc. mass for C14H13ClN4O4S, 368,0; received m/z: 369,0 [M+H]+.1H NMR (600 MHz, DMSO-d6that is tomaree broadening): 14,05 (s, 1H); 13,02 (s, 1H); of 8.95 (s, 1H); at 8.36 (s, 1H); 8.30 to-8,08 (m, 1H); 8.07-a to 7.64 (m, 1H); 3,57-3,44 (m, 2H); 1,64-of 1.55 (m, 2H); 0,94 (t,J=7,4 Hz, 3H).

Example 103: 1-[6-(propane-2-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 102, except using 5-chloro-2-nitro-4-triptoreline instead of 4,5-dichloro-2-nitrophenylamino and 2-propandiol instead of 1-propanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O4S: 402,1; received m/z: 403,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,68-12,50 (m, 1H); 8,99 (s, 1H); 8,39 (s, 1H); 8,29 (s, 1H); 8,18 (s, 1H); 3,59-3,47 (m, 1H); 1,22 (l,J=6,8 Hz, 6H).

Example 104: 1-[6-(propane-1-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 102, except using 5-chloro-2-nitro-4-triptoreline instead of 4,5-dichloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O4S: 402,1; received m/z: 403,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,37 (s, 1H); 13,08 (s, 1H); 8,99 (s, 1H); 8,51-7,88 (m, 3H); 3,40-of 3.32 (m, 2H); 1,75-of 1.57 (m, 2H); of 0.95 (t,J=7,4 Hz, 3H).

Example 105: 1-6-(propane-2-sulfonyl)-5-triptoreline-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 102, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 4,5-dichloro-2-nitrophenylamino and 2-propandiol instead of 1-propanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O5S: 418,1; received m/z: 419,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,17 (s, 1H); 13,07 (s, 1H); of 8.95 (s, 1H); 8,40-8,35 (m, 1H); 8,08 (s, 1H); for 7.78 (s, 1H); 3,59 is-3.45 (m, 1H); 1,20 (l,J=6,8 Hz, 6H).

Example 106: 1-[6-(propane-1-sulfonyl)-5-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 102, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 4,5-dichloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C15H13F3N4O5S: 418,1; received m/z: 419,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,17 (s, 1H); 13,06 (s, 1H); of 8.95 (s, 1H); of 8.37 (s, 1H); of 8.09 (s, 1H); for 7.78 (s, 1H); 3,44-to 3.34 (m, 2H); 1,67-is 1.51 (m, 2H); 0,93 (t,J=7,4 Hz, 3H).

Example 107: 1-(5-benzosulfimide-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 82, ethyl ester 1-[6-chloro-5-(4-chlorophenylsulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product from Example 61). Mass spectroscopy (ESI/CI): calc. mass for C17H10Cl2N4O3S: 420,0; received m/z: 421,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,94 (ush s, 1H); of 13.05 (ush s, 1H); 8,93 (s, 1H); 8.34 per (s, 1H); 8,06 (ush s, 1H); 7,78 (ush s, 1H); 7,76 (l,J=8.6 Hz, 2H); 7,65-7,58 (m, 2H). The enantiomers were separated on columns for preparative chromatography supercritical fluid Kromasil®DMB 250×21,2 mm (length×internal). dia.) at 40°C, using an 8.5 ml/min MeOH with the addition of 0.2% Diisopropylamine and 34 g/min CO2with UV detection at a wavelength of 214 nm. Two enantiomers were identified as relevant diisopropylamino salts. Mass spectroscopy (ESI/CI): calc. mass for C17H10Cl2N4O3S: 420,0; received m/z: 421,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,56 (s, 1H); a 7.85 (s, 1H); 7,71 (s, 1H); 7,70-7,66 (m, 2H); 7,60-7,56 (m, 2H); 7,39 (s, 1H); 1,11 (l,J=6,4 Hz, 12H).

Example 108: 1-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-methylsulfinyl-5-trifluoromethyl-1H-benzoimidazol the l-2-yl]-1 H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-[1-(2-methoxyethoxymethyl)-6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product of EXAMPLE 71, the product of Stage (B) (0,300 g, 0,654 mmol) and methanol (3.3 ml) was added a solution of reagent OXONE®/peroxymonosulfate potassium (0,402 g, 0,654 mmol) in water (3.3 ml). The resulting mixture was stirred at 23°C for 4 h and Then added EtOAc (40 ml) and water (20 ml) and the biphasic mixture stirred it up. The layers were separated and the aqueous layer was subjected to extraction with EtOAc (30 ml). The combined organic layers were washed brine (15 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (20-100% EtOAc/hexane) and obtained the desired compound (0,249 g, yield 80%) as a mixture of regioisomers 10:9. Mass spectroscopy (ESI/CI): calc. mass for C19H21F3N4O5S: 474,1; received m/z: 475,1 [M+H]+.1H NMR (400 MHz, CDCl3): to 8.94 (d,J=0.6 Hz, 1H); 8,58 (s, 1H); by 8.22 (s, 1H); 8,08 (s, 1H); 6,34-6,23 (m, 2H); to 4.38 (kV,J=7,1 Hz, 2H); 3,74-3,66 (m, 2H); 3,51-to 3.41 (m, 2H); or 3.28 (s, 3H); of 2.81 (s, 3H); 1,40 (t,J=7,1 Hz, 3H).

Stage B: 1-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. m is a solution for C 13H9F3N4O3S, 358,0; received m/z: 359,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,25 (ush s, 1H); 13,06 (ush s, 1H); 8,98 (s, 1H); scored 8.38 (d,J=0.5 Hz, 1H); 8.34 per (ush s, 1H); 8,05 (ush s, 1H); and 2.79 (s, 3H).

The resulting enantiomers were identified as relevant Isopropylamine salts using preparative chiral chromatography in the supercritical fluid. Separation was carried out on a column Chiralpak®AD-H at 40°C at a flow rate of methanol with addition of 0.2% Isopropylamine to 8.6 ml/min and the flow rate of CO233 ml/min and the column pressure 3700 kPa (bar 37). The absolute stereochemical assignment for these compounds was not performed. Mass spectroscopy (ESI/CI): calc. mass for C13H9F3N4O3S, 358,0; received m/z: 359,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,78 (s, 1H); compared to 8.26-7,14 (ush s, 3H); is 8.16 (s, 1H); 8,04 (s, 1H); to 7.77 (s, 1H); 3,29 (m, 1H); 2,70 (s, 3H); 1,17 (l,J=6.5 Hz, 6H).

Example 109: 1-(6-bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 5-bromo-4-fluoro-2-nitrophenylamino. A mixture of 1-bromo-2,5-debtor-4-nitrobenzene (1.50 g, 6,30 mmol) and 7M ammonia solution in methanol (25 ml) was kept in a sealed tube at 60°C for 15 hours and Then the reaction mixture was transferred into a round bottom flask, rinse tube EtOAc. The mixture was concentrated and polucheniya product used in the next stage without further purification.

Stage B: 1-(6-bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 60, Stage B-H, except using 5-bromo-4-fluoro-2-nitrophenylamino instead of 4-chloro-2-nitro-5-m-tolylsulfochloride on Stage B and diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C11H6BrFN4O2, 324,0; received m/z: 325,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,92 (s, 1H); 8,88 (s, 1H); 8,29 (s, 1H); 7,84 (ush s, 1H); EUR 7.57 (ush s, 1H).

Example 110: 1-(4-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, Stage B-H, except for using 2-fluoro-6-nitrophenylamino instead of 4-chloro-2-nitro-5-m-tolylsulfochloride on Stage B and diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C11H7FN4O2, 246,1; received m/z: 247,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,91 (l,J=0.5 Hz, 1H); 8,28 (l,J=0,4 Hz, 1H); to 7.35 (d,J=8.0 Hz, 1H); 7,22 (TD,J=8,1 and 4.9 Hz, 1H); 7,06 (DD,J=11,0; 8,1 Hz, 1H).

Example 111: 1-(4,5-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired connection Policlinico to as described in EXAMPLE 60, Stage D-H, except 4,5-differentitate instead of 6-chloro-5-m-tamilselvan-1H-benzoimidazole on Stage B and diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C11H6F2N4O2: 264,1; received m/z: 265,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,76 (ush s, 1H); 12,97 (ush s, 1H); to 8.94 (s, 1H); 8,31 (l,J=0.6 Hz, 1H); 7,38-7,21 (m, 2H).

Example 112: 1-(4,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, Stage C-H, except using 3,5-differenza-1,2-diamine instead of 4-chloro-5-m-tolilsulfonil-1,2-diamine in Stage C and diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C11H6F2N4O2: 264,1; received m/z: 265,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): at 13.84 (ush s, 1H); 12,95 (ush s, 1H); 8,91 (s, 1H); 8.30 to (s, 1H); 7,19-7,11 (m, 2H).

Example 113: 1-(6-chloro-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The way A:

The desired compound was obtained in the same way as described in EXAMPLE 27, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 3-chloro-2-n is triphenylamine on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H6ClF3N4O3: 346,0; received m/z: 347,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,37 (s, 1H); 8,88 (s, 1H); 8,29 (s, 1H); 7,80 (s, 1H); 7,71 (s, 1H).

The way B:

Stage A: 6-chloro-5-triptoreline-1H-benzoimidazol. A mixture of 5-chloro-2-nitro-4-triphtalocyaninine (2.00 g, 7,80 mmol), dithionite sodium (7,06 g, 40,5 mmol), triethylorthoformate (23.1 ml, 210 mmol), DMF (23 ml) and acetic acid (4.0 ml) was kept in a sealed tube at 100°C for 15 h the Reaction mixture allowed to cool to a temperature of 23°C and divided it between EtOAc (100 ml) and saturated aqueous NaHCO3(100 ml). The organic layer was collected, the aqueous layer was extracted with EtOAc (2×80 ml). The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-15% MeOH/DCM) to give the desired compound (1,46 g, 78%). Mass spectroscopy (ESI/CI): calc. mass for C8H4ClF3N2O: 236,0; received m/z: 237,0 [M+H]+.1H NMR (500 MHz, CDCl3): 8,11 (s, 1H); 7,74 (s, 1H); to 7.64 (s, 1H).

Stage B: 1-(6-chloro-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 60, Stage D-H. Mass spectrometry (ESI/CI): calc. mass for C12H6ClF3N4O2: 346,0; received the m/z: 347,0 [M+H] +.1H NMR (600 MHz, DMSO-d6): of 8.90 (s, 1H); 8,32 (s, 1H); 7,83 (ush s, 1H); 7,74 (ush s, 1H).

The way C:

Stage A: 4-chloro-5-cryptomaterial-1,2-diamine. 5-chloro-2-nitro-4-cryptomaterial (180 g, 0.7 mol, 1.0 EQ.) dissolved in dry DMF (1 l) and then added the catalyst (5% Pt/C with a water content of 50.2% (4.0 g). The hydrogenation was carried out at hydrogen pressure 344,7 kPa (50 psi) at room temperature for 16 hours, HPLC analysis showed complete reaction. Mass spectroscopy [M+H]+: received 225,2. The resulting reaction mixture was used in the next stage without selection of products.

Stage B: 5-chloro-6-triptoreline-1,3-dehydrobenzperidol-2-it. From the obtained at the Stage And the mixture was filtered Pt/C catalyst and washed it dry DMF (250 ml). The filtrate was concentrated to 750 ml of solution was added activated molecular sieves type 3A (100 g) and the mixture was stirred at room temperature for 3 hours Then the molecular sieve was filtered and washed with dry DMF (250 ml). To the resulting dried solution in DMF at room temperature was added solid CDI (125 g, 0.77 mol, 1.1 equiv.) the mixture was slightly heated. The mixture was mixed at room temperature for 30 min and then added water (1.8 l). The resulting suspension was stirred at room temperature overnight. Precipitated precipitated solid white cotsarelis filtering, washed with water and thoroughly dried, obtaining the desired compound (154, 6mm g, 87%). Mass spectroscopy [M+H]+: received 253,1.

Stage C: 2,6-dichloro-5-triptoreline-1H-benzoimidazol. Carefully dried 5-chloro-6-triptoreline-1,3-dehydrobenzperidol-2-he (154, 6mm g, 0.61 mol, 1.0 EQ.) suspended in POCl3(450 ml, 8.0 EQ.). The reaction solution was heated at a temperature of phlegmy for 6 h and then cooled to room temperature. The solution slowly with constant stirring, poured into a mixture of crushed ice and water (~3 years). The resulting solution was neutralized with NaOH to pH=6,0. Precipitated precipitated solid was collected by filtration, washed with water and dried, obtaining the desired compound (159,97 g, 96%). The crude product was used in the following reaction without further purification.

These three stages were carried out in the mode of "one-pot", the intermediate products were not identified.

Stage D: 1-(6-chloro-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. 2,6-dichloro-5-triptoreline-1H-benzoimidazol (160 g, 0.59 mol, 1.0 EQ.) dissolved in dry DMF (1.5 l) and then added K2CO3(98 g, 0.71 mol, 1.2 EQ.) and chloride of dimethylsulphamoyl (85 g, 0.59 mol, 1.0 EQ.). The resulting reaction mixture was stirred at room temperature for 16 h, after receiving dimethylamide 2,6-dichloro-5-cryptomaterial the ol-1-sulfonic acid. Without allocation of dimethylamide 2,6-dichloro-5-cryptomaterial-1-sulfonic acid in the reaction mixture were added ethyl ester 1H-pyrazole-4-carboxylic acid (91 g of 0.65 mol, 1.1 EQ.) and K2CO3(98 g, 0.71 mol, 1.2 EQ.). The resulting reaction mixture was stirred at 70°C for 10 h and then cooled to room temperature, obtaining the ethyl ester of 1-(6-chloro-1-dimethylsulphamoyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. Without releasing products in the reaction mixture was added LiOH H2O (124 g, 2,95 mol, 5.0 EQ.) 2.5 l of water. The reaction mixture is passed at a temperature of 70°C for 6 h and then cooled to room temperature. Added concentrated HCl, bringing the pH to 4.0. Precipitated precipitated solid was collected by filtration, washed with water and dried. The obtained solid substance was recrystallize from hot EtOAc (~3 years). After cooling to room temperature and filtering received the pure desired compound in the form of solid white (109 g, 0.31 mol, 54% for stage 3). Mass spectroscopy (ESI/CI): calc. mass for C12H6ClF3N4O2: 346,0; received m/z: 347,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,79 (s, 1H); 13,06 (s, 1H); 8,91 (s, 1H); with 8.33 (s, 1H); 7,79 (ush d, 2H).

Example 114: 1-(1H-oil[2,3-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

p>

The desired compound was obtained in the same way as described in EXAMPLE 60, Stage C-H, except using 4-chloro-5-m-tolilsulfonil-1,2-diamine instead of naphthalene-2,3-diamine in Stage C. Mass spectroscopy (ESI/CI): calc. mass for C15H10N4O2: 278,1; received m/z: 279,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,12-12,83 (m, 1H); 9,00 (l,J=0.6 Hz, 1H); 8.34 per (e,J=0.6 Hz, 1H); of 8.06 (s, 2H); 8,01 (DD,J=6,3; and 3.3 Hz, 2H); 7,40 (DD,J=6,4; 3,2 Hz, 2H).

Example 115: 1-(3H-oil[1,2-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, Stage C-H, except using 4-chloro-5-m-tolilsulfonil-1,2-diamine instead of naphthalene-1,2-diamine in Stage C. Mass spectroscopy (ESI/CI): calc. mass for C15H10N4O2: 278,1; received m/z: 279,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,92 (s, 1H); 8,95 (l,J=0.6 Hz, 1H); 8,51 (l,J=8.0 Hz, 1H); 8,32 (l,J=0.5 Hz, 1H); 8,02 (l,J=8.0 Hz, 1H); 7,75 (kV,J=8,8 Hz, 2H); to 7.67-to 7.59 (m, 1H); 7,51 (DDD,J=8,2; 6,9; 1.2 Hz, 1H).

Example 116: 1-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[5-fluoro-1-(2-methoxy-ethoxymethyl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carbon is th acid. The desired compound was obtained in the same way as described in EXAMPLE 60, Stage B-F, except using 3-fluoro-2-methyl-6-nitrophenylamino instead of 4-chloro-2-nitro-5-m-tolylsulfochloride on Stage B and diisopropylamide lithium instead of utility on Stage E. Mass spectrometry (ESI/CI): calc. mass for C18H21FN4O4: 376,2; received m/z: 377,1 [M+H]+.

Stage B: 1-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester 1-[5-fluoro-1-(2-methoxy-ethoxymethyl)-4-methyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,131 g, 0,481 mmol), glacial acetic acid (4.8 ml) and 6M aqueous HCl solution (4.8 ml) was kept in a sealed tube at 100°C for 4 h Reational the mixture is cooled to a temperature of 23°C and then to 0°C. the precipitate was filtered and washed with cold water to obtain the desired compound (75,0 mg, 60%). Mass spectroscopy (ESI/CI): calc. mass for C12H9FN4O2: 260,1; received m/z: 261,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,88 (s, 1H); 8,29 (s, 1H); to 7.35 (DD,J=8,7; and 4.5 Hz, 1H); 7,06 (DD,J=10,4; 8,8 Hz, 1H); 2,46 (l,J=1.3 Hz, 3H).

Example 117: 1-(5-piperidine-1-yl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 2-nitro-5-piperidine-1-yl-4-cryptomaterial. Pieper is Dean (1.2 ml) was added to 5-chloro-2-nitro-4-cryptomaterial (0,757 g, to 2.94 mmol) and the resulting mixture was kept in a sealed tube at 100°C for 2 hours the mixture is Then cooled to a temperature of 23°C was added water (50 ml) and was extracted with EtOAc (3×80 ml). The combined organic layers were washed brine (50 ml), dried, filtered, and concentrated under reduced pressure, obtaining the desired compound (to 0.900 g of 99.9%). Mass spectroscopy (ESI/CI): calc. mass for C12H14F3N3O3: 305,1; received m/z: 306,1 [M+H]+.

Stage B: 5-piperidine-1-yl-6-triptoreline-1H-benzoimidazol. A mixture of 2-nitro-5-piperidine-1-yl-4-triphtalocyaninine (to 0.900 g, to 2.94 mmol), dithionite sodium (2.67 g, and 15.3 mmol), triethylorthoformate (8,72 ml of 79.6 mmol), DMF (8,56 ml) and acetic acid (1,45 ml) was kept in a sealed tube at 100°C for 15 h the Reaction mixture allowed to cool to a temperature of 23°C and divided it between EtOAc (80 ml) and saturated aqueous NaHCO3(80 ml). The organic layer was collected, the aqueous layer was extracted with EtOAc (2×80 ml). The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (0-15% MeOH/DCM) and obtained the desired compound (0,589 g, 71%). Mass spectroscopy (ESI/CI): calc. mass for C13H14F3N3O: 285,1; received m/z: 286,1 [M+H]+.

Stage C: ethyl ester of 1-[1-(2-methoxy shall oxymethyl)-5-piperidine-1-yl-6-triptoreline-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in a 1:1 mixture of regioisomers in the same way as described in EXAMPLE 60, Stage D-F, except for the use of diisopropylamide lithium instead of utility on Stage that is Mass spectroscopy (ESI/CI): calc. mass for C23H28F3N5O5: 511,2; received m/z: 512,2 [M+H]+.1H NMR (400 MHz, CDCl3): 8,82 (l,J=0.6 Hz, 1H); 8,80 (l,J=0.6 Hz, 1H); 8.17-a of 8.15 (m, 2H); 7,56-of 7.55 (m, 1H); of 7.48-7,46 (m, 1H); of 7.36 (s, 1H); 7,19 (s, 1H); between 6.08 (s, 2H); 6,07 (s, 2H); 4,39-4,32 (m, 4H); 3,67-3,61 (m, 4H); 3,48-of 3.42 (m, 4H); and 3.31 (s, 3H); 3,30 (s, 3H); 3,05-2,95 (m, 8H); 1,79 is 1.70 (m, 8H); 1,63-of 1.55 (m, 4H); 1,41 is 1.34 (m, 6H).

Stage D: 1-(5-piperidine-1-yl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-[1-(2-methoxyethoxymethyl)-5-piperidine-1-yl-6-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,300 g, 0,586 mmol), glacial acetic acid (5,9 ml) and 6M aqueous HCl solution (6.9 ml) was kept in a sealed tube at 100°C for 4.5 hours Reational the mixture is cooled to a temperature of 23°C and then to 0°C. Precipitated precipitated solid was filtered and washed with cold water, having the desired compound (60,0 mg, 26%). Mass spectroscopy (ESI/CI): calc. mass for C17H16F3N5O3: 395,1; received m/z: 396,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,84 (l,JJ=0.6 Hz, 1H); 7,47 (ush s, 1H); 7,21 (ush s, 1H); 2,98-2,89 (m, 4H); 1,71-to 1.59 (m, 4H); 1,58 to 1.47 (m, 2H).

Example 118: 1-(5-fluoro-6-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 117, except using 2-nitro-4,5-diferencia instead of 2-nitro-4-triptoreline-5-Chloroaniline at the Stage A. Mass spectroscopy (ESI/CI): calc. mass for C16H16FN5O2: 329,1; received m/z: 330,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,88 (s, 1H); of 8.28 (s, 1H); 7,99 (ush s, 1H); 7,56 (l,J=and 12.2 Hz, 1H); 3,39 (ush s, 4H); 1.93 and (ush s, 4H); 1,64 (ush m, 2H).

Example 119: 1-(6-ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 117, except using 2-nitro-4,5-diferencia instead of 2-nitro-4-triptoreline-5-Chloroaniline and ethoxide sodium (21 wt.% solution in ethanol) instead of piperidine in Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H11FN4O3: 290,1; received m/z: 291,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,63-12,41 (m, 2H); 8,82 (s, 1H); of 8.25 (s,J=0.5 Hz, 1H); to 7.61-6,97 (m, 2H); 4,13 (K,J=7,0 Hz, 2H); to 1.38 (t,J=6,9 Hz, 3H).

Example 120: 1-(5-phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid is the same.

Stage A: methyl ester of 2-oxo-2,3-dihydro-1H-benzoimidazol-5-carboxylic acid. To a solution of methyl ester of 3,4-diaminobenzoic acid (5,00 g, to 30.1 mmol) and THF (40 ml) at 0°C was added carbonyldiimidazole (7,32 g, 45,1 mmol). The resulting mixture was stirred for 16 h and then gave it to warm up to a temperature of 23°C. At 0°C was added 1M aqueous HCl solution (50 ml) and then water (70 ml), the mixture was stirred for 1 h Precipitated precipitated solid was filtered and dried under reduced pressure for 18 h, after receiving the desired compound, which was used in the next stage without further purification (of 5.45 g, 94%). Mass spectroscopy (ESI/CI): calc. mass for C9H8N2O3: USD 192.1; received m/z: 193,1 [M+H]+.1H NMR (400 MHz, CDCl3): br11.01 (s, 1H); 10,84 (s, 1H); 7,63 (DD,J=8,2; and 1.6 Hz, 1H); 7,47 (s, 1H); 7,02 (l,J=8,2 Hz, 1H); is 3.82 (s, 3H).

Stage B: methyl ester of 2-chloro-1H-benzoimidazol-5-carboxylic acid. Methyl ester 2-oxo-2,3-dihydro-1H-benzoimidazol-5-carboxylic acid (3.00 g, 15.6 mmol) was mixed with phosphorus oxychloride (30 ml) and the resulting mixture is passed at a temperature of 100°C for 48 hours the Mixture is cooled to a temperature of 23°C and concentrated under reduced pressure. The residue was cooled to 0°C and carefully added a cold saturated aqueous solution of NaHCO (60 ml). After stirring at 23°C for 15 min, the mixture was subjected to ultrasonic treatment and the resulting precipitate was filtered to obtain the desired compound (3.13 g, 95%)which was used in the next stage without further purification. Mass spectroscopy (ESI/CI): calc. mass for C9H7ClN2O2: 210,02; received m/z: 211,0 [M+H]+.

Stage C: methyl ether of 2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid. To a mixture of methyl ester of 2-chloro-1H-benzoimidazol-5-carboxylic acid (2.00 g, 9.50 mmol) and THF (17 ml) at 23°C was added DIPEA (2,46 ml of 14.3 mmol)and then 1-chloromethoxy-2-methoxyethane (1,30 ml of 11.4 mmol). After stirring for 18 h the reaction mixture was concentrated under reduced pressure. The residue was purified (KFH) (5-50% EtOAc/hexane) and got the desired compound in the form of a mixture of regioisomers (1,71 g, 60%). Mass spectroscopy (ESI/CI): calc. mass for C13H15ClN2O4: 298,1; received m/z: 299,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8.34 per-8,31 (m, 1H); 8,21-to 8.20 (m, 1H); 7,98 (DD,J=8,6; and 1.6 Hz, 1H); to $ 7.91 (DD,J=8,5; and 1.6 Hz, 1H); 7,83 (DD,J=8,6; 0.5 Hz, 1H); 7,74 (DD,J=8,5; 0.5 Hz, 1H); 5,78 (s, 1H); 5,73 (s, 1H); to 3.89 (d,J=6.3 Hz, 6H); 3,64-of 3.60 (m, 5H); 3,43-3,39 (m, 5H); 3,17 (l,J=2,6 Hz, 6H).

Stage D: 2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid. To a mixture of methyl ester of 2-chloro-1-(2-methoxyethoxy is methyl)-1 H-benzoimidazol-5-carboxylic acid (0,600 g, 0,200 mmol), THF (10 ml) and water (to 3.33 ml) was added LiOH·H2O (47.0 mg, a 1.96 mmol). The mixture was stirred for 18 h at 23°C. the Solvent is evaporated, was added water (5 ml) and the mixture was acidified with 1M HCl. Precipitated precipitated solid white color was filtered and dried, obtaining the desired compound (0,490 g, 86%). Mass spectroscopy (ESI/CI): calc. mass for C12H13ClN2O4: 284,1; received m/z: 285,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,93 (s, 2H); 8,30 (s, 1H); 8,18 (l,J=1.4 Hz, 1H); of 7.96 (DD,J=8,6; 1.5 Hz, 1H); of 7.90 (DD,J=8,5; and 1.6 Hz, 1H); 7,80 (l,J=8.6 Hz, 1H); 7,71 (l,J=8,5 Hz, 1H); 5,74 (l,J=17.5 Hz, 4H); 3,64-of 3.60 (m, 4H); 3.43 points-3,39 (m, 4H); 3,18 (l,J=0.6 Hz, 6H).

Stage E: phenylamide 2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid. To a solution of 2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid (0,235 g, 0,825 mmol) in acetonitrile (4 ml) was added HATU (0,408 g, 1.07 mmol). The resulting suspension was mixed at 23°C for 5 min, treated with DIPEA (0,428 ml, 2.48 mmol) and mixed for an additional 20 minutes and Then the reaction mixture was treated with aniline (90,0 μl, 0,990 mmol) and mixed for a further 2 h then the reaction mixture was diluted with water (10 ml) and was extracted with EtOAc (3×20 ml). The combined organic layers are washed with saline, dried, who was railtrail and concentrated under reduced pressure. The residue was purified (KFH) (5-70% EtOAc/hexane) and obtained the desired compound (0,265 g, 89%) as a mixture of regioisomers. Mass spectroscopy (ESI/CI): calc. mass for C18H18ClN3O3: 359,1; received m/z: 360,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 10,26 (l,J=7.5 Hz, 2H); 8,32 (DD,J=3,6; 1.5 Hz, 2H); 7,99 (DD,J=8,6; and 1.6 Hz,1H); 7,94 (DD,J=8,5; and 1.6 Hz, 1H); 7,87-7,73 (m, 6H); 7,41-to 7.32 (m, 4H); 7,16-7,02 (m, 2H); 5,75 (l,J=8.6 Hz, 4H); 3,67-3,61 (m, 4H); 3.43 points (DDD,J=6,3; 4,7; 3,1 Hz, 4H); 3,19 (l,J=1.5 Hz, 6H).

Stage F: 1-(5-phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stages E-g Mass spectroscopy (ESI/CI): calc. mass for C18H13N5O3: 347,1; received m/z: 348,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,73 (s, 1H); 12,93 (s, 1H); of 10.25 (s, 1H); to 8.94 (s, 1H); 8,32 (s, 1H); 8,24 (s, 1H); of 7.90 (d,J=8,4 Hz, 1H); 7,81 (l,J=8,1 Hz, 1H); 7,68 (s, 1H); of 7.36 (t,J=7.9 Hz, 2H); 7,10 (t,J=7.2 Hz, 1H).

Example 121: 1-(5-benzylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 120, except for the use of benzylamine instead of aniline in Stage E. Mass spectrometry (ESI/CI): calc. mass for C19H15N5O3: 361,1; received m/z: 362,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,63 (s, 1H); 12,93 (s, 1H); remaining 9.08 (s, 1H); of 8.92 (s, 1H); 8,31 (s, 1H); by 8.22 (s, 0,5H); with 8.05 (s, 0,5H); a 7.85 (s, 1H); of 7.70 (s, 0,5H); at 7.55 (s, 0,5H); 7,44-7,27 (m, 4H); to 7.25 (s, 1H); 4,51 (l,J=5,9 Hz, 2H).

Example 122: 1-[5-(morpholine-4-ylcarbonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 120, except morpholine-4-ylamine instead of aniline in Stage E. Mass spectrometry (ESI/CI): calc. mass for C16H16N6O4: 356,1; received m/z: 357,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 12,95 (s, 1H); of 9.56 (s, 1H); of 8.92 (s, 1H); 8,31 (s, 1H); 8,02 (s, 1H); 7,71 (l,J=8,4 Hz, 1H); to 7.59 (d,J=8.0 Hz, 1H); 3,68 (s, 6H); of 2.93 (s, 5H).

Example 123: 1-(5-benzoyloxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: [2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-yl]-methanol. To a mixture of methyl ester of 2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-carboxylic acid (Intermediate product from EXAMPLE 120, the product of Stage C) (0,500 g, 1,67 mmol) and THF (30 ml) at 0°C with stirring dropwise within 10 min added alumoweld lithium (2M solution in THF, 0,836 ml). The resulting mixture was stirred for 48 h, allowing her to warm up to a temperature of 23°C. Then the reaction mixture was cooled to 0°C, was added water (20 ml) and was acidified mixture is by using 1M HCl. The product was extracted with EtOAc (3×40 ml), the combined organic layers are washed with saline, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (5-80% EtOAc/hexane) and obtained the desired compound (0,356 g, 78%) as a mixture of regioisomers 1:1. Mass spectroscopy (ESI/CI): calc. mass for C12H15ClN2O3: 270,1; received m/z: 271,1 [M+H]+.1H (600 MHz, CDCl3): the 7.65 to 7.61 (m, 2H); 7,52 (d,J=0.7 Hz, 1H); 7,45 (l,J=8,3 Hz, 1H); to 7.35 (DD,J=8,3; 1.5 Hz, 1H); 7,27 (DD,J=8,2; 1.5 Hz, 1H); 5,63 (s, 2H); 5,62 (s, 2H); to 4.81 (s, 2H); of 4.77 (s, 2H); 3,64-of 3.60 (m, 4H); 3,49 (DD,J=5,4; 3,6 Hz, 4H); at 3.35 (s, 3H); to 3.34 (s, 3H); 2,59 (s, 1H); 2.50 each (s, 1H).

Stage B: 5-benzoyloxymethyl-2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol. To a solution of [2-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-5-yl]-methanol (100 mg, 0,370 mmol) and DMF (3 ml) at 0°C was added NaH (30.0 mg, 0,740 mmol, 60% suspension in mineral oil). The resulting mixture was stirred at 0°C for 1 h and then treated with benzylbromide (52,0 μl, 0,440 mmol). The resulting mixture was stirred for 16 hours Then added water (5 ml) and product was extracted with EtOAc (3×20 ml). The combined organic layers are washed with saline, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (5-50% EtOAc/hexane) and got the desired connection of the tell (100 mg, 75%). Mass spectroscopy (ESI/CI): calc. mass for C19H21ClN2O3: 360,1; received m/z: 361,1 [M+H]+

Stage C: obtain 1-(5-benzoyloxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, Stages E-g Mass spectroscopy (ESI/CI): calc. mass for C19H16N4O3: 348,1; received m/z: 349,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,31 (s, 1H); 12,93 (s, 1H); 8,88 (s, 1H); of 8.27 (s, 1H); a 7.62 (s, 1H); of 7.48 (s, 1H); 7,39-7,35 (m, 4H); 7,32-7,21 (m, 2H); with 4.64 (s, 2H); 4,55 (s, 2H).

Example 124: 1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 1-benzoyl-3-(2,6-dibromo-4-forfinal)-thiourea. A mixture of 2,6-dibromo-4-ftorhinolona (1,00 g, 3.72 mmol), isothiocyanate benzoyl (0,600 ml of 4.46 mmol), dimethylpyridin-4-ylamine (45,0 g, 0,370 mmol) and toluene (5 ml) was stirred at 23°C for 16 hours Precipitated precipitated solid was collected by filtration and washed with hexane, obtaining the desired compound (1,37 g, 85%). Mass spectroscopy (ESI/CI): calc. mass for C14H9Br2FN2OS: 429,9; received m/z: 430,9 [M+H]+.1H NMR (400 MHz, CD3OD-d4): 8,05-7,98 (m, 2H); 7,73-7,66 (m, 1H); 7,62-of 7.55 (m, 4H).

Stage B: (2,6-dibromo-4-forfinal)-thiourea. To a solution of 1-benzoyl-3-(2,6-dibromo-4-forfinal)-thiourea (1,37 is, 3,17 mmol) in MeOH (12 ml) at 0°C dropwise added a solution of sodium methoxide (5,4M in MeOH, 1,29 ml of 6.96 mmol). The resulting mixture was let warm up to a temperature of 23°C and was stirred for 16 h MeOH was concentrated under reduced pressure. The residue was dissolved in water, the resulting solution was cooled to 0°C and acidified to pH 4 with 1M HCl. Precipitated precipitated solid was collected by filtration and washed with hexane, having the desired compound (1.04 g, 99%). Mass spectroscopy (ESI/CI): calc. mass for C7H5Br2FN2S: 325,9; received m/z: 326,9 [M+H]+.1H NMR (400 MHz, CD3OD-d4): 8,05 shed 8.01 (m, 2H).

Stage C: 2,6-dibromo-4-perteneciente. A solution of (2,6-dibromo-4-forfinal)-thiourea (0,300 g, 0,920 mmol) in 1M aqueous KOH solution (of 7.23 ml) was heated to a temperature of 100°C and was added to the solution of three-hydrate of lead acetate (II) (0.400 g, 1.05 mmol) in water (2 ml). The resulting mixture is passed at a temperature of 100°C for another 10 min, watching the sediment. The mixture is then cooled to a temperature of 0°C and was filtered, obtaining a clear, colorless solution. The filtrate with acetic acid was acidified to pH 5. Precipitated precipitated solid was collected by filtration, obtaining the desired compound (0,170 g, 63%).1H NMR (400 MHz, DMSO-d6): 7,80 for 7.78 (m, 2H).

Stage D: ethyl ester of 1-[N-(2,6-dibromo-4-forfinal)-carbamimidoyl]-1H-feast of the ol-4-carboxylic acid. A mixture of 2,6-dibromo-4-perteneciente (0.167 g, 0,570 mmol), aripirazole-4-carboxylate (80.0 mg, 0,570 mmol), 4M HCl solution in dioxane (0,156 ml, 0,630 mmol) and 1,4-dioxane (2 ml) was heated at a temperature of phlegmy within 2 h, which resulted in a precipitate. The mixture is allowed to cool to a temperature of 23°C. To the mixture was added Et2O (10 ml). Precipitated precipitated solid was collected by filtration, washed Et2O and dried, obtaining the desired compound (0,134 g, 50%) in the form of cleaners containing hydrochloride salt. Mass spectroscopy (ESI/CI): calc. mass for C13H11Br2FN4O2: 431,9; received m/z: 432,9 [M+H]+.1H NMR (400 MHz, DMSO-d6): to 8.20 (s, 1H); the 7.43 (s, 1H); 6,82 (l,J=7.9 Hz, 2H); 3,56 (K,J=7,1 Hz, 2H); 2,85 (s, 3H); 0,57 (t,J=7,1 Hz, 3H).

Stage E: ethyl ester of 1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester 1-[N-(2,6-dibromo-4-forfinal)-carbamimidoyl]-1H-pyrazole-4-carboxylic acid (0,134 g, 0,290 mmol), CuI (6,00 mg, 0,0290 mmol), Cs2CO3(0,464 g of 1.43 mmol) and DMF (2 ml) was passed at a temperature of 80°C for 1 h the mixture is Then cooled to a temperature of 23°C, diluted EtOAc (3 ml) and was filtered through Celite®that washed EtOAc. The obtained filtrate was washed 1M aqueous solution of HCl, then with water, dried (MgSO4), filtered, and concentrated under reduced pressure. Then added dihl rmean and loose precipitated solid was collected by filtration, having obtained the desired compound (17,0 mg, 17%). Mass spectroscopy (ESI/CI): calc. mass for C13H10BrFN4O2: 353,2; received m/z: 354,2 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,86 (s, 1H); of 8.95 (s, 1H); at 8.36 (s, 1H); 7,45 (DD,J=9,6; and 2.3 Hz, 1H); to 7.32 (s, 1H); 4,30 (K,J=7,1 Hz, 2H); of 1.33 (t,J=7,1 Hz, 3H).

Stage F: 1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester of 1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (16.0 mg, 45,0 mmol), LiOH (10.0 mg, 0,230 mmol), THF (0.5 ml) and H2O (0.17 ml) was stirred at 23°C for 16 hours and Then THF was distilled under reduced pressure and added an aqueous solution of HCl. Precipitated precipitated solid was collected by filtration and washed with water, having the desired compound (10.0 mg, 67%). Mass spectroscopy (ESI/CI): calc. mass for C11H6BrFN4O2: 325,1; received m/z: of 326.0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,82 (s, 1H); 12,94 (s, 1H); 8,87 (s, 1H); 8.30 to (q,J=0.5 Hz, 1H); 7,45 (DD,J=9,6; and 2.3 Hz, 1H); to 7.32 (s, 1H).

Example 125: 1-(8H-imidazo[4',5':3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 124, Phase A-E, except using 4-bromobenzoate-5-ylamine instead of 2,6-dibromo-4-ftorhinolona on Stage A. Stage E were made SL is blowing changes:

Stage E: ethyl ester of 1-(8H-imidazo[4',5':3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylic acid. A mixture of cleaners containing hydrochloride salt of ethyl ester 1-[N-(4-bromobenzoate-5-yl)-carbamimidoyl]-1H-pyrazole-4-carboxylic acid (0,128 g, 0,297 mmol), 1,10-phenanthroline (10,7 mg, to 59.4 mmol), cesium carbonate (0,290 g, 0,891 mmol) and DME (5.5 ml) were placed in a resealable tube for microwave heating. The mixture was probabtionary dry nitrogen, and was added copper iodide (I) (5,70 mg, 29.7 mmol). The resulting mixture again was probabtionary nitrogen, the tube was tightly closed and kept at a temperature of 80°C for about 1.75 hours and Then the reaction mixture is divided between 1M aqueous solution of HCl (15 ml) and EtOAc (25 ml). The aqueous layer was further extracted with EtOAc (2×20 ml)and the combined organic layers are washed with saline (10 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-60% EtOAc/hexane, dry load), purified fractions were concentrated and the obtained residue was washed with diethyl ether, obtaining the desired compound (19.5 mg, yield 21%). Mass spectroscopy (ESI/CI): calc. mass for C14H11N5O2S: 313,1; received m/z: 314,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 13.75 (s, 1H); to 9.45 (s, 1H); 9,05 (s, 1H); of 8.37 (s, 1H); 8,00 (l,J=8.6 Hz, 1H); the 7.65 (d,J=6,0 Hz, 1H); or 4.31 (K,J=7,0 Hz, 2H); of 1.34 (t,J=7,1 Hz, 3H).

tadia F: 1-(8 H-imidazo[4',5':3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 124, step F. Mass spectrometry (ESI/CI): calc. mass for C12H7N5O2S: 285,0; received m/z: 286,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,94 (ush s, 1H); 9,46 (s, 1H); 8,98 (l,J=0,47 Hz, 1H); 8,31 (s, 1H); 8,00 (l,J=8.6 Hz, 1H); of 7.69 (d,J=8,5 Hz, 1H).

Example 126: 1-(5,6-bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 124, except for using 2-bromo-4,5-bis-triptoreline instead of 2,6-dibromo-4-ftorhinolona on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H6F6N4O2: 364,0; received m/z: 365,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 14,29 (s, 1H); 13,06 (s, 1H); 8,97 (l,J=0,4 Hz, 1H); of 8.37 (s, 1H); 8,15 (s, 2H).

Example 127: 1-(4,5,6-trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 2,3,4-trichloro-6-nitrovanillin. A mixture of 4,5-dichloro-2-nitrophenylamino (0,500 g, 2,42 mmol),Nchlorosuccinimide (0,403 g, to 3.02 mmol) and DMF (5 ml) was passed at a temperature of 100°C for 1 h, After cooling to a temperature of 23°C the resulting solution was poured into ice-cold water. Drawn in solid precipitate prophetic the STW yellow was collected by filtration and dissolved in dichloromethane. The organic phase is washed with water, dried (MgSO4), filtered, and concentrated, obtaining the desired compound (0,468 g, 81%).1H NMR (400 MHz, CDCl3): of 8.28 (s, 1H); 6,70 (s, 2H). For this connection has not been obtained mass spectrometric data.

Stage B: 4,5,6-trichloro-1H-benzoimidazol. A mixture of 2,3,4-trichloro-6-nitrophenylamino (0,250 g, 1.04 mmol), dithionite sodium (0,907 g, to 5.21 mmol), triethylorthoformate (4 ml), DMF (4 ml) and acetic acid (0.5 ml) was kept in a sealed tube at 100°C for 15 h the Reaction mixture allowed to cool to a temperature of 23°C and divided it between EtOAc and saturated aqueous NaHCO3. The organic layer was collected, the aqueous layer was extracted with EtOAc. The combined organic layers were dried (MgSO4), was filtered and concentrated, obtaining the desired compound (0,098 g, 43%). Mass spectroscopy (ESI/CI): calc. mass for C7H3Cl3N2: 219,9; received m/z: 221,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,16 (s, 1H); 8,43 (s, 1H); of 7.90 (s, 1H).

Stage C: 4,5,6-trichloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol. To a mixture of 4,5,6-trichloro-1H-benzoimidazole (0,098 g, 0,446 mmol) and THF (2.5 ml) at 23°C was added DIPEA (0,155 ml, 0,892 mmol) and then 1-chloromethoxy-2-methoxyethane (0,057 ml, 0.49 mmol). The resulting mixture was stirred for 18 h and then added EtOAc. The organic layer is washed with a saturated aqueous solution of NaHCO 3. The aqueous layer was further extracted with EtOAc. The organic layer was dried over MgSO4that was filtered and concentrated under reduced pressure. The residue was purified (KFH) and got the desired compound in the form of a mixture of regioisomers (0,084 g, 61%). Mass spectroscopy (ESI/CI): calc. mass for C11H11Cl3N2O2: 308,0; received m/z: 309,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,59 (s, 1H); 8,58 (s, 1H); of 8.09 (s, 1H); 8,04 (l,J=8,5 Hz, 1H); of 5.84 (s, 2H); 5,71 (s, 2H); 3,59 is 3.57 (m, 2H); 3,56-of 3.53 (m, 2H); 3.42 points-to 3.38 (m, 4H); 3,18 (s, 3H); 3,17 (s, 3H).

Stage D: 2,4,5,6-tetrachloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol. A solution of 4,5,6-trichloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazole (0,388 g of 1.26 mmol) and THF (6 ml) cooled to a temperature of -78°C in a bath of acetone and dry ice. Dropwise added diisopropylamide lithium (a 1.0 M solution in THF, 2,52 ml, 2,52 mmol) and the resulting mixture was stirred at -78°C for 1 h and Then added a solution ofNchlorosuccinimide (0,336 g, 2,52 mmol) in THF (2 ml). The resulting reaction mixture allowed to warm up to a temperature of 23°C and stirred for 2 hours Then the mixture was added saturated aqueous solution of NH4Cl and the crude product is extracted with EtOAc. The combined organic layers were dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) and got the desired compound in the form of a mixture is regioisomers (0,267 g, 62%). Mass spectroscopy (ESI/CI): calc. mass for C11H10Cl4N2O2: 342,0; received m/z: 343,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,18 (s, 1H); 8,03 (s, 1H); 5,88 (l,J=5.8 Hz, 2H); 5,71 (s, 2H); 3,71-3,66 (m, 2H); 3,64-3,61 (m, 2H); 3,44-to 3.38 (m, 4H); 3,17 (t,J=1.7 Hz, 6H).

Stage E: ethyl ester of 1-[4,5,6-trichloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of 2,4,5,6-tetrachloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazole (0,275 g, 0.80 mmol), Cs2CO3(0,524 g of 1.61 mmol), ethyl ester 1H-pyrazole-4-carboxylic acid (0.124 g, 0.89 mmol) and DMF (4 ml) was passed at a temperature of 80°C for 2 hours the mixture was cooled to a temperature of 23°C was added EtOAc and washed mixture of saline solution. The organic layer was dried (MgSO4), was filtered and was concentrated under reduced pressure. The residue was purified (KFH) and got the desired compound in the form of a mixture of regioisomers (0,166 g, 46%). Mass spectroscopy (ESI/CI): calc. mass for C17H17Cl3N4O4: 446,0; received m/z: 447,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 9,01-8,97 (m, 2H); 8,40 (t,J=2.3 Hz, 1H); of 8.37 (s, 1H); 8,21 (s, 1H); 8,13 (s, 1H); 6,09 (s, 2H); 6,01 (s, 2H); 4,30 (qud,J=7,1; 2,9 Hz, 8H); to 3.58-3,51 (m, 2H); 3,44 (l,J=4,9 Hz, 2H); 3,11 (s, 3H); is 3.08 (s, 3H); 1.32 to (TT,J=7,1; 1,7 Hz, 6H).

Stage F: 1-(4,5,6-trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl Avira-[4,5,6-trichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,166 g, 0,372 mmol) in acetic acid (6 ml) under stirring was added 6 M aqueous solution of hydrochloric acid (6 ml). The reaction mixture was heated at 100°C for 18 h, then was cooled to 23°C. the Precipitated precipitated solid is collected, obtaining the desired compound in the form of cleaners containing hydrochloride salt (0,91 g, yield 74%). Mass spectroscopy (ESI/CI): calc. mass for C11H5Cl3N4O2: 330,0; received m/z: 331,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 8.92 (s, 1H); 8.34 per (s, 1H); 7,74 (s, 1H).

Example 128: 1-(4-bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester 1-[4-bromo-5,6-dichloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 127, Phase A-E, exceptN-bromosuccinimide instead ofNchlorosuccinimide on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H17BrCl2N4O4: 490,0; received m/z: 491,0 [M+H]+.

Stage B: ethyl ester of 1-(4-bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester 1-[4-bromo-5,6-dichloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,132 g, 0.27 mmol) and EtOH (2 ml) was added 4 M HCl in dioxane (2 ml). The mixture peremeci the Ali for 18 h at 23°C. Precipitated precipitated solid white collected by filtration and washed EtOH, having the desired compound (0,088 g, 81%). Mass spectroscopy (ESI/CI): calc. mass for C13H9BrCl2N4O4: 402,9; received m/z: 403,9 [M+H]+.1H NMR (500 MHz, DMSO-d6): 14,22-13,94 (m, 1H); 8,98 (s, 1H); to 8.40 (s, 1H); 7,74 (s, 1H); 4,30 (K,J=7,1 Hz, 2H); of 1.33 (t,J=7,1 Hz, 3H).

Stage C: 1-(4-bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a mixture of ethyl ester of 1-(4-bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (0,088 g, 0.22 mmol), THF (1 ml) and water (0.33 ml) was added LiOH·H2O (0,046 g of 1.09 mmol) and the resulting mixture was stirred at 23°C for 18 hours the Solvent is evaporated, was added water (3 ml) and the mixture was acidified with 1M HCl. Precipitated precipitated solid white color was filtered and dried under reduced pressure, obtaining the desired compound (0,068 g, 83%). Mass spectroscopy (ESI/CI): calc. mass for C11H5BrCl2N4O2: 374,9; received m/z: 375,9 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,89 (s, 1H); 8,32 (s, 1H); 7,74 (s, 1H).

Example 129: 1-(6-fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A:N-(3-fluoro-4-triptoreline)-ndimethylacetamide. To a mixture of 3-fluoro-4-triptoreline (16,9 g of 92.6 mmol),N,N-dimethyl-4-am is nephridia (1.13 g, 9,26 mmol) and toluene (230 ml) was added acetic anhydride (13.1 ml, 0,139 mol). The resulting mixture was heated at a temperature of phlegmy for 3 h and then stirred at 23°C for 16 hours Then the reaction mixture was concentrated and dissolved obtained crude product in EtOAc (100 ml). The organic layer was washed with water (40 ml) and then brine Rasbora (40 ml), dried, filtered and concentrated under reduced pressure. Obtained in the form of a solid crude product is raked from a mixture of DCM/hexane, having the desired compound (16.5 g, yield 81%). Mass spectroscopy (ESI/CI): calc. mass for C9H7F4NO: to 221.1; received m/z: 222,0 [M+H]+.1H NMR (400 MHz, CDCl3): to 7.68 (d,J=12,5 Hz, 1H); 7,52 (t,J=8,3 Hz, 1H); 7,45 (ush s, 1H); 7,19 (l,J=8.5 Hz, 1H); 2,22 (s, 3H).

Stage B:N-(5-fluoro-2-nitro-4-triptoreline)-ndimethylacetamide. To a solution ofN-(3-fluoro-4-triptoreline)-ndimethylacetamide (0,663 g, 3.00 mmol) in sulfuric acid (3 ml) at 0°C under vigorous stirring dropwise added a solution of potassium nitrate (0,607 g, 6,00 mmol) in concentrated sulfuric acid (3 ml). The resulting mixture was stirred at 0°C for 1 h and then under stirring slowly pietravalle in a mixture of water with ice. Precipitated precipitated solid is collected and driedin vacuoreceiving the desired compound (0,648 g, yield 81%) in the form of edinstvennoj is regioisomer. For this connection has not been obtained mass spectrometric data.1H NMR (600 MHz, CDCl3): 10,67 (ush s, 1H); 8,86 (l,J=12.9 Hz, 1H); to 8.57 (d,J=7.2 Hz, 1H); to 2.35 (s, 3H).

Stage C: 5-fluoro-2-nitro-4-triptorelin. SuspensionN-(5-fluoro-2-nitro-4-triptoreline)-ndimethylacetamide (17.8 g, 67,0 mmol) in aqueous HCl (3M, 400 ml) was heated at a temperature of phlegmy for 3 hours, the resulting suspension was cooled to 0°C and NaHCO3brought to pH 8. Precipitated precipitated solid is collected, obtaining the desired compound (13,7 g, yield 91%). For this connection has not been obtained mass spectrometric data.1H NMR (400 MHz, CDCl3): 8,48 (l,J=7,3 Hz, 1H); 6.75 in-6,18 (m, 3H).

Stage D: 1-(6-fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 71, Stage B-C. Mass spectroscopy (ESI/CI): calc. mass for C12H6F4N4O2: 314,0; received m/z: 315,1 [M+H]+.1H NMR (400 MHz, CD3OD, tautomeric broadening): 8,93 (s, 1H); to 8.20 (s, 1H); 7,87 (ush s, 1H); 7,49 (ush s, 1H).

Example 130: 1-(6-chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-5-ethylamino-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of cereals is s of 4 Å molecular sieves (1.2 g) and ethyl ester of 1-[5-amino-6-chloro-1-(2-methoxyethoxymethyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of Example 41, the product of Stage A) (0,300 g, 0,762 mmol) and ethanol (3 ml) were placed in a resealable tube for microwave heating and the temperature is 0°C was added acetaldehyde (0,500 ml, 8,91 mmol). The tube is hermetically closed and gave the reaction mixture to warm up to a temperature of 23°C for 16 hours the mixture stood at 60°C for 1 h From the resulting solution by filtration removed the molecular sieve and the filtrate concentrated under reduced pressure. To the residue was added triacetoxyborohydride sodium (0,242 g to 1.14 mmol), THF (3 ml) and glacial acetic acid (0.04 ml) and stirred the resulting suspension at a temperature of 23°C for a period of 7.5 hours Then the reaction mixture was concentrated and divided the residue between saturated aqueous sodium bicarbonate and EtOAc (35 ml). The aqueous layer was extracted further with EtOAc (2×35 ml)and the combined organic layers were washed brine (15 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-45% EtOAc/hexane) and obtained the desired compound (0,169 g, crude yield 47%). The compound obtained was used in the subsequent reactions without further purification. Mass spectroscopy (ESI/CI): calc. mass for C19H24ClN5O4: UAH 421,2; p the received m/z: 422,1 [M+H] +.

Stage B: 1-(6-chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C13H12ClN5O2: 305,1; received m/z: 306,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 8,84 (s, 1H); of 8.27 (s, 1H); of 7.60 (s, 1H); 7.03 is (ush s, 1H); 3,22 (kV,J=6,9 Hz, 2H); 1,25 (t,J=7,1 Hz, 3H).

Example 131: 1-(6-chloro-5-propylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-5-ethylamino-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[5-amino-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product of Example 41, the product of Stage A) (0,300 g, 0,762 mmol) and Propionaldehyde (61,0 μl, 0,838 mmol) in THF (3 ml) was added triacetoxyborohydride sodium (0,226 g, 1.07 mmol) and then acetic acid (40,9 μl, 0,762 mmol). The resulting mixture was stirred at 23°C for 22 h and Then added molecular sieves (4 Å, 1.2 g) and withstood the reaction mixture at a temperature of 40-50°C for 24 h for the next 48 hours the mixture was added in two portions of Propionaldehyde and triacetoxyborohydride sodium. Then implement the operating mixture repaid saturated aqueous sodium bicarbonate (10 ml). The aqueous layer was extracted with EtOAc (3×35 ml), the combined organic layers were washed brine (25 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-45% EtOAc/hexane) and obtained the desired compound (0,178 g, yield 54%) as a mixture of regioisomers 1:1.1H NMR (400 MHz, CDCl3): 8,83 (s, 1H); 8,76 (s, 1H); 8,15 (s, 2H); 7,63 (s, 1H); at 7.55 (s, 1H); 6,94 (s, 1H); 6,76 (s, 1H); 6,03 (s, 4H); 4,42 (ush s, 1H); 4,35 (kV,J=7,1 Hz, 4H); 4,27 (ush s, 1H); 3,65-3,59 (m, 4H); 3.49 points-to 3.41 (m, 4H); to 3.33 (s, 3H); of 3.32 (s, 3H); 3,23-of 3.12 (m, 4H); 1,82 was 1.69 (m, 4H); to 1.37 (t,J=7,1 Hz, 6H); 1,11-a 1.01 (m, 6H).

Stage B: 1-(6-chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C14H14ClN5O2: 319,1; received m/z: 320,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 12,91 (ush s, 1H); 8,80 (s, 1H); 8,24 (s, 1H); 7,51 (ush s, 1H); of 6.71 (ush s, 1H); 3,10 (t,J=7,1 Hz, 2H); 1,69-to 1.59 (m, 2H); to 0.96 (t,J=7,4 Hz, 3H).

Example 132: 1-(5-benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[5-(benzylideneamino)-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. A mixture of benzaldehyde (93,0 mg, 0,876 mmol), ethyl ester 1-[5-amino-6-chloro-1-(2-marks ethoxymethyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of Example 41, the product of Stage A) (0,300 g, 0,762 mmol), THF (3 ml) and 4 Å molecular sieves (0.910 g) was stirred at 23°C for 18 h Then the mixture was added triacetoxyborohydride sodium (0,242 g to 1.14 mmol) and continued stirring for another 4 days. The reaction mixture is repaid saturated aqueous sodium bicarbonate (15 ml) and stirred with dichloromethane (25 ml). The resulting mixture was filtered and separated layers. The aqueous layer was extracted with dichloromethane (2×25 ml)and the combined organic layers are washed with saline (20 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-45% EtOAc/hexane) and obtained the desired compound (in 0.288 g, yield 78%) as a mixture of regioisomers 4:3. Received the connection was not stable enough to gain mass spectrometric data.1H NMR (400 MHz, CDCl3): 8,87 (s, 1H); 8,48 (s, 1H); 8,19 (s, 1H); 8,03-7,94 (m, 2H); 7,73 (s, 1H); 7,58-of 7.48 (m, 3H); 7,39 (s, 1H); 6,12 (s, 2H); 4,36 (kV,J=7,1 Hz, 2H); 3,7-3,6 (m, 2H); 3,5-3,4 (m, 2H); of 3.32 (s, 3H); 1.39 in (t,J=7,1 Hz, 3H).

Stage B: ethyl ester of 1-[5-benzylamino-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a slurry of ethyl ester 1-[5-(benzylideneamino)-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-and the]-1 H-pyrazole-4-carboxylic acid (0,177 g, 0,366 mmol) in ethanol (7 ml) at 0°C was added sodium borohydride (to 41.6 mg, 1.10 mmol). The yellow slurry was warming to a temperature of 23°C for 24 h, the Reaction mixture was concentrated and added to the residue saturated aqueous sodium bicarbonate solution (25 ml). The reaction mixture was extracted with EtOAc (3×25 ml)and the combined organic layers are washed with saline (20 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-45% EtOAc/hexane) and got the desired compound in the form of a mixture of regioisomers 6:5 (0,144 g, yield 81%). Mass spectroscopy (ESI/CI): calc. mass for C24H26ClN5O4: 483,2; received m/z: 484,2 [M+H]+.1H NMR (400 MHz, CDCl3): 8,79 (s, 1H); to 8.14 (s, 1H); 7,58 (s, 1H); 7,43-7,27 (m, 5H); 6,92 (s, 1H); 6,03 (s, 2H); 4.75 in (t,J=6,0 Hz, 1H); 4,49-4,43 (m, 2H); 4,34 (kV,J=7.2 Hz, 2H); 3,65-3,61 (m, 2H); 3,47-3,44 (m, 2H); of 3.32 (s, 1H); 1,36 (t,J=7,1 Hz, 3H).

Stage C: 1-(5-benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C18H14ClN5O2: 367,1; received m/z: 368,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 12,87 (ush s, 1H); 8,76 (l,J=0.5 Hz, 1H); to 8.20 (s, 1H); 7,52 (ush s, 1H); 7,40-7,31 (m, 4H); 7,25-7,20 (m, 1H);6,56 (ush with, 1H); 6,00 (ush s, 1H); of 4.44 (s, 2H).

Example 133: 1-(6-chloro-5-phenylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-phenylamino-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. In kiln dried flask was placed ethyl ester 1-[5-amino-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of Example 41, the product of Stage A) (0,100 g, 0,254 mmol), brobinson (43,8 mg, 0,279 mmol), Pd(dba)2(1.50 mg, of 2.50 mmol), Q-Phos (3,60 mg, 5,10 µmol) andtert-piperonyl sodium (36,6 mg, 0,381 mmol). The flask was probabtionary N2. To the mixture was added dry toluene (0.5 ml) and the resulting slurry was subjected to a short ultrasonic treatment. The resulting mixture is passed at a temperature of 50°C for 18 h Then the reaction mixture was diluted with dichloromethane and filtered through a layer of Celite®. Remaining on the filter cake washed EtOAc and the filtrate concentrated under reduced pressure. The residue was purified (KFH) (10-45% EtOAc/hexane) and obtained the desired compound (7,1 mg, yield 6%), which was used in the next stage without further purification. Mass spectroscopy (ESI/CI): calc. mass for C23H24ClN5O4: 469,2; received m/z: 470,1 [M+H]+.

Stage B: 1-(6-chloro-5-phenylamino-1H-benzo idazole-2-yl)-1 H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C17H12ClN5O2: 353,1; received m/z: 354,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 12,94 (ush s, 1H); 8,86 (s, 1H); of 8.28 (s, 1H); 7,74-of 7.69 (m, 2H); 7,40 (s, 1H); 7.24 to to 7.18 (m, 2H); 6,95 (l,J=7.8 Hz, 2H); for 6.81 (t,J=7,3 Hz, 1H).

Example 134: 1-[6-chloro-5-(2-morpholine-4-ylethylamine)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(2-morpholine-4-ylethylamine)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a slurry of 4 Å molecular sieves (0.9 g), ethyl ester 1-[5-amino-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of Example 41, the product of Stage A) (0.187 g, 0.475 mmol), 1-hydroxy-2-morpholine-4-retensioned sodium (0,122 g, 0,523 mmol) and THF (2.5 ml) was added triethylamine (0,300 ml of 2.15 mmol). The resulting slurry was stirred at 23°C for 24 h and then added triacetoxyborohydride sodium (0,282 g of 1.33 mmol). The resulting reaction mixture was stirred for another 24 hours and Then added another portion of 1-hydroxy-2-morpholine-4-retensioned sodium (62,0 mg, 0,270 mmol) and has withstood the reaction zespri 23°C for another 24 hours The resulting mixture was diluted with EtOAc, filtered and washed with a saturated aqueous solution of NaHCO3. The aqueous layer was extracted further with EtOAc (2×30 ml). The combined organic layers are washed with saline, dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (EtOAc/hexane) and obtained the desired compound (30 mg, crude yield : 12%). The compound obtained was used in the subsequent reactions without further purification. Mass spectroscopy (ESI/CI): calc. mass for C23H31ClN6O5: 506,2; received m/z: 507,2 [M+H]+.

Stage B: 1-[6-chloro-5-(2-morpholine-4-ylethylamine)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C17H19ClN6O3: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (600 MHz, CD3OD-d4, tautomeric broadening): 8,77 (s, 1H); to 8.12 (s, 1H); 7,50 (ush s, 1H); 6,86 (ush s, 1H); 3,79-3,74 (m, 4H); 3,38 (t,J=6.3 Hz, 2H); 2,89-2,82 (ush m, 2H); 2,69 (ush s, 4H).

Example 135: 1-(6-chloro-5-cyclopropanemethylamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-5-cyclopropanemethylamine-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic what iSlate. To a solution of ethyl ester 1-[5-amino-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product of Example 41, the product of Stage A) (0,100 g, 0,254 mmol) in pyridine (1.5 ml) at 0°C with stirring dropwise added chloride cyclopropanesulfonyl (71,0 mg, 0,510 mmol). The resulting mixture was slowly warmed to a temperature of 23°C and maintained at this temperature for 42 hours and Then reational mixture repaid saturated aqueous sodium bicarbonate (10 ml) and was extracted with EtOAc (3×15 ml). The combined organic layers are washed with saline (10 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-55% EtOAc/hexane) and obtained the desired compound (96.0 mg, 76%) as a mixture of regioisomers 5:4. Mass spectroscopy (ESI/CI): calc. mass for C20H24ClN5O6S: 497,1; received m/z: 498,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,83 (s, 1H); 8,19 (s, 1H); 8,03 (s, 1H); 7,71 (s, 1H); 6.73 x (s, 1H); 6,14 (s, 2H); or 4.31-to 4.28 (m, 2H); 3,71-to 3.64 (m, 2H); 3,51 is-3.45 (m, 2H); of 3.32 (s, 3H); 2,54 is 2.44 (m, 1H); 1,43-of 1.35 (m, 3H); 1,21-1,11 (m, 2H); 1,00 to 0.92 (m, 2H).

Stage B: obtain 1-(6-chloro-5-cyclopropanemethylamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 71, step C. Mass spectroscopy (ESI/CI): calc. mass for C14 H12ClN5O4S: 381,0; received m/z: 382,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,55 (ush s, 1H); 12,97 (ush s, 1H); 9,46 (ush s, 1H); 8,89 (s, 1H); 8,31 (s, 1H); 7,94 was 7.45 (m, 2H); 2,69 at 2.59 (m, 1H); 0,98-of 0.79 (m, 4H).

Example 136: 1-(6-chloro-5-methanesulfonamido-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 135 except for the use of chloride methanesulfonyl instead chloride cyclopropanesulfonyl on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C12H10ClN5O4: 355,0; received m/z: 356,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 9,48 (s, 1H); of 8.90 (s, 1H); 8,31 (s, 1H); 7,72 (s, 1H); to 7.61 (s, 1H); 3,01 (s, 3H).

Example 137: 1-(6-chloro-5-ethanolamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 135 except for the use of chloride acanalonia instead chloride cyclopropanesulfonyl on Stage In the spectrum of A.1H NMR was observed 5:4 mixture of tautomers. Mass spectroscopy (ESI/CI): calc. mass for C13H12ClN5O4S: 369,0; received m/z: 370,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,60-13,48 (m, 1H); 12,97 (ush s, 1H); 9,46 (s, 1H); 8,89 (s, 1H); 8,31 (s, 1H); a 7.85-7,52 (m, 2H); 3,18 totaling 3.04 (m, 2H); 1,35-1,20 (m, 3H).

the example 138: 1-(5-benzosulfimide-6-chloro-1 H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 135 except for the use of chloride benzosulfimide instead chloride cyclopropanesulfonyl on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H12ClN5O4S: 417,0; received m/z: 418,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): of 13.58-13,46 (m, 1H); 12,97 (ush s, 1H); 10,02-9,90 (m, 1H); 8,93-8,81 (m, 1H); 8,29 (s, 1H); 7,70-7,42 (m, 6H); 7,34 (s, 1H).

Example 139: 1-(5-acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[5-acetylamino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a suspension of ethyl ester 1-[5-amino-6-chloro-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (Intermediate product of Example 41, the product of Stage A) (0,300 g, 0,762 mmol) in THF (4 ml) at 0°C under stirring added diisopropylethylamine (0,330 ml, 1,90 mmol). Then, the resulting mixture was added acetylchloride (57,0 ál HDI, 0.800 mmol). After 3 h the reaction mixture was extinguished with water (10 ml) and was extracted with EtOAc (3×35 ml). The combined organic layers were washed brine (15 ml), dried, filtered and concentrated, propanganda pressure. The residue was purified (KFH) (5-65% EtOAc/hexane) and obtained the desired compound (0,270 g, 81%) as a mixture of regioisomers 2:1. Mass spectroscopy (ESI/CI): calc. mass for C19H22ClN5O5: 435,1; received m/z: 436,1 [M+H]+.1H NMR (400 MHz, CDCl3): 8,83 (s, 1H); 8,71 (s, 1H); 8,18 (s, 1H); 7,79 (ush s, 1H); 7,74 (s, 1H); 6,10 (s, 1H); 4,36 (kV,J=7,1 Hz, 2H); 3,66-3,62 (m, 2H); 3,48-of 3.43 (m, 2H); 3,29 (s, 3H); to 2.29 (s, 3H); to 1.38 (t,J=7,1 Hz, 3H).

Stage B: 1-(5-acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C13H10ClN5O3: 319,1; received m/z: 320,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 9,54 (s, 1H); 8,89 (s, 1H); to 8.94 (s, 1H); 8.30 to (s, 1H); of 7.82 (s, 1H); of 7.69 (s, 1H); 2,11 (s, 3H).

Example 140: 1-(6-chloro-5-propionamido-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 139 except use Propionaldehyde instead of acetylchloride on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H12ClN5O3: 333,1; received m/z: 334,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,48 (ush s, 1H); 12,96 (ush s, 1H); 9,41 (s, 1H); 8,88 (s, 1H); 8.30 to (s, 1H); 7,93-the 7.43 (m, 2H); 2,46 to 2.35 (m, 2H); 1,11 (t,J=7,6 Hz, 3H).

Example 141: 1-5-benzoylamine-6-chloro-1 H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 139 except using benzoyl chloride instead of acetylchloride on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H12ClN5O3: 381,1; received m/z: 382,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 12,96 (ush s, 1H); 10,10 (s, 1H); 8,93 (s, 1H); 8,32 (s, 1H); 8,06-of 8.00 (m, 2H); 7,78-7,72 (m, 2H); 7,65-7,51 (m, 3H).

Example 142: 1-[6-chloro-5-(2-morpholine-4-ylacetamide)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[5-(2-bromoacetamide)-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of diisopropylethylamine (0,86 ml of 4.95 mmol) and ethyl ester of 1-[5-amino-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of Example 41, the product of Stage A) (0,650 g of 1.65 mmol) and THF (8 ml) at 0°C was added bromide bromacetyl (0,244 ml of 2.81 mmol). The resulting mixture gave slowly heated to a temperature of 23°C was added to the second aliquot bromide bromacetyl (0,244 ml of 2.81 mmol) and has withstood the reaction mixture at a temperature of 23°C for another 25 minutes and Then the mixture was added water (20 ml) and the aqueous layer was extracted with EtOAc (2×75 ml). The combined organic layers were washed brine (25 ml), dried, filtered and concentrated under reduced pressure. The residue was purified (KFH) (10-45% EtOAc/hexane) and after trituration with EtOAc got the desired compound (0,361 g, yield 42%). In the spectrum of1H NMR was observed mixture of regioisomers 3:2. Mass spectroscopy (ESI/CI): calc. mass for C19H21BrClN5O5: 513,0; received m/z: 514,0 [M+H]+.1H NMR (400 MHz, CDCl3): 8,89 (s, 1H); 8,87 (ush s, 1H); 8,71 (s, 1H); 8,18 (s, 1H); of 7.70 (s, 1H); 6,13 (s, 2H); 4,36 (kV,J=7.2 Hz, 2 H); 4,13 (s, 2H); 3,68-3,62 (m, 2H); 3.49 points-of 3.43 (m, 2H); and 3.31 (s, 3H); to 1.38 (t,J=7,1 Hz, 3H).

Stage B: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(2-morpholine-4-ylacetamide)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a suspension of ethyl ester 1-[5-(2-bromoacetamide)-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (0,100 g, 0,194 mmol) in dichloromethane (1 ml) was added morpholine (51,0 μl, 0,580 mmol). The resulting mixture was stirred at 23°C for 50 min, divided between EtOAc (15 ml) and water (10 ml) and then was extracted aqueous layer with EtOAc (2×15 ml). The combined organic layers were washed brine (15 ml), dried, filtered and concentrated under reduced pressure, obtaining the desired compound (97 mg, yield 96%) as a mixture of regioisomers 3:1. Mass SPECT is oscope (ESI/CI): calc. mass for C23H29ClN6O6: 520,2; received m/z: 521,2 [M+H]+.1H NMR (400 MHz, CDCl3): 10,00 (s, 1H); 8,89 (s, 1H); cent to 8.85(s, 1H); 8,18 (s, 1H); 7,68 (s, 1H); 6,12 (s, 2H); 4,36 (K,J=7,1 Hz, 2H); a 3.87-of 3.80 (m, 4H); 3,67-of 3.60 (m, 2H); 3,48-of 3.42 (m, 2H); of 3.32 (s, 2H); 3.24 in (s, 3H); 2,73-to 2.67 (m, 4H); to 1.38 (t,J=7,1 Hz, 3H).

Stage C: 1-[6-chloro-5-(2-morpholine-4-ylacetamide)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27, the Stage F-G. Mass spectrometry (ESI/CI): calc. mass for C17H17ClN6O4: 404,1; received m/z: 405,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,46 (ush s, 1H); 12,95 (ush s, 1H); 10,04-9,86 (m, 1H); 8,88 (s, 1H); 8,46 (s, 1H); 8,29 (s, 1H); of 7.96-the 7.43 (m, 1H); to 3.73-the 3.65 (m, 4H); is 3.21 (s, 2H); 2,64-of 2.56 (m, 4H).

Example 143: 1-[6-chloro-5-(2-piperidine-1-ylacetamide)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 142, except using piperidine instead of the research Stage, and provided in the form of cleaners containing hydrochloride salt. Mass spectroscopy (ESI/CI): calc. mass for C18H19ClN6O3: 402,1; received m/z: 403,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,68 (ush s, 1H); 13,00 (ush s, 1H); of 10.47 (s, 1H); 10,02 (ush s, 1H); 8,91 (s, 1H); 8,32 (s, 1H); 7,89 to 7.62 (m, 2H); 4,32 is 4.13 (m, 2H); 3,60 is-3.45 (m, 2H); 3,21-to 3.02 (m,2H); 1,90-to 1.61 (m, 5H); of 1.50 and 1.33 (m, 1H).

Example 144: 1-{6-chloro-5-[2-(4-methylpiperazin-1-yl)-acetylamino]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 142, exceptN-methylpiperazine instead of the research on Phase C. the Desired compound was isolated in the form of cleaners containing hydrochloride salt. Mass spectroscopy (ESI/CI): calc. mass for C18H20ClN7O3: 417,1; received m/z: 418,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,53 (ush s, 1H); 12,98 (ush s, 1H); 10,67 (ush s, 1H); 9,77 (s, 1H); 8,89 (s, 1H); 8,33-8,23 (m, 2H); to 7.77 (ush s, 1H); 3,50-to 3.35 (m, 4H); 3,18-3,03 (m, 4H); 2,85-2,70 (m, 5H).

Example 145: 1-[6-chloro-5-(4-methoxyphenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for using 4-methoxyphenol instead of 3,4-dichlorophenol and 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H13ClN4O4: 384,1; received m/z: 385,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,23 (s, 2H); 8,86 (l,J=0.5 Hz, 1H); 8,28 (l,J=0.5 Hz, 1H); of 7.75 (s, 1H); 7,13 (s, 1H); to 6.95 (s, 4H); of 3.75 (s, 3H).

Example 146: 1-[6-chloro-5-(4-chloro-2-pertenece)-1H-benzoimidazol-2-and the]-1H-pyrazole-4-carboxylic acid.

The desired compound was prepared analogously to EXAMPLE 50, except for using 4-chloro-2-terfenol instead of 3,4-dichloro-2-phenol and 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H9Cl2FN4O3: 406,0; received m/z: 407,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,33 (s, 1H); 8,87 (s, 1H); 8,29 (s, 1H); 7,79 (s, 1H); the 7.65 (DD,J=10,9; 2,5 Hz, 1H); of 7.36 (s, 1H); 7.23 percent (DD,J=8,8; and 1.6 Hz, 1H); 6,91 (t,J=a 8.9 Hz, 1H).

Example 147: 1-[6-chloro-5-(4-triftormetilfosfinov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 50, except for using 4-cryptomaterial instead of 3,4-dichlorophenol and 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H10ClF3N4O4, 438,0; received m/z: 439,0 [M+H]+.1H NMR (mixture of tautomers, 500 MHz, DMSO-d6): 13,64 (s, 0,5H); of 13.58 (s, 0,5H); 12,97 (s, 1H); 8,89 (s, 1H); 8,31 (s, 1H); 7,92 (s, 0,5H); to 7.67 (s, 0,5H); to 7.59 (s, 0,5H); 7,37 (l,J=7,6, 2H); 7,28 (s, 0,5H); 7.03 is (s, 2H).

Example 148: 1-[6-chloro-5-(3-chloro-4-pertenece)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired connection Policlinico to as described in EXAMPLE 50, except using 3-chloro-4-terfenol instead of 3,4-dichlorophenol and 4,5-dichloro-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C17H9Cl2FN4O3: 406,0; received m/z: 407,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,88 (s, 1H); 8,31 (l,J=0,4 Hz, 1H); 7,79 (s, 1H); 7,41 (t,J=9,0 Hz, 2H); 7,19 (l,J=2,8 Hz, 1H); 6,94 (l,J=9,0 Hz, 1H).

Example 149: 1-(5-ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 4-chloro-5-ethylsulfanyl-2-nitrophenylamino. To a solution of 5-chloro-2-nitro-4-triptoreline (2,23 g, a 9.25 mmol) and DMF (46 ml) was added titoxd sodium (2.16 g, and 23.1 mmol). The reaction mixture is passed at a temperature of 100°C for 18 h, cooled and poured into a mixture of brine with ice (350 ml). Precipitated precipitated solid is collected, obtaining the desired compound (2.10 g, yield 85%). For this connection has not been obtained mass spectrometric data.1H NMR (400 MHz, CDCl3): to 8.41 (s, 1H); 6,59 (s, 1H); 6,38 (s, 3H); 3,02 (K,J=7,4 Hz, 2H); 1,43 (t,J=7,4 Hz, 3H).

Stage B: 1-(5-ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27. Mass SPECT is oscope (ESI/CI): calc. mass for C14H11F3N4O2S: 356,1; received m/z: 357,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,02 (s, 1H); of 8.92 (d,J=0.6 Hz, 1H); 8.34 per (e,J=0.6 Hz, 1H); to $ 7.91 (s, 1H); 7,79 (s, 1H); 3,06 (K,J=7,3 Hz, 2H); of 1.23 (t,J=7,3 Hz, 3H).

Example 150: 1-(5-ethylsulfanyl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 149, except using 5-chloro-2-nitro-4-triphtalocyaninine instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H11F3N4O3S: 372,1; received m/z: 373,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,60 (s, 1H); 12,99 (s, 1H); 8,88 (l,J=0.6 Hz, 1H); 8,32 (l,J=0.6 Hz, 1H); 7,83 and 7.36 (m, 2H); 3,02 (K,J=7,3 Hz, 2H); 1,25 (t,J=7,3 Hz, 3H).

Example 151: 1-(5-ethylsulfanyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 149, except 4,5-debtor-2-nitrophenylamino instead of 5-chloro-2-nitro-4-triptoreline on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H11FN4O2S: 306,1; received m/z: 307,0 [M+H]+.1H NMR (400 MHz, DMSO-d6: 13,46 (s, 1H); 12,97 (s, 1H); 8,87 (l,J=0.6 Hz, 1H); 8.30 to (q,J=0.6 Hz, 1H); 7,58 (s, 1H); 7,44 (s, 1H); 2.95 and (kV,J=7,3 Hz, 2H); to 1.21 (t,J=7,3 Hz, 3H).

Example 152: 1-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: 4-fluoro-2-nitro-5-propylsulfonyl. To a mixture of 4,5-debtor-2-nitrophenylamino (1.51 g, 8,67 mmol), potassium carbonate (2,40 g, 17.3 mmol) and DMF (43 ml) was added 1-propanethiol (0,865 ml, 9,54 mmol). The reaction mixture is passed at a temperature of 90°C for 1.5 h and then gave it to cool to a temperature of 23°C. the Mixture was poured into a mixture of brine with ice (400 ml) and collected sludge having the desired compound (1.97 g, yield 98%). Mass spectroscopy (ESI/CI): calc. mass for C9H11FN2O2S: 230,1; received m/z: 231,1 [M+H]+.1H NMR (400 MHz, CDCl3): 7,78 (l,J=10.3 Hz, 1H); of 6.52 (d,J=6.3 Hz, 1H); 6,04 (s, 2H); 2,93 (t,J=7,3 Hz, 2H); 1,84 is 1.70 (m, 2H); 1,09 (t,J=7,4 Hz, 3H).

Stage B: 1-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. The desired compound was obtained in the same way as described in EXAMPLE 27. Mass spectroscopy (ESI/CI): calc. mass for C14H13F3N4O2S: 320,1; received m/z: 321,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,99-12,55 (m, 2H); 8,87 (l,J=0.6 Hz, 1H); 8.30 to (q,J=0.6 Hz, 1H); 7,87-to 7.18 (m, 2H); 2.91 in (t,J7,1 Hz, 2H); from 1.66 to 1.48 (m, 2H); and 0.98 (t,J=7,3 Hz, 3H).

Example 153: 1-(6-fluoro-5-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 152, except using 2-propandiol instead of 1-propanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H13FN4O2S: 320,1; received m/z: 321,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,88-13,19 (m, 1H); 12,97 (s, 1H); 8,88 (l,J=0.6 Hz, 1H); 8.30 to (q,J=0.6 Hz, 1H); 7,87-7,22 (m, 2H); 3.46 in-to 3.33 (m, 1H); 1,21 (l,J=6,4 Hz, 6H).

Example 154: 1-(5-ethylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 101, except for using 5-chloro-2-nitro-4-triptoreline instead of 4,5-dichloro-2-nitrophenylamino and titoxd sodium instead of diisopropoxide sodium on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H11F3N4O4S: 388,0; received m/z: 389,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,38 (s, 1H); 13,08 (s, 1H); 8,99 (s, 1H); 8,39 (l,J=0.6 Hz, 1H); scored 8.38-7,94 (m, 2H); 3,39 (kV,J=7,4 Hz, 2H); 1.18 to (t,J=7,4 Hz, 3H).

Example 155: 1-(5-ethylsulfonyl-6-triptoreline-1H-benzoimidazol-2-the l)-1 H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 101, except for using 5-chloro-2-nitro-4-triphtalocyaninine instead of 4,5-dichloro-2-nitrophenylamino and titoxd sodium instead of diisopropoxide sodium on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H11F3N4O5S: 404,0; received m/z: 405,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 14,19 (s, 1H); 13,07 (s, 1H); of 8.95 (s, 1H); scored 8.38 (s, 1H); of 8.09 (s, 1H); 7,80 (s, 1H); 3.40 in (kV,J=7,4 Hz, 2H); 1,13 (t,J=7,4 Hz, 3H).

Example 156: 1-(5-ethylsulfonyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 101, except for using 4,5-debtor-2-nitrophenylamino instead of 4,5-dichloro-2-nitrophenylamino and titoxd sodium instead of diisopropoxide sodium on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C13H11FN4O4S: 338,1; received m/z: 339,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,04 (s, 1H); 13,04 (s, 1H); 8,95 (l,J=0.5 Hz, 1H); at 8.36 (s, 1H); 8,09-7,35 (m, 2H); 3.42 points (kV,J=7,4 Hz, 2H); to 1.15 (t,J=7,3 Hz, 3H).

Example 157: 1-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 102, except 4,5-debtor-2-nitrophenylamino instead of 4,5-dichloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H13FN4O4S: 352,1; received m/z: 353,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,04 (s, 1H); 13,04 (s, 1H); to 8.94 (d,J=0.6 Hz, 1H); at 8.36 (s, 1H); 8,09-7,46 (m, 2H); 3,44-3,37 (m, 2H); 1,72-of 1.53 (m, 2H); 0,94 (t,J=7,4 Hz, 3H).

Example 158: 1-(6-fluoro-5-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 102, except 4,5-debtor-2-nitrophenylamino instead of 4,5-dichloro-2-nitrophenylamino and 2-propandiol instead of 1-propanethiol on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C14H13FN4O4S: 352,1; received m/z: 353,1 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 14,03 (s, 1H); 13,04 (s, 1H); to 8.94 (d,J=0.6 Hz, 1H); at 8.36 (s, 1H); 8,08 was 7.45 (m, 2H); 3,61-of 3.46 (m, 1H); 1,22 (l,J=6,8 Hz, 6H).

Example 159: 1-(5-phenylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using bentolila instead of 3-m is telesocial and 5-chloro-2-nitro-4-triptoreline instead of 4,5-dichloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C18H11F3N4O2S: 404,1; received m/z: 405,0 [M+H]+.1H NMR (600 MHz, DMSO): 8,80 (l,J=0.5 Hz, 1H); 8,11 (s, 1H); 7,92 (s, 1H); 7,63 (s, 1H); 7,31-7,26 (m, 2H); 7,20-7,16 (m, 1H); 7,12-to 7.09 (m, 2H).

Example 160: 1-[5-(4-methoxybenzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 60, except using 4-methoxybenzoyl instead of 3-methylbenzoyl and 5-chloro-2-nitro-4-triptoreline instead of 4,5-dichloro-2-nitrophenylamino on Stage A. Mass spectroscopy (ESI/CI): calc. mass for C19H13F3N4O3S: of 434.1; received m/z: 435,1 [M+H]+.1H NMR (500 MHz, DMSO): 8,79 (s, 1H); 8,15 (s, 1H); 7,87 (s, 1H); of 7.36 (s, 1H); to 7.32 (d,J=8.6 Hz, 2H); 6,98 (l,J=8,7 Hz, 2H); 3,76 (s, 3H).

Example 161: 1-(5-benzazolyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[1-(2-methoxy-ethoxymethyl)-5-phenylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 159). Mass spectroscopy (ESI/CI): calc. mass for C18H11F3N4O4S: km 436.0; received mz: 437,0 [M+H] +.1H NMR (600 MHz, DMSO): 14,40 (s, 1H); 13,03 (s, 1H); 8,98 (s, 1H); 8,61 (s, 1H); scored 8.38 (s, 1H); 8,11 (s, 1H); a 7.85 (d,J=7.7 Hz, 2H); 7,70-7,66 (m, 1H); 7,63-7,58 (m, 2H).

Example 162: 1-[5-(4-methoxybenzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[1-(2-methoxy-ethoxymethyl)-5-(4-methoxybenzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 160). Mass spectroscopy (ESI/CI): calc. mass for C19H13F3N4O5S: 466,1; received m/z: 467,1 [M+H]+.1H NMR (600 MHz, DMSO): 14,35 (s, 1H); of 13.05 (s, 1H); 8,97 (s, 1H); 8,55 (s, 1H); scored 8.38 (s, 1H); 8,11 (ush s, 1H); 7,81 (l,J=7.9 Hz, 2H); 7,16-7,07 (m, 2H); a 3.83 (s, 3H).

Example 163: 1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 1-methyl bromide-4-chlorobenzene instead of benzyl bromide at Stage D. Mass spectroscopy (ESI/CI): calc. mass for C18H12Cl2N4O2S, 418,0; received m/z: 419,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,50 (s, 1H); 12,95 (s, 1H); 8,87 (s, 1H); 8,29 (s, 1H); 7,84-7,49 (m, 2H); 7,37 (K,J=8.6 Hz, 4H); the 4.29 (s, 2H).

The use of the 164: 1-[6-chloro-5-(3-chlorobenzenesulfonyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 1-methyl bromide-3-chlorobenzene instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C18H12Cl2N4O2S, 418,0; received m/z: 419,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,86 (l,J=0,5, 1H); 8,28 (l,J=0.5 Hz, 1H); to 7.67 (s, 1H); 7,53 (s, 1H); 7,44 (s, 1H); 7,34-7,29 (m, 3H); 4,30 (s, 2H).

Example 165: 1-(6-chloro-5-cyclohexanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using bromeilles instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C18H19ClN4O2S: 390,1; received m/z: to € 391.1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,87 (l,J=0.5 Hz, 1H); 8,29 (l,J=0.5 Hz, 1H); to 7.67 (s, 1H); 7,53 (s, 1H); 2,90 (l,J=6,7 Hz, 2H); 1,88 (l,J=12.3 Hz, 2H); 1.69 in (DD,J=9,6; 3,1 Hz, 2H); 1.61 of (l,J=10,9 Hz, 1H); 1.57 in to 1.47 (m, 1H); 1,25-1,10 (m, 3H); 1,10-1,00 (m, 2H).

Example 166: 1-[6-chloro-5-(2-morpholine-4-reticular)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained analogion the fact, as described in EXAMPLE 66, Method B, except using 4-(2-bromacil)-the research instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C17H18ClN5O3S: 407,1; received m/z: 408,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,62 (s, 1H); 12,99 (s, 1H); 8,86 (s, 1H); 8,32 (s, 1H); 7,86 (s, 1H); to 7.61 (s, 1H); of 3.97 (s, 2H); 3,71 (s, 2H); 3,50 (s, 2H); to 3.41 (s, 2H); at 3.35 (s, 2H); of 3.12 (s, 2H).

Example 167: 1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 4-methyl bromide-1,2-dichlorobenzene instead of benzyl bromide at Stage D. Mass spectroscopy (ESI/CI): calc. mass for C18H11Cl3N4O2S: 452,0; received m/z: 452,9 [M+H]+.1H NMR (600 MHz, DMSO-d6): 13,52 (s, 1H); 12,95 (s, 1H); 8,87 (s, 1H); 8,29 (l,J=0.5 Hz, 1H); 7,86 - 7,28 (m, 5H); 4,30 (s, 2H).

Example 168: 1-[6-chloro-5-(2,6-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 2-methyl bromide-1,3-dichlorobenzene instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C18H11Cl3N4O2S: 452,0; p the received m/z: 452,9 [M+H] +.1H NMR (600 MHz, DMSO-d6): 8,89 (s, 1H); 8,31 (s, 1H); 7,72 (s, 1H); EUR 7.57 (s, 1H); 7,45 (l,J=8.0 Hz, 2H); 7,33 (DD,J=8,4; and 7.8 Hz, 1H); to 4.38 (s, 2H).

Example 169: 1-[6-chloro-5-(4-methylbenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 1-methyl bromide-4-methylbenzene instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C19H15ClN4O2S: 398,1; received m/z: 399,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 8,86 (l,J=0.5 Hz, 1H); 8,29 (l,J=0.5 Hz, 1H); to 7.67 (s, 1H); 7,53 (s, 1H); 7,27 (l,J=8.0 Hz, 2H); for 7.12 (d,J=7.8 Hz, 2H); 4.25 in (s, 2H); and 2.26 (s, 3H).

Example 170: 1-[6-chloro-5-(4-triftormetilfullerenov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 1-methyl bromide-4-cryptomelane instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C19H12ClF3N4O2S: 452,0; received m/z: 453,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,25 (s, 2H); 8,86 (l,J=0,4 Hz, 1H); 8,29 (l,J=0.5 Hz, 1H); 7,70-7,47 (m, 6H); however, 4.40 (s, 2H).

Example 171: 1-[5-(2,4-bis-triftormetilfullerenov)-6-chloro-1HBen is imidazol-2-yl]-1 H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 1-methyl bromide-2,4-bis-cryptomelane instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C20H11ClF6N4O2S: 520,0; received m/z: 521,0 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13.56MHz (s, 2H); 12,99 (s, 1H); 8,88 (s, 1H); 8,31 (s, 1H); 8,05-to 7.99 (m, 2H); of 7.90-7,33 (m, 5H); of 4.45 (s, 2H).

Example 172: 1-[6-chloro-5-(2'-cyanobiphenyl-4-elmersolver)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 66, Method B, except using 4'-bromomethylbiphenyl-2-carbonitrile instead of benzylbromide on Stage D. Mass spectroscopy (ESI/CI): calc. mass for C25H16ClN5O2S: 485,1; received m/z: 486,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): 13,50 (s, 1H); 12,98 (s, 1H); 8,88 (s, 1H); 8.30 to (s, 1H); to 7.95 (DD,J=7,7; 1.0 Hz, 1H); for 7.78 (TD,J=7,7; 1.3 Hz, 1H); 7,74 is 7.50 (m, 8H); however, 4.40 (s, 2H).

Example 173: 1-[6-chloro-5-(4-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(4-chlorobenzenesulfonyl the l)-1-(2-methoxyethoxymethyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 163). Mass spectroscopy (ESI/CI): calc. mass for C18H12Cl2N4O4S, 450,0; received m/z: 451,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 14,01 (s, 1H); 13,02 (s, 1H); 8,96-of 8.90 (m, 1H); 8.34 per (s, 1H); 7,87 (s, 2H); to 7.35 (d,J=8.5 Hz, 2H); 7,25 - 7,20 (m, 2H); of 4.90 (s, 2H).

Example 174: 1-[6-chloro-5-(3-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(3-chlorobenzenesulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 164). Mass spectroscopy (ESI/CI): calc. mass for C18H12Cl2N4O4S, 450,0; received m/z: 451,0 [M+H]+.1H NMR (600 MHz, DMSO-d6): 14,03 (s, 1H); 13,03 (s, 1H); 8,93 (s, 1H); with 8.33 (s, 1H); of 7.96-7,86 (m, 2H); 7,37 (DDD,J=8,0; 2,1; and 0.9 Hz, 1H); 7,34-7,28 (m, 2H); 7,14 (l,J=7.8 Hz, 1H); 4,91 (s, 2H).

Example 175: 1-(6-chloro-5-cyclohexanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-cyclohexanesulfonyl-1-(2-methoxy-ethoxymethyl)-1H-benzoimidazol-2-yl]-1i> H-pyrazole-4-carboxylic acid (intermediate product from Example 165). Mass spectroscopy (ESI/CI): calc. mass for C18H19ClN4O4S: 422,1; received m/z: 423,1 [M+H]+.1H NMR (600 MHz, DMSO-d6): 14,06 (s, 1H); 13,02 (s, 1H); of 8.95 (s, 1H); 8,35 (s, 1H); 8,19 (s, 1H); of 7.90 (s, 1H); 3,44 (l,J=6.2 Hz, 2H); 1,89-of 1.81 (m, 1H); 1.75 of (l,J=10.0 Hz, 2H)and 1.60 (DD,J=9,3; 3,4 Hz, 2H); 1,53 (l,J=to 11.9 Hz, 1H); 1,22-of 1.05 (m, 5H).

Example 176: 1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 167). Mass spectroscopy (ESI/CI): calc. mass for C18H11Cl3N4O4S: 484,0; received m/z: 484,9 [M+H]+.1H NMR (600 MHz, DMSO-d6): 14,05 (s, 1H); 13,02 (s, 1H); 8,94-8,93 (m, 1H); 8,35 (s, 1H); 8,10-of 7.82 (m, 2H); EUR 7.57 (d,J=8,3 Hz, 1H); 7,52 (d,J=2.0 Hz, 1H); 7,16 (DD,J=8,3 Hz, 2.0 Hz, 1H); is 4.93 (s, 2H).

Example 177: 1-[6-chloro-5-(2,6-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(2,6-dichlorobenzyl the Nile)-1-(2-methoxyethoxymethyl)-1 H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 168). Mass spectroscopy (ESI/CI): calc. mass for C18H11Cl3N4O4S: 484,0; received m/z: 484,9 [M+H]+.1H NMR (600 MHz, DMSO-d6): 8,95 (l,J=0.5 Hz, 1H); 8,35 (l,J=0.5 Hz, 1H); 8,03-a 7.85 (m, 2H); 7,50 (d,J=7.9 Hz, 2H); 7,41 (DD,J=8,7 Hz, 7.5 Hz, 1H); 5,16 (s, 2H).

Example 178: 1-(6-chloro-5-p-trimethylsulfonium-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(4-methylbenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product of Example 169). Mass spectroscopy (ESI/CI): calc. mass for C19H15ClN4O4S, 430,1; received m/z: 431,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,98 (s, 1H); 13,02 (s, 1H); 8,93 (s, 1H); 8.34 per (s, 1H); 8,03 (s, 1H); a 7.85 (s, 1H); 7,07 (s, 4H); 4,82 (s, 2H); 2,22 (s, 3H).

Example 179: 1-[6-chloro-5-(4-triftormetilfullerenov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-(4-triftormetilfullerenov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-arbonboy acid (intermediate product from Example 170). Mass spectroscopy (ESI/CI): calc. mass for C19H12ClF3N4O4S: 484,0; received m/z: 485,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 14,05 (l,J=57.4 Hz, 1H); 13,03 (s, 1H); 8,93 (s, 1H); 8,35 (s, 1H); 8,10-7,74 (m, 3H); of 7.69 (d,J=8,1 Hz, 2H); 7,46 (l,J=8,1 Hz, 2H); 5,02 (s, 2H).

Example 180: 1-[5-(2,4-bis-triftormetilfullerenov)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[5-(2,4-bis-triftormetilfullerenov)-6-chloro-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product from Example 171). Mass spectroscopy (ESI/CI): calc. mass for C20H11ClF6N4O4S: 552,0; received m/z: 553,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): to 14.10 (s, 1H); 13,04 (s, 1H); 8,96 (s, 1H); at 8.36 (s, 1H); 8,16 (l,J=8,2 Hz, 1H); 8,13-7,98 (m, 3H); 7,87 (l,J=8.0 Hz, 1H); 5,16 (s, 2H).

Example 181: 1-[6-chloro-5-(2'-cyanobiphenyl-4-elmersolver)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 85, ethyl ester 1-[6-chloro-5-(2'-cyanobiphenyl-4-elmersolver)-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (intermediate product is from Example 172). Mass spectroscopy (ESI/CI): calc. mass for C25H16ClN5O4S: 517,1; received m/z: 518,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,97 (s, 1H); 13,03 (s, 1H); 8,93 (s, 1H); 8.34 per (s, 1H); of 7.96 (s, 1H); 7,94-7,83 (m, 2H); 7,76 (TD,J=7,9; 1.3 Hz, 1H); 7,60-of 7.55 (m, 2H); 7,52 (d,J=8,3 Hz, 2H); 7,39 (l,J=8,3 Hz, 2H); equal to 4.97 (s, 2H).

Example 182: 1-(1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid.

Stage A: ethyl ether 1-carbamimidoyl-1H-pyrazole-4-carboxylic acid hydrochloride. To a solution of ethyl ester 1H-pyrazole-4-carboxylic acid (5,00 g, 35,7 mmol) and cyanamide (1.50 g, 35,7 mmol) in dioxane (25 ml) was added 4M solution of HCl in dioxane (9,80 ml, or 39.3 mmol). The reaction mixture is passed at a temperature of 100°C for 3 hours the mixture is Then cooled to a temperature of 23°C and added Et2O (20 ml). Precipitated precipitated solid white color was filtered, obtaining the desired compound (7,26 g, 93%).1H NMR (400 MHz, DMSO-d6): 9,65 (ush m, 4H); 9,29 (s, 1H); 8,43 (s, 1H); or 4.31 (kV,J=7,1 Hz, 2H); 1,31 (t,J=7,1 Hz, 3H).

Stage B: ethyl ether 1-(1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid. A solution of the hydrochloride of the ethyl ester 1-carbamimidoyl-1H-pyrazole-4-carboxylic acid (0,220 g, 1.00 mmol), 2,3-dechlorination (200 mg, 1.00 mmol) and Cs2CO3(1.63 g, 5.00 mmol) in DMF (2 ml) was stirred for hours Then to the mixture was added H2O (3 ml) and was acidified her to pH 2 with 1M aqueous HCl solution having a white precipitate. The precipitation was filtered, washed with anhydrous EtOH (2 ml) and was filtered, obtaining the desired compound (0,130 g, 43%). Mass spectroscopy (CI): calc. mass for C15H12N6O2: 308,1; received m/z: 309,1 [M+H]+.1H NMR (400 MHz, DMSO-d6): the remaining 9.08 (s, 1H); 8,23 (s, 1H); 7,92 (l,J=8,1 Hz, 1H); 7,87 (l,J=8,2 Hz, 1H); of 7.75 (t,J=7,1 Hz, 1H); to 7.59 (t,J=7.5 Hz, 1H); or 4.31 (kV,J=7,1 Hz, 2H); 1.32 to (t,J=7,1 Hz, 3H).

Stage C: 1-(1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of ethyl ester 1-(1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid (0,110 g, 0,360 mmol), aqueous KOH (1M, 3.0 ml) and THF (3.0 ml) was stirred for 4 h Then the mixture was concentrated and the aqueous residue was acidified to pH 2 with 1M aqueous HCl. Precipitated precipitated substance was collected by filtration, obtaining the desired compound (89,0 mg, 89%). Mass spectroscopy (ESI/CI): calc. mass for C13H8N6O2: 280,2; received m/z: 281,1 [M+H]+.1H NMR (500 MHz, DMSO-d6): 13,32-12,37 (ush m, 1H); 9,03 (s, 1H); 8,19 (s, 1H); 7,94 (l,J=8,2 Hz, 1H); 7,89 (l,J=8,3 Hz, 1H); 7,76 (t,J=7,6 Hz, 1H); to 7.61 (t,J=7,0 Hz, 1H).

Example 183: 1-(6,7-dichloro-1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid.

p> The desired compound was obtained in the same way as described in EXAMPLE 182, except 2,3,6,7-tetrachloronaphthalene instead of 2,3-dechlorination on Stage B. Mass spectroscopy (CI): calc. mass for C13H6Cl2N6O2: 349,1; received m/z: 349,0 [M]+.1H NMR (500 MHz, CD3OD-d4): 9,23 (s, 1H); to 8.20 (s, 1H); to 8.12 (s, 1H); 8,03 (s, 1H).

Example 184: 1-(1H-imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 182, except for using 2,3-dichloropyrazine instead of 2,3-dechlorination on Stage B. Mass spectroscopy (ESI): calc. mass for C9H6N6O2: 230,2; received m/z: 229,2 [M-H]-1H NMR (500 MHz, DMSO-d6): 13,21-12,59 (ush m, 1H); 8,93 (s, 1H); to 8.41 (s, 1H); of 8.25 (s, 1H); 8,21 (s, 1H).

Example 185: 1-(6-chloro-9H-purine-8-yl)-1H-pyrazole-4-carboxylic acid.

The desired compound was obtained in the same way as described in EXAMPLE 182, except 4,5,6-trichloropyridine instead of 2,3-dechlorination on Stage B. Mass spectrometry (ESI/CI): calc. mass for C9H5ClN6O2: 264,6; received m/z: 265,0 [M+H]+.1H NMR (500 MHz, DMSO-d6): 8,76 (s, 1H); 8,51 (s, 1H); 8,19 (s, 1H).

Example 186: 1-(6-chloro-5-phenylsulfanyl-1HBen is imidazol-2-yl)-1 H-pyrazole-4-carboxylic acid.

Stage A: ethyl ester of 1-[6-chloro-5-chlorosulfonyl-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a suspension disulfide (Example 66, Method B, stage C, a by-product of large-scale synthesis) (0,100 g, 0,122 mmol) in a mixture of 2M aqueous HCl (0.15 ml, 0,305 mmol) and acetonitrile (0.75 ml) at 0°C was addedN-chlorosuccinimide (97,7 mg, 0,732 mmol). The resulting mixture was stirred for 75 min, then diluted it EtOAc (20 ml), washed with saline (10 ml), dried, filtered and concentrated. The residue was purified (KFH) (5-40% EtOAc/hexane) and obtained the desired compound (77.0 mg, yield 66%) as a mixture of regioisomers 1:1. Mass spectroscopy (ESI/CI): calc. mass for C17H18Cl2N4O6S: 476,0; received m/z: 477,0 [M+H]+.1H NMR (400 MHz, CDCl3): 8,96 (l,J=0.6 Hz, 1H); of 8.92 (d,J=0.6 Hz, 1H); 8,54 (s, 1H); and 8.50 (s, 1H); 8,23 (l,J=0.5 Hz, 1H); by 8.22 (d,J=0.5 Hz, 1H); 7,92 (s, 1H); of 7.90 (s, 1H); 6,29 (s, 2H); and 6.25 (s, 2H); to 4.38 (kV,J=7,1 Hz, 4H); 3.75 to to 3.67 (m, 4H); 3,51-of 3.43 (m, 4H); 3,29 (s, 3H); 3,29 (s, 3H); 1,43 to 1.37 (m, 6H).

Stage B: ethyl ester of 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-phenylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-chloro-5-chlorosulfonyl-1-(2-methoxyethoxymethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-arbonboy acid (75,0 mg, of) 0.157 mmol) in pyridine (0,79 ml) was added aniline (15,8 μl, 0,173 mmol) and the resulting mixture was stirred at 23°C for 1.5 hours Then the mixture was separated between EtOAc (20 ml) and water (20 ml). The aqueous layer was further extracted with EtOAc (20 ml), the combined organic layers are washed with saline (10 ml), dried, filtered and concentrated. The residue was purified (KFH) (5-80% EtOAc/hexane) and obtained the desired compound (36,0 mg, yield 43%). Mass spectroscopy (ESI/CI): calc. mass for C23H24ClN5O6S: 533,1; received m/z: 534,1 [M+H]+.

Stage C: ethyl ester of 1-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. To a solution of ethyl ester 1-[6-chloro-1-(2-methoxyethoxymethyl)-5-phenylsulfanyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid (35,0 mg, 65,5 mmol) in ethanol (0,50 ml) was added a solution of hydrochloric acid in dioxane (4M, 0,241 ml) and the resulting mixture was stirred at 23°C for 2.5 h and Then the solvent was distilled and purified the residue (KFH) (5-100% EtOAc/hexane), having the desired compound (28,7 mg, yield 98%). Mass spectroscopy (ESI/CI): calc. mass for C19H16ClN5O4S: 445,1; received m/z: 446,0 [M+H]+.

Stage D: 1-(6 - chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid. A mixture of the monohydrate of lithium hydroxide (of 7.90 mg, 0,188 m is ol), ethyl ester of 1-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid (28.0 in mg, of 62.8 mmol), THF (0,24 ml) and water (79 ml) was subjected to a short ultrasonic treatment and then was stirred at 23°C for 18 hours Then drove the solvent and added 2 ml of water. The resulting solution was brought to pH 1 with 1M aqueous HCl, precipitated precipitated solid was filtered and dried, obtaining the desired compound (20.6 mg, 75%yield). Mass spectroscopy (ESI/CI): calc. mass for C17H12ClN5O4S: 417,0; received m/z: 418,0 [M+H]+.1H NMR (400 MHz, DMSO-d6, tautomeric broadening): 13,96 (s, 1H); 13,02 (s, 1H); 10,55 (s, 1H); 8,91 (s, 1H); with 8.33 (s, 1H); 8,31-8,08 (m, 1H); 7,95-7,53 (m, 1H); 7,26? 7.04 baby mortality (m, 4H); of 6.96 (t,J=7.2 Hz, 1H).

Biological protocols:

As indicated earlier (see table above), the biological activity of compounds in accordance with the present invention was determined according to the following protocols.

Expression and purification PHD2181-417

Design for ekspressirovali gene PHD2 person containing amino acids 181-417 sequence GenBank NM_022051, cloned in the vector pBAD (Invitrogen), and introducing the N-terminal his-tag, and Smt3 signal peptides, both of which hatshepsuts Ulp1. Proteins were developed by the expression in BL21 cells grown in the medium of Terrific Broth with the addition of 100 μg/ml ampicillinampicillin culture infected at 37°C and grown to an optical density of 0.8 at a wavelength of 600 nm. The culture was induced with 0.1% arabinose and were grown overnight at 20°C under continuous shaking to shake with a speed of 225 rpm and Then cells were collected by centrifugation and kept at a temperature of -80°C. Cell mass suspended in Buffer A (50 mm Tris-HCl pH to 7.2, 100 mm NaCl, 100 mm L-arginine, 1 mm TCEP, 0,05% (wt./about.) NP-40, 50 mm imidazole) and then added to it secrete lysozyme and benzonase endonuclease. Cells were literally in ultrasonic bath, and cleared by centrifugation (15,000 rpm, 90 min, 4°C). Accumulated protein was purified using nickeliferous chromatography on a column (HisTrap FF Crude column (GE Healthcare). Samples were suirable in the Buffer with A gradient of imidazole 50-200 mm. Cleavage of the signal peptide Smt by Ulp1 protease was performed by incubation overnight with dialysis against Buffer A. Then the obtained sample PHD2181-417skipped through the second column HisTrap FF Crude column (GE Healthcare) to remove protein from neotdalennyh label. Passed through the second column the solution then were dialyzed in 50 mm MES pH of 6.0, 1 mm TCEP, 5 mm NaCl for ionoobmennoi chromatography on a cation-exchange column (HiTrap SP Cation Exchange column (GE Healthcare). Protein PHD2181-417was suirable with a gradient of NaCl 0-0,2 M. the Collected fractions were pooled for further purification by gelfiltration (size exclusion chromatography) on a column of Superdex 75 Size Exclusion Column (GE Healthcare). Total protein was concentrated to 4 mg/ml were dialyzed is 10 mm PIPES pH 7.0, 100 mm NaCl, 0.5 mm TCEP. The results gelelectrophoresis analysis the purity of the obtained protein was >95%.

Analysis of enzyme activity

The obtained polypeptide PHD2181-417(3 µg) before measuring the enzymatic activity of the polypeptide pre-incubated for 30 min with the analyzed compound. Then determined the enzymatic activity of PHD, transferring the mixture is purified polypeptide PHD2181-417(3 µg) with the analyzed compound in 0.5 ml reaction mixture containing the following components: a synthetic peptide HIF-1α containing residues [KNPFSTGDTDLDLEMLAPYIPMDDDFQLRSFDQLS] (10 µm, California Peptide Research Inc., NAPA, California, USA), and [5-14C]-2-oxoglutaric acid (activity 50 mcurie/mmol, Moravek Chemicals, Brea, CA, USA)in reaction buffer (40 mm Tris-HCl, pH 7.5, 0.4 mg/ml catalase, 0.5 mm DTT, 1 mm ascorbate) for 10 min in the presence of compounds. The reaction was stopped by adding 50 μl of 70 mm H3PO4and 50 ál of 500 mm NaH2PO4pH of 3.2. Detection of [14C]-succinic acid was performed by separation of [5-14C]-2-oxoglutaric acid, incubare the reaction mixture with 100 μl of 0.16 M DNP prepared in 30% perchloro acid. Then to the mixture as a carrier for radioactive compounds were added 50 μl of a mixture of unlabeled 20 mm 2-oxoglutaric acid/20 mm succinic acid, and incubated it for 30 min the ri room temperature. Then the reaction mixture for a further 30 min were incubated at room temperature with 50 μl of 1M solution of 2-oxoglutaric acid to precipitate excess DNP. After the reaction mixture was centrifuged at 2800×gat room temperature for 10 min to separate [14C]-succinic acid in the supernatant from the precipitated precipitates [14C]-dinitrophenylhydrazine. The activity fractions of the supernatant (400 μl) was determined on the counter beta-particles (Beckman Coulter, Fullerton, CA, USA). The degree of inhibition of activity of PHD2181-417was defined as a decrease in the production of [14C]-succinic acid. The value of the IC50was estimated by fitting the obtained data, the three-parameter logistic function in the program GraphPad Prism, version 4.02 (Graph Pad Software, San Diego, CA, USA). The value of the IC50up to 10 μm was determined quantitatively at high concentrations was indicated as >10 μm. All the analyzed compounds were diluted to a concentration of 10 mm in 100% DMSO (weight/about.) and tested in the concentration range from 10 μm to 3 nm in semi-logarithmic sequence of dilutions, with final concentration of DMSO in the medium was 2% (wt./vol.).

Cell analysis

Cell line Hep-3B (ATCC, Manassas, Virginia, USA) were sown in 96-well tablets with a density of 20 000 cells per well in 100 μl DMEM medium with addition of 10% is mrinalini bovine serum, 1% nonessential amino acids, 50 IU/ml penicillin and 50 µg/ml streptomycin (all reagents for cell culture medium company Invitrogen, carlsbad, CA, USA). At 24 h after seeding in the wells was added to the analyzed compounds and incubated tablet within 24 hours All of the analyzed compounds were diluted to a concentration of 10 mm in 100% DMSO (weight/about.) and tested under conditions of saturation, while the final concentration of the analyzed compounds was 100 μm in 1% DMSO (weight/vol.). Then fifty microliters supernatant was transferred into a test kit human Hypoxia assay kit (Meso-Scale Discovery, Gaithersburg, MD, USA). Erythropoietin in the supernatant was determined in accordance with the manufacturer's recommendations set as follows. Tablets for detection of EPO during the night was blocked by 3% BSA in phosphate buffer, and 50 μl of the supernatant were incubated at room temperature on an orbital shaker for 2 hours Then the wells were added to the twenty-five microliters 0.5 μg/ml anti-EPO detection of antibodies and shake the plate on an orbital shaker at room temperature for another 2 hours After triple rinsing phosphate buffer in the wells was added 150 μl of 1X buffer for measurement and the measured optical density analyzer MSD SECTOR. Then data was analyzed by determining the percentage of EPO secretion in the presence of 10 µm or 100 the km of the analyzed compounds in relation to the level of secretion in the presence of a control connection for this test, 7-[(4-chlorophenyl)-(5-methylisoxazol-3-ylamino)-methyl]-quinoline-8-ol. The obtained data are presented as percentages of the level of EPO secretion relative to control connection and is reproduced with an accuracy of 10%.

Although the invention has been described with specific examples and preferred options for implementation, it should be clear that the present invention is not limited to the above detailed description.

1. The compound of formula (I)

where
n is from 2 to 4;
each of the substituents R1independently selected from H, halogen, -C1-4of alkyl, -C1-4pergolla, trifter-C1-4alkoxy, -NO2, -CN, CO2H, -OS1-4of alkyl, -SC1-4of alkyl, -S(C1-4alkyl)-Rc, -S(O)2(C1-4alkyl)-Rc, -S(O)-C1-4of alkyl, -SO2-C1-4of alkyl, -S-Rc, -S(O)-Rc, -SO2-Rc, -SO2-NH-Rc, -O-Rc, -CH2-O-Rc-C(O)NH-Rc, -NRaRb, benzyloxy, phenyl, optionally substituted with one or two Rd, cyanobiphenyl-4-ylmethylene, cyanobiphenyl-4-ylmethanone or-S-(CH2)2-research and two adjacent groups R1can be connected with the formation of aromatic 5-6 membered ring, optionally substituted by one methyl group or two at the Mami halogen, optionally containing one or two S or N;
Raand Rbeach independently represents H, C1-4alkyl, -C(O)C1-4alkyl, -C(O)-Rc, -C(O)CH2-ReC1-4alkyl-Re, -SO2-Rc, -SO2-C1-4alkyl, phenyl, benzyl; or Raand Rbtogether with the nitrogen atom to which they are connected, form a monocyclic 5-6-membered geteroseksualnoe ring, optionally containing one heteroatom selected from O;
Rcrepresents a C3-8cycloalkyl, phenyl, optionally substituted with one or two Rd, benzyl, optionally substituted by one to three Rd; morpholine;
Rdindependently represents a halogen, -OH, -C1-4alkyl or C1-4perhalogenated, trifter C1-4alkoxy, -OC1-4alkyl, or -- O-benzyl, optionally substituted with halogen;
Rerepresents a C6heteroseksualci, optionally containing one or two O atoms, or N, optionally substituted methyl group;
R2and R3both represent H, -CF3or C1-3alkyl;
each Z is a C atom or an N atom, provided that not more than two Z are N; and
enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts of these compounds with inhibitory activity in which the compared PHD.

2. The compound according to claim 1, where R2and R3each represent-H.

3. The compound according to claim 1, in which each substituent R1independently selected from the group consisting of: H, halogen, -CF3, -OCF3, phenyl (optionally substituted or unsubstituted, carrying up to two groups-CF3, halogen, -OH, C1-4of alkyl, C1-4alkoxy, and-OCF3), benzyloxyphenyl (optional substituted or unsubstituted by halogen), benzyloxy, benzoyloxymethyl, phenylsulfanyl (optional substituted or unsubstituted, carrying up to two groups-With1-4of alkyl, halogen, -CF3, -OCF3and-C1-4alkoxy), benzylmorphine (optional substituted or unsubstituted, carrying up to three groups of halogen, C1-4of alkyl, -CF3and-OCF3), penetralia, benzosulfimide (optional substituted or unsubstituted, carrying up to two groups With1-4of alkyl, C1-4alkoxy, halogen, -CF3and-OCF3), phenylmethanesulfonyl (optional substituted or unsubstituted, carrying up to three groups With1-4of alkyl, C1-4alkoxy, halogen, -CF3and-OCF3), phenylethanolamine, benzosulfimide, cyanobiphenyl-4-ylmethylene, cyanobiphenyl-4-ylmethanone, phenylcarbamoyl, benzylcarbamoyl, benzylamino, phenylsulfonyl, phenylamino, benzoylamine and bensalah is ylamino.

4. The compound according to claim 1, where two adjacent groups R1combined with the formation of substituted 5-6-membered ring containing one or two heteroatom S or N.

5. The compound according to claim 1 where the above-mentioned substituted 5-6-membered ring is aromatic.

6. The compound according to claim 1, where each of the substituents R1independently selected from H, halogen, -C1-4of alkyl, -CF3, -OCF3- 1-4alkylsulfonyl, -C1-4alkylsulfonyl, -C1-4alkylsulfanyl, -NO2, -NH2, -NH-C1-4of alkyl, -NH-SO2-C3-8cycloalkyl, -NH-SO2-C1-4of alkyl, -NH-C(O)-C1-4of alkyl, -CN, -CO2H, -OS1-4of alkyl, -NH-(CH2)2-research, -NH(CO)CH2-research, -NHC(O)-CH2-piperidine, -NHC(O)-CH2-(N-methylpiperazine), -NH-C1-4alkylphosphine, -S-(CH2)2-research, -C(O)-NH-research, pyrrolidine, piperidine and research.

7. A compound selected from the group consisting of the following:
1-(1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-bromo-1H-benzoimidazol-2-yl)-1H-pyrazole-4-Kurbanova the acid;
1-(5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-chloro-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4,5-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-{5-[3-(3-chlorobenzoyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;
1-{5-[3-(2-chlorobenzoyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;
1-{5-[3-(4-chlorobenzoyloxy)-phenyl]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;
1-[5-(3-benzyloxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(4-benzyloxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(3-triptoreline)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(3,4-dichlorophenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-bromo-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;
1-(5,6-dichloro-1H-benzoimidazol-2-yl)-3-trifluoromethyl-1H-pyrazole-4-carboxylic acid;
1-(5-bromo-1H-benzoimidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;
1-(5,6-dichloro-1H-benzoimidazol-2-yl) - for 3,5-dimethyl-1H-pyrazole-4-carboxylic acid;
1-[5-(4-hydroxyphenyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5(3-hydroxyphenyl)-1H-benzimidazole-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-bromo-6,7-dimethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-7-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(7-bromo-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4,5,6-Cryptor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-bromo-5,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-bromo-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-bromo-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-cyano-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-nitro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-amino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-pyrrolidin-1-yl-1H-BAA is tinidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-morpholine-4-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-methoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
2-(4-carboxybenzoyl-1-yl)-1H-benzoimidazol-5-carboxylic acid;
1-(5-bromo-7-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-bromo-7-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-bromo-7-methyl-1H-imidazo[4,5-f]quinoline-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-(3,4-dichlorophenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-chlorphenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(4-chlorphenoxy)-6-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-phenoxy-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-(4-pertenece)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(4-chlorphenoxy)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-phenoxy-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-phenoxy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-benzyloxy-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-m-tamilselvan-1H-benzoimidazol-2-yl)-1 is-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-benzylmethyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-(4-tert-butylbenzenesulfonyl)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-perpenicular)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-penicillanic-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methylsulfanyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-propylsulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-isopropylphenyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-fluoro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-methylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-x is the PR-6-ethylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methylsulfanyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-isopropylphenyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-propylsulfonyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(toluene-3-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-benzazolyl-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-trifloromethyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3-methoxybenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-phenylmethanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2,4,6-trimethylphenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-methoxybenzenesulfonyl)-1H-benzamid the evils-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-PerformanceCounter)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-phenylethanone)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-econsulting-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-econsultancy-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-fluoro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-chloro-6-methanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonyl-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-chloro-6-(propane-2-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-chloro-6-(propane-1-sulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(propane-2-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(propane-1-sulfonyl)-5-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(propane-2-sulfonyl)-5-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-(propane-1-sulfonyl)-5-triptoreline-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid is the same;
1-(5-benzosulfimide-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-methanesulfonyl-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-bromo-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4,5-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4,6-debtor-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(1H-oil[2,3-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(3H-oil[1,2-d]imidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-fluoro-4-methyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-piperidine-1-yl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-fluoro-6-piperidine-1-yl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-ethoxy-5-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-phenylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-benzylcarbamoyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-(morpholine-4-ylcarbonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-benzoyloxymethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-bromo-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-Carbo the OIC acid;
1-(8H-imidazo[4',5':3,4]benzo[2,1-d]thiazol-7-yl)-1H-pyrazole-4-carboxylic acid;
1-(5,6-bis-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4,5,6-trichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(4-bromo-5,6-dichloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-fluoro-5-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-ethylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-propylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-benzylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-phenylamino-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-morpholine-4-yl-ethylamino)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-cyclopropanemethylamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-methanesulfonamido-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-ethanolamine-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-benzosulfimide-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-acetylamino-6-chloro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-propionamido-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-benzoylamino-6-chloro-1H-benzoimidazol the l-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-morpholine-4-ylacetamide)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-piperidine-1-ylacetamide)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-{6-chloro-5-[2-(4-methylpiperazin-1-yl)-acetylamino]-1H-benzoimidazol-2-yl}-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-methoxyphenoxy)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-chloro-2-pertenece)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-triftormetilfosfinov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3-chloro-4-pertenece)-1H-benzimidazole-2-yl]-1H-pyrazole-4-carboxylic acid
1-(5-ethylsulfanyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-ethylsulfanyl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-ethylsulfanyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-fluoro-5-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-ethylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-ethylsulfonyl-6-triptoreline-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-ethylsulfonyl-6-fluoro-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
-(6-fluoro-5-propylsulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-fluoro-5-isopropylphenyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(5-phenylsulfonyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-(4-methoxy-phenylsulfanyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(5-benzazolyl-6-trifluoromethyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[5-(4-methoxybenzenesulfonyl)-6-trifluoromethyl-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3-chlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-cyclohexanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2-morpholine-4-yl-ethylsulfanyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2,6-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-methylbenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-triftormetilfullerenov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(2,4-bis-triftormetilfullerenov)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2'-C is enalipril-4-elmersolver)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3-chlorophenylsulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-cyclohexanesulfonyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(3,4-dichlorobenzenesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2,6-dichloro-phenylmethanesulfonyl)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-p-trimethylsulfonium-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(4-triftormetilfullerenov)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[5-(2,4-bis-triftormetilfullerenov)-6-chloro-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-[6-chloro-5-(2'-cyanobiphenyl-4-elmersolver)-1H-benzoimidazol-2-yl]-1H-pyrazole-4-carboxylic acid;
1-(1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6,7-dichloro-1H-imidazo[4,5-b]cinoxacin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(1H-imidazo[4,5-b]pyrazin-2-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-N-purine-8-yl)-1H-pyrazole-4-carboxylic acid;
1-(6-chloro-5-phenylsulfanyl-1H-benzoimidazol-2-yl)-1H-pyrazole-4-carboxylic acid,
and their pharmaceutically acceptable salts.

8. Pharmaceutical composition having inhibitory AK is ewnetu in relation PHD, including pharmaceutically acceptable excipient and an effective amount of the compounds of formula (I) according to claim 1, or enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts of these compounds.

9. Pharmaceutical composition having inhibitory activity against PHD, comprising one of the compounds according to claim 7 or its pharmaceutically acceptable salt.

10. A method of treating anemia, hypoxia, ischemia, peripheral vascular disease, myocardial infarction, stroke, diabetes, obesity, inflammatory bowel disease, ulcerative colitis, Crohn's disease, wounds, infections, burns, and bone fractures, comprising an introduction to the needy in this patient a therapeutically effective amount of possessing inhibitory activity against PHD compounds of formula (I) according to claim 1, or enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts of these compounds.

11. A method of treating hypoxic disorders, including introduction to the needy in this patient a therapeutically effective amount of possessing inhibitory activity against PHD compounds of formula (I) according to claim 1, or enantiomers, diastereoisomers, racemates and pharmaceutically acceptable salts of these compounds.



 

Same patents:

FIELD: chemistry.

SUBSTANCE: invention relates to (3aR,6aR)-N-(4-(3-ethylphenylamino)-7-methoxyquinazolin-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide or its pharmaceutically acceptable salt, as well as to a pharmaceutical composition for treatment of the cancer disease, sensible to inhibition of hyper-expression and/or hyperactivity of a receptor of an epidermal growth factor, which contains the claimed compound, a method of the cancer disease treatment, a method of inhibition and to the application of the claimed compound for a drug preparation.

EFFECT: (3aR,6aR)-N-(4-(3-ethylphenylamino)-7-methoxyquinazoline-6-yl)-1-methylhexahydropyrrolo[3,4-b]pyrrole-5(1H)-carboxamide, which shows an inhibition activity to hyperexpression and/or hyperactivity of the epidermal growth factor receptor.

12 cl, 4 tbl, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a novel 5-methyl-6-nitro-7-oxo-4,7-dihydro-1,2,4-triazolo[1,5-α]pyrimidinide l-argininium monohydrate of formula (1) The compound has antiviral activity with respect to group A and B strain viruses in in vitro and in vivo systems.

EFFECT: compound has low toxicity.

4 dwg, 3 tbl, 4 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: chemistry.

SUBSTANCE: there are described new derivatives of imidazo[1,2-b][1,2,4,5]tetrazines of general formula (I) wherein: Het=4-methylimidazol-1-yl, R=H or Het=3,5-dimethylpyrazol-1-yl, R=propylthio, and based anticancer agents for treating oncological patients.

EFFECT: higher clinical effectiveness.

2 cl, 1 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to compounds or their pharmaceutically acceptable salts, where compound has formula 1-a, in which R1 and R3 are absent, m represents integer number from 1 to 2, n represents integer number from 1 to 3, A represents , B represents or , where X2 represents O or S, R4a is absent, R4b is selected from the group, consisting of: , , , , and ; Rk is selected from C1-6alkyl and C1-6halogenalkyl, L and E are such as given in i.1 of the invention formula; or compound is such as given in b) of i.1 of the invention formula. Invention also relates to pharmaceutical composition, which contains said compounds.

EFFECT: compounds by i1, possessing inhibiting activity with respect to anti-apoptosis protein Bcl-XL.

27 cl, 6 dwg, 2 tbl, 126 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: in formula R1 is H or (1-6C alkyl); R2 represents NRbRc, (1-4C)alkyl, (1-4C)fluoroalkyl, CF3, (1-4C)hydroxyalkyl, -(1-4Calkyl)hetAr1, -(1-4Calkyl)NH2, -(1-4C alkyl)NH(1-4Calkyl), -(1-4Calkyl)N(1-4Calkyl)2, hetAr2, hetCyc1, hetCyc2, phenyl substituted where applicable by NHSO2(1-4Calkyl) or (3-6C)cycloalkyl, substituted where applicable by (1-4C alkyl), CN, OH, OMe, NH2, NHMe, N(CH3)2, F, CF3, CO2(1-4C alkyl), CO2H; C(=O)NReRf or C(=O)ORg; Rb is H or (1-6C alkyl); Rc represents H, (1-4C)alkyl, (1-4C)hydroxyalkyl, hetAr3 or phenyl, wherein the above phenyl is substituted where applicable by one or more substitutes independently from halogen, CN, CF3 and -O(1-4C alkyl); Re represents H or (1-4C)alkyl; Rf represents H, (1-4C)alkyl or (3-6C)cycloalkyl; Rg represents H or (1-6C)alkyl; X is absent or represents -CH2-, -CH2CH2-, -CH2O- or -CH2NRd; Rd represents H or (1-4C alkyl); R3 represents H or (1-4C alkyl); and n is equal to 0-6. The radical values NRbRc, Y, hetAr1, hetAr2, hetAr3, hetCyc1, hetCyc2, NReRf, R4 are specified in the patent claim. The invention also refers to a pharmaceutical composition containing the above compounds, to a method of treating Trk kinase mediated diseases and conditions, such as pain, cancer, inflammation, neurodegenerative disease, Typanosoma cruzi infection, osteolytic disease, and to a method of preparing the above compounds.

EFFECT: invention refers to new derivatives of pyrazolo[1,5-a]pyrimidines possessing an inhibitory activity on tropomyosin-related kinases (Trk).

42 cl, 1 tbl, 105 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to pharmaceutically acceptable (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid salts, wherein an acid addition salt is specified in a group consisting of phosphate, malate and tartrate; a base addition salt is specified in a group consisting of sodium salt, lithium salt, potassium salt, calcium salt, magnesium salt, tetramethylammonium salt, tetraethylammonium salt, ethanolamine salt, choline salt and arginine salt. The invention also refers to methods for preparing the above salts, to a therapeutic agent as a dipeptidyl peptidase (DPP-IV) inhibitor based thereon.

EFFECT: there are prepared new (R)-7-[3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-trifluoromethyl-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylic acid salts which can find application in medicine as the therapeutic agent for treating type 2 diabetes, hyperglycemia, obesity or insulin resistance.

16 cl, 4 tbl, 13 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to quinazolinone compounds of formula (I) and its pharmaceutically acceptable salts, wherein n is equal to 0 to 3, and R1 is defined as stated in the patent claim. The above compounds are prolyl hydroxylase inhibitors and can be used in pharmaceutical compositions and methods of treating pathological conditions, disorders and conditions mediated by prolyl hydroxylase activity.

EFFECT: compounds can be administered into the patient for treating, eg anaemia, vascular diseases, metabolic disorders, as well as for wound healing.

22 cl, 2 tbl, 211 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new dihydroindenamide specified in compounds described by general formula II, or their pharmaceutically acceptable salts. In general formula II, R1 represents piperazinyl which can be optionally substituted by one R1a; R1a represents H, CH3, C(O)Rd or C(O)ORa; Y represents pyrimidyl; Z represents pyridyl or pyrimidyl; Ra represents tert-butyl and Rd represents CH3. The above compounds represent tert-butyl-4-{5-[({(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl}amino)carbonyl)-2,3-dihydro-1H-inden-1-yl}piperazine-1-carboxylate; N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-1-piperazin-1-yl-2,3-dihydro-1H-indene-5-carboxamide; 1-[4-acetylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1R)-N-[3-(4,5′-bipyrimidin-2-ylamino)-4-methylphenyl]-1-(4-methylpiperazin-1-yl)-2,3-dihydro-1H-inden-5-carboxamide; (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-4-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide and (1S)-1-(4-methylpiperazin-1-yl)-N-(4-methyl-3-[(4-pyridin-3-ylpyrimidin-2-yl)amino]phenyl)-2,3-dihydro-1H-inden-5-carboxamide sulphate.

EFFECT: compounds inhibit activity of protein kinases specified in Abl, c-Kit and PDGFR, and can find application for treating diseases related to disturbed activity of the above protein kinases, eg leukaemia and other cancers.

4 cl, 4 tbl, 16 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula (I), wherein A means morpholinyl, 1,4-oxazepamyl, piperidinyl, pyrrolidinyl or azetidinyl which is bound to N; R1 means C1-C6-alkyl group; R2 means bicyclic aryl group specified in 1H-indolyl, 1H-pyrrolo[3,2-b]pyridyl, quinolyl, naphthyl, 1H-pyrrolo[2,3-b]pyridyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3-d]pyrimidinyl, benzo[b]thiophenyl, imidazo[1,2-a]pyridyl, benzo[b]thiazolyl, 5H-pyrrolol[2,3-b]pyrazinyl and quinoxalinyl which can be substituted by R4; R3 means hydrogen or halogen atom; R4 means C1-C6-alkyl group, C1-C6-halogenalkyl group, OR1A, halogen, -(CH2)aOH, CN, NHCOR1A, SO2R1A or NHSO2R1A; R5 means C1-C6-alkyl group, -(CH2)aOH, -(CH2)aOR1B, halogen or CONH2; provided p is a plural number, R5 can be identical or different, or R5 can be combined with another R5; each of R1A and R1B independently means C1-C6-alkyl group; a is equal to 0, 1 or 2; n is equal to 1 or 2; p is equal to 0, 1, 2, 3, 4 or 5. Besides, the invention refers to intermediate compounds of formulas (IA) and (IB) for preparing the compounds of formula (I), to a preventive or therapeutic agent containing the compounds of formula (I), pharmaceutical compositions, using the compounds of formula (I) and to a method for preventing or treating diseases.

EFFECT: compounds of formula (I) as selective 5-HT2B receptor antagonists.

11 cl, 1 dwg, 18 tbl, 88 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to imidazole derivatives of general formula or its pharmaceutically acceptable salt, wherein R1 means halogen, C1-6-alkyl or C1-6-alkoxy; R2 means C1-6-alkyl; R3 means hydrogen, C1-6-alkyl; Q means -N= or -CH=; R4 represents a group of formula or , wherein X, Y and Z independently represent -CH= or -N=, and only one of X or Y can be a nitrogen atom; R5 and R6 independently represent a hydrogen atom, C1-6-alkyl, C1-6-hydroxyalkyl, C1-6-alkoxyalkyl, -(CH2)m-(CO)O-C1-6-alkyl, -(CH2)m-S(O)2-C1-6-alkyl, -(CH2)m-C(O)-NR'R" and wherein m=1 and R' and R" independently represent hydrogen or C1-6-alkyl. Also, the invention refers to a therapeutic agent based on the compound of formula (I) and using the compound of formula (I).

EFFECT: there are prepared new imidazole derivatives effective for treating and preventing mGluR5 receptor mediated disorders.

26 cl, 60 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: described is a specific list of various novel azaazulene compounds, which contain 6,5-condensed heterocycle of an indole type, benzimidazole type, purine type, 3H-imidaso[4,5-b]pyrene,3H-imidaso[4,5-c] pyridine, etc., which can be described by the general formula , where R1 is =O; R2 is H or diethylaminoalkyl; R3-R7 is H; other variables in the formula (I) are given in the specific structural formulas of the described compounds. A pharmaceutical composition which contains thereof is also described.

EFFECT: compounds possess an anti-tumour activity and can be used for treatment of cancer, such as breast cancer, lung cancer, pancreas cancer, cancer of large intestine, and acute myeloid leukemia.

5 cl, 2 dwg, 6 tbl, 14 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to compounds of formula , wherein A means a six-merous aryl radical or a five-merous heteroaryl radical which contains one heteroatom specified in oxygen and sulphur; one or more hydrogen atoms in the above aryl or heteroaryl radicals can be substituted by substituting groups R1 which are independently specified in a group consisting of: F, Cl, Br, I, (C1-C10)-alkyl-, (C1-C10)-alkoxy-, -NR13R14; B means a radical with mono- or condensed bicyclic rings specified in a group consisting of: six-ten-merous aryl radicals, five-ten-merous heteroaryl radicals and nine-fourteen-merous cycloheteroalkylaryl radicals, wherein cycloheteroalkyl links can be saturated or partially unsaturated, while the heterocyclic groups can contain one or more heteroatoms specified in a group consisting of nitrogen, oxygen and sulphur, one or more hydrogen atoms in the radical groups B can be substituted by substituting groups R5 (as specified in the patent claim), L means a covalent bond, X means the group -O-, R2 is absent or means one or more substitutes specified in F and (C1-C4)-alkyl radical; R3 and R4 independently mean (C1-C10)-alkyl, (C3-C14)-cycloalkyl, (C4-C20)-cycloalkylalkyl, (C2-C19)-cycloheteroalkyl, (C3-C19)-cycloheteroalkylalkyl, (C6-C10)-aryl, (C7-C20)-arylalkyl, (C1-C9)-heteroaryl, (C2-C19)-heteroarylalkyl radicals, or R3 and R4 together with nitrogen attached whereto can form a four-ten-merous saturated, unsaturated or partially unsaturated heterocyclic compound which can additionally contain one or more heteroatoms among -O-, -S(O)n-, =N- and -NR8-; other radicals are such as specified in the patient claim. Also, the invention refers to using the compound of formula I for preparing a drug.

EFFECT: compounds of formula (I) as Na+/H+ metabolism inhibitors NHE3.

22 cl, 27 dwg, 1 tbl, 756 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel alkyl [2-(2-{5-[4-(4-{2-[1-(2-methoxycarbonylamino-acetyl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-phenyl)-buta-1,3-diinyl]-1H-imidazol-2-yl}-pyrrolidin-1-yl)-2-oxo-ethyl]-carbamates or their naphthalene-1,5-disulfonates, which possess properties of NS5A protein inhibitor and can be used for prevention and treatment of viral diseases, caused by viruses of hepatitis C (HCV) and hepatitis GBV-C. In claimed invention compounds, corresponding to general formula 1 R1, R2, R3 and R4 independently on each other stand for C1-C3 alkyl; R5 and R6 independently on each other stand for C1-C3alkyloxymethyl, or R3, and R5, and R4, and R6, together with carbon atoms, which they are bound with, independently on each other form tetrahydrofurane cycle.

EFFECT: improved propertied of compounds.

7 cl, 2 tbl, 7 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel indole and benzomorpholine derivatives of a formula (I) or its pharmaceutically acceptable salt, where R1 represents C1-6-alkyl or C1-3alkyl, substituted with C3-7cycloalkyl; R2 represents halogeno; R3 represents hydrogen; n equals 2, X represents -CH2CH2-O or -CH=CH-; Y represents -O- or -CR4(OH)-; R4 represents hydrogen or C1-3 alkyl. Invention also relates to a pharmaceutical composition based on formula (I) compound and a method of treatment or prevention of the said pathological states.

EFFECT: obtained are novel compounds, which are positive allosteric modulators of matabotropic subtype 2 receptors (mGluR2), which are useful for treatment or prevention of neurological and psychiatric disorders, associated with glutamate dysfunction, and diseases, involving metabotropic subtype 2 receptors GluR2.

22 cl, 2 tbl, 8 ex

FIELD: chemistry.

SUBSTANCE: invention relates to 5-membered heterocyclic compounds of general formula (I), their prodrugs or pharmaceutically acceptable salts, which possess xanthine oxidase inhibiting activity. In formula (I) T represents nitro, cyano or trifluoromethyl; J represents phenyl or heteroaryl ring, where heteroaryl represents 6-membered aromatic heterocyclic group, which has one heteroatom, selected from nitrogen, or 5-membered aromatic heterocyclic group, which has one heteroatom, selected from oxygen; Q represents carboxy, lower alkoxycarbonyl, carbomoyl or 5-tetrasolyl; X1 and X2 independently represent CR2 or N, on condition that both of X1 and X2 do not simultaneously represent N and, when two R2 are present, these R2 are not obligatorily similar or different from each other; R2 represents hydrogen atom or lower alkyl; Y represents hydrogen atom, hydroxy, amino, halogen atom, perfluoro(lower alkyl), lower alkyl, lower alkoxy, optionally substituted with lower alkoxy; nitro, (lower alkyl)carbonylamino or (lower alkyl) sulfonylamino; R1 represents perfluoro(lower alkyl), -AA, -A-D-L-M or -A-D-E-G-L-M (values AA, A, D, E, G, L, M are given in i.1 of the invention formula).

EFFECT: invention relates to xanthine oxidase inhibitor and pharmaceutical composition, which contain formula (I) compound.

27 cl, 94 tbl, 553 ex

FIELD: chemistry.

SUBSTANCE: invention relates to N-[2,4-dioxo-6-(tetrahydrofuran-2-yl)-7-trifluoromethyl-1,4-dihydro-2H-quinazolin-3-yl]methanesulphonamide and N-[6-(1-isopropoxyethyl)-2,4-dioxo-7-trifluoromethyl-1,4-dihydro-2H- quinazolin-3-yl] methanesulphonamide, having antagonistic activity on the AMPA receptor. The invention also relates to a pharmaceutical composition.

EFFECT: use of said compounds to produce drugs for treating AMPA mediated conditions and primarily for treating epilepsy or schizophrenia.

6 cl, 81 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to new compounds of formula I: cis-COOR-XCH-(CH2)a-CH=CH-(CH2)b-CH3, wherein (a) and (b) can take any value from 0 to 14, (X) is specified in: OH, NH2, CH3, F, F3C, HS, O-CH3, PO4(CH2-CH3)2 and CH3COO, and (R) represents sodium (Na) applicable for preventing and/or treating obesity, hypertension and/or cancer. Also, the invention refers to using the compounds of formula I for preparing a pharmaceutical and/or nutrient composition, to the pharmaceutical and/or nutrient composition based on the compounds of formula I, to a cosmetic, non-therapeutic method for improving skin manifestations and to a method for preventing and/or treating the diseases in humans and animals with using the compounds of formula I.

EFFECT: preparing the new compounds.

18 cl, 22 dwg, 5 tbl, 9 ex

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